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Depression is a frequent comorbidity in HIV infection that has been associated with worse treatment outcomes and increased mortality. Recent studies suggest that increased innate immune activation and tryptophan catabolism are associated with higher risk of depression in HIV infection and other chronic inflammatory diseases, but the mechanisms leading to depression remain poorly understood.The severity of depressive symptoms was assessed by Beck Depression Inventory or Center for Epidemiological Studies Depression Scale. Untargeted metabolomic profiling of plasma from 104 subjects (68 HIV-positive and 36 HIV-negative) across 3 independent cohorts was performed using liquid or gas chromatography followed by mass spectrometry. Cytokine profiling was by Bioplex array. Bioinformatic analysis was performed in Metaboanalyst and R.Decreased monoamine metabolites (phenylacetate, 4-hydroxyphenylacetate) and acylcarnitines (propionylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine) in plasma distinguished depressed subjects from controls in HIV-positive and HIV-negative cohorts, and these alterations correlated with the severity of depressive symptoms. In HIV-positive subjects, acylcarnitines and other markers of mitochondrial function correlated inversely with tryptophan catabolism, a marker of interferon responses, suggesting interrelationships between inflammatory pathways, tryptophan catabolism, and metabolic alterations associated with depression. Altered metabolites mapped to pathways involved in monoamine metabolism, mitochondrial function, and inflammation, suggesting a model in which complex relationships between monoamine metabolism and mitochondrial bioenergetics contribute to biological mechanisms involved in depression that may be augmented by inflammation during HIV infection.Integrated approaches targeting inflammation, monoamine metabolism, and mitochondrial pathways may be important for prevention and treatment of depression in people with and without HIV.

There is limited research examining the relationship between socioeconomic status (SES) and neuropsychological functioning, particularly in racial/ethnic minority and HIV+ populations. However, there are complex associations between poverty, education, HIV disease, race/ethnicity, and health outcomes in the US.We explored these relationships among an ethnically diverse sample of 134 HIV+ adults using a standardized SES measure (i.e., the Hollingshead scale), a comprehensive NP test battery, and a functional evaluation (i.e., Patient's Assessment of Own Functioning Inventory and Modified Instrumental Activities of Daily Living Scale).Bivariate analyses showed that adult SES was significantly, positively correlated with neuropsychological performance on specific tests within the domains of verbal fluency, attention/concentration, learning, memory, processing speed, and executive functioning, and childhood SES was significantly linked to measures of verbal fluency, processing speed, and executive functioning. In a series of linear regressions, controlling for SES significantly attenuated group differences in NP test scores between racial/ethnic minority individuals and non-Hispanic White individuals. Finally, SES scores significantly differed across HIV-Associated Neurocognitive Disorder (HAND) diagnoses. In a binary logistic regression, SES was the only independent predictor of HAND diagnosis.HIV+ individuals with lower SES may be more vulnerable to HIV-associated neuropsychological sequelae due to prominent health disparities, although the degree to which this is influenced by factors such as test bias remains unclear. Overall, our results suggest that SES is significantly linked to neuropsychological test performance in HIV+ individuals, and is an important factor to consider in clinical practice.

To the Editor—Haddow and colleagues [1] have expressed 2 concerns regarding interpretation of the longitudinal CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study of neurocognitive (NC) outcomes in 436 human immunodeficiency virus (HIV)-infected patients—namely, that “NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions” [2]. Haddow et al are correct that the probability of a person experiencing NC decline at any point across multiple visits is somewhat greater than the 5% defined by the published norms for NC change [3] at a single follow-up. However, these authors' use of standard binomial probability estimates to arrive at an overall chance-based “decliner” rate of 20.4% over 6 follow-up visits is inaccurate (excessive), because of the acknowledged assumption that all visits for any individual patient are independent. In fact, in the survival analysis used in our article, “decline” was an absorbing state. Visits were not independent: Once a patient was first classified as a “decliner,” the endpoint of interest in our study, that person had no opportunities to (or chance-based risk for) decline at any future visit. Also, of the 99 decliners in our study, 62.3% had declined by their second follow-up visit, and 85% had declined by their third. In the published study that provided norms for NC change in controls [3], the overall prevalence of “decliner” status for participants with ≥4 visits (required for the CHARTER study) was 12.3%. The 22.7% rate of decliners in CHARTER is almost double that in the normative study, a consequential difference that is not easily attributable to chance. Importantly, if the 99 participants in the CHARTER longitudinal study had evidenced NC declines on the basis of chance alone, one would not expect the large number of observed, statistically significant associations with disease and treatment variables. The second issue raised by Haddow et al was our failure to consider that the observed association between NC decline and antiretroviral therapy (ART) status could be bidirectional: being off ART (as a time-dependent predictor) could increase risk for NC decline, or NC decline and impairment could cause disengagement from care and nonadherence to ART. Regarding the term “risk,” this terminology is used in an associational rather than causative sense in the scientific literature in a variety of settings. For example, when an epidemiologist says that “being male increases the risk of subsequent incarceration for criminal activity,” it does not mean that “maleness” causes criminality, nor does one question the validity of the original statement. Although we have acknowledged that causal associations cannot be established in an observational study such as this, we would note that our “off ART” variable was not an adherence indicator but, instead, reflected the fact that that these participants were not being prescribed ART at the times of their NC declines. While not impossible, it seems unlikely that patients’ NC impairment, when detected clinically, led medical providers to avoid prescribing ART. We appreciate the opportunity to address the concerns raised by Haddow et al [1], but maintain that the conclusion quoted above is warranted.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. A multicenter cross-sectional study involving five sites in the USA was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein-1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell-derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM), and frontal gray matter (FGM): N-acetylaspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Eighty-three HIV-infected individuals were included, 78 % on cART and 37 % with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R 2 0.179, p

Background: There is paucity of data about arterial wall characteristics of the smallest and largest caliber cerebral vessels. Determining the relationship between the lumen and the wall might shed new insights into cerebral artery remodeling. Objective: To test the hypotheses that arteries with larger luminal diameters have a thinner wall and that arteries with the smallest lumina have thicker walls. Methods: Cross-sectional segments from large arteries (N=1392) were obtained from the circle of Willis in 196 autopsied brains (mean age 55 ± 17 yrs, 39% with hypertension, 15% with diabetes and 20% with dyslipidemia). Lumen diameter, stenosis percentage, and thicknesses of intima, media, and adventitia were calculated in digital microphotography after staining. Atheromas and internal elastic lamina (IEL) disruption were rated visually. Arteries were categorized into the top 5% (“dilated”) and bottom 5% (“narrowed”) of the luminal diameters, as well as an intermediate category (90% of sample as reference). We used logistic regression to obtain the odds of association (OR, 95% CI) after adjusting for demographic and vascular variables. Results: Narrowed arteries were more frequently found in men (OR 2.7, 95%CI 1.3-5.9) and with dyslipidemia (4.2, 1.6-11.1) while dilated arteries were more frequently found in women (5.6, 2.2-14.0), in smokers (2.6, 1.0-6.5) and those with prior MI (7.7, 1.2-48.7). Narrowed arteries were more likely to have atheromas (20.8, 4.8-90.3), greater luminal stenosis (per %, 1.1, 1.1-1.2), thicker vessel walls (1.3, 1.2-1.4), but thinner medias (0.9, 0.8-1.0). Conversely, larger arteries exhibited less IEL disruption (0.3, 0.1-0.9), atheromas (0.34, 0.1-0.9) and stenosis (0.8, 0.8-0.9), their walls were thinner (0.8, 0.8-0.9) but the media was thicker (1.1, 1.1-1.2). Conclusions: Narrowed cerebral arteries were more likely to have atheromas while dilated arteries had thinner walls and were more frequent in subjects with prior MI. These findings suggest that both extremes of the arterial spectrum might be differentially related with vascular disease, underscoring the need to revisit whether standard preventive measures for vascular disease are equally effective in patients harboring such disparate arterial phenotypes.

Objectives: To examine the effects of liver function and hepatitis C virus (HCV) serostatus on neurological, neuropsychological, and psychiatric abnormalities in an advanced-stage HIV-infected cohort. Design: A correlational analysis of baseline data accumulated on 137 participants in the Manhattan HIV Brain Bank, a longitudinal study of HIV-infected individuals. Methods: Patients underwent a battery of neuropsychological tests, a semi-structured psychiatric interview, and a neurological examination. The resulting diagnostic data were correlated with biochemical indices of hepatic function and HCV serostatus. Results: Biochemical indices of liver function correlated with motor dysfunction determined by neurological evaluation, but nor with neuropsychological or psychiatric disorders. Discrete neurological diagnostic entities showed no relationship with biochemical indices, with one exception: patients with cryptococcal leptomeningitis had worse liver function than those without. HCV had no relationship with any neurological disorder or symptom complex. In contrast, HCV serostatus was related to neuropsychological and psychiatric abnormalities, and indices of liver function were not. HCV-seropositive patients were more likely to have histories of opiate, cocaine or stimulant dependency, to have greater impairment in executive functioning, and to meet diagnostic criteria for AIDS dementia, compared with HCV-negative individuals of similar immunological and virological status. Conclusions: HCV and biochemical indices of liver function associate differentially with nervous system abnormalities in this HiV-infected population. Neurological abnormalities correlate with biochemical indices of liver function, whereas neuropsychological and psychiatric dysfunction an I inked to HCV infection. We postulate that multifactorial impacts of HCV and liver disease on HIV-related nervous system disorders may originate in different anatomical and cellular compartments.

Co-infection with HIV and hepatitis C has become increasingly prevalent. It is a major source of morbidity in HIV-infected populations. Distal symmetric polyneuropathy is the most common form of peripheral neuropathy in HIV as well as hepatitis C mono-infection. There is considerable overlap in the symptoms and signs of HIV and hepatitis C neuropathy. It is not known whether there are additive or synergistic effects on the peripheral nerve by these two viruses. There is a need for studies to further elucidate the mechanisms involved.

AIDS dementia complex (ADC) in human immunodeficiency virus (HIV)-infected patients continues to be a problem in the era of highly active antiretroviral therapy (HAART). A better understanding of the drug resistance mutation patterns that emerge in the central nervous system (CNS) during HAART is of paramount importance as these differences in drug resistance mutations may explain underlying reasons for poor penetration of antiretroviral drugs into the CNS and suboptimal concentrations of the drugs that may reside in the brains of HIV-infected individuals during therapy. Thus, we provide a detailed analysis of HIV type 1 (HIV-1) protease and reverse transcriptase (RT) genes derived from different regions of the brains of 20 HIV-1-infected patients (5 without ADC, 2 with probable ADC, and 13 with various stages of ADC) on antiretroviral therapy. We show the compartmentalization and independent evolution of both primary and secondary drug resistance mutations to both RT and protease inhibitors in diverse regions of the CNS of HIV-infected patients, with and without dementia, on antiretroviral therapy. Our results suggest that the independent evolution of drug resistance mutations in diverse areas of the CNS may emerge as a consequence of incomplete suppression of HIV, probably related to suboptimal drug levels in the CNS and drug selection pressure. The emergence of resistant virus in the CNS may have considerable influence on the outcome of neurologic disease and also the reseeding of HIV in the systemic circulation upon failure of therapy.

Objective:To determine whether hepatitis C (HCV) contributes to CNS dysfunction among HIV-infected individuals.Methods:Using a cross-sectional design, the neuropsychiatric profile of individuals with advanced HIV coinfected with hepatitis C (HIV+/HCV+) was compared to similarly advanced HIV patients without HCV coinfection (HIV+/HCV−). Participants were derived from the Manhattan HIV Brain Bank and underwent neurocognitive testing and semistructured psychiatric interviews. Evidence of HCV infection was determined by serology performed prior to study entry. Hepatic function was determined by serum chemistries (bilirubin, creatinine, and international normalized ratio) at the time of the cognitive assessments.Results:Coinfected (HIV+/HCV+) individuals were significantly more likely to have had past opiate or cocaine or stimulant dependence. HIV+/HCV+ participants also had significantly greater rates of past substance-induced major depression. There were no significant differences in rates of primary mental disorders. Forty-two percent of both the HIV+/HCV+ and HIV+/HCV− participants met criteria for current major depression. There was a trend for HIV+/HCV+ patients to perform worse neurocognitively. On tests of executive functioning, HIV+/HCV+ individuals exhibited a greater rate of impairment and had significantly more perseveration. Differences in cognitive functioning were associated with serology but did not correlate with indices of liver disease severity. The HCV+ patients were also more likely to be diagnosed with HIV-associated dementia.Conclusions:There appears to be a neuropsychiatric impact of HCV that is detectable even among an advanced HIV cohort.

Objective: To investigate the effect of hepatitis C virus (HCV) on neurocognitive performance in chronically HIV-infected patients enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study. Methods: A total of 1,582 participants in CHARTER who were tested for HCV antibody underwent neurocognitive testing; serum HCV RNA was available for 346 seropositive patients. Neurocognitive performance was compared in 408 HCV-seropositive and 1,174 HCV-seronegative participants and in a subset of 160 seropositive and 707 seronegative participants without serious comorbid neurologic conditions that might impair neurocognitive performance, using linear regression and taking into account HIV-associated and demographic factors (including IV drug use) and liver function. Results: Neurocognitive performance characterized by global deficit scores and the proportion of individuals who were impaired were the same in the HCV-seropositive and HCV-seronegative groups. In univariable analyses in the entire sample, only verbal domain scores showed small statistically different superior performance in the HCV+ group that was not evident in multivariable analysis. In the subgroup without significant comorbidities, scores in all 7 domains of neurocognitive functioning did not differ by HCV serostatus. Among the HCV-seropositive participants, there was no association between neurocognitive performance and serum HCV RNA concentration. Conclusion: In HIV-infected patients, HCV coinfection does not contribute to neurocognitive impairment, at least in the absence of substantial HCV-associated liver damage, which was not evident in our cohort.

White matter vacuolization of the spinal cord is common in patients with AIDS and may lead to clinical manifestations of myelopathy. The pathogenesis of AIDS-associated myelopathy (AM) is unknown and may be related to metabolic abnormalities rather than to direct HIV infection. The striking pathologic similarity between AM and the vacuolar myelopathy associated with vitamin B(12) deficiency suggests that abnormal metabolism of the B(12)-dependent transmethylation pathway may be important in the pathogenesis of AM.The authors compared S-adenosyl-methionine (SAM), methionine, homocysteine, and glutathione in serum and CSF of 15 patients with AM vs. 13 HIV-infected controls without myelopathy (HWM). They also compared the results with a non-HIV--infected reference population (NC). All patients had normal B(12), folate, and methylmalonic acid levels.There was a decrease in CSF SAM in the AM group compared with the HWM group (p0.0001) and the NC group (p0.0001). CSF SAM in the HWM group was also lower than that in the NC group (p = 0.015). Serum methionine was also reduced in serum of the myelopathic group compared with the NC group (p = 0.006).AM is associated with an abnormality of the vitamin B(12)-dependent transmethylation pathway.

Objectives.—To examine autopsy pathology in an urban population infected with the human immunodeficiency virus (HIV) and to determine if age at death and disease frequencies are associated with gender, HIV risk factors, ethnicity, and therapeutic era. Design and Methods.—Retrospective analysis of autopsy data from 394 HIV-infected adults. The population was divided into 3 therapeutic eras for analysis: group A, 1979–1986; group B, 1987–1995; and group C, 1996–2000. Results.—Women died at significantly younger ages than men (mean ± SEM age, 38.9 ± 1.0 years vs 42.5 ± 0.64 years), even after adjustment for risk factors, ethnicity, and therapeutic era. This age discrepancy occurred despite a lower prevalence of arteriosclerosis, cachexia, and hepatitis B in women and no significant differences in the frequencies of other infectious diseases. Whites had a longer survival than patients of other ethnicities (mean age at death, 44.7 ± 1.2 years for whites, 39.9 ± 0.80 years for blacks, and 41.3 ± 0.87 years for Hispanic individuals). Renal, cardiac, and splenic pathologies, Mycobacterium avium-intracellulare (MAI) infection, and cachexia were more common in blacks than in whites and/or Hispanic individuals, and cytomegalovirus and systemic lymphoma were more common in whites and Hispanic individuals than in blacks. Diseases associated with intravenous drug use were hepatitis C, cirrhosis, and tuberculosis; those with all sexual risk factors, cytomegalovirus infection, herpes simplex virus infection, and Pneumocystis carinii pneumonia; and those with homosexual risk, Kaposi sarcoma and MAI infection. The prevalence of many disease entities changed over time: compared with the other groups, group C had lower prevalences of many viral and fungal illnesses, MAI infection, systemic lymphoma, cachexia, and Kaposi sarcoma and higher prevalences of hepatitis, cirrhosis, arteriosclerosis, staphylococcal and streptococcal infections, and traumatic lesions. When the data were adjusted for changing demographic and risk composition, the only significant changes in disease frequency for period C were decreased prevalences of PCP and Kaposi sarcoma and increased prevalences of cirrhosis and arteriosclerosis. Conclusions.—Significant gender- and ethnicity-related differences in age of death occurred in this HIV-infected population, and these differences were not explained by the frequencies of diseases. The lower prevalences of PCP and Kaposi sarcoma in group C are likely a reflection of the impact of potent therapies on causes of mortality. The higher prevalences of cirrhosis and arteriosclerosis suggest that entities not targeted by antiretroviral reconstitution of immunity will play an increasingly important role in HIV-related mortality in the future.

Monocyte transmigration across the BBB is a critical step in the development of cognitive deficits termed HAND that affect 40–70% of HIV-infected individuals, even with successful antiretroviral therapy. The monocyte subsets that enter the CNS during HIV infection are not fully characterized. We examined PBMC from HIV-positive individuals from 2 distinct cohorts and enumerated monocyte populations, characterized their transmigration properties across an in vitro human BBB model, and identified surface proteins critical for the entry of these cells into the CNS. We demonstrated that the frequency of peripheral blood CD14+CD16+ and CD14lowCD16+ monocytes was increased in HIV-seropositive compared with -seronegative individuals, despite virologic control. We showed that CD14+CD16+ monocytes selectively transmigrated across our BBB model as a result of their increased JAM-A and ALCAM expression. Antibody blocking of these proteins inhibited diapedesis of CD14+CD16+ monocytes but not of T cells from the same HIV-infected people across the BBB. Our data indicate that JAM-A and ALCAM are therapeutic targets to decrease the entry of CD14+CD16+ monocytes into the CNS of HIV-seropositive individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs.

Background The natural history of intracranial large artery atherosclerosis has been mainly described from lumen-based imaging studies, and much of what is reported to be known about atherosclerosis is derived from non-cerebral arteries. Aims To test the hypothesis that atherosclerosis is only partially represented by stenosis and that advanced atherosclerosis is more common that severe stenosis in noncardioembolic infarcts. Methods Cerebral large arteries from 196 autopsy cases were studied. The revised American Heart Association classification for atherosclerosis was used to determine the phenotype in each available artery. Cross-sectional lumen stenosis was obtained as defined by the Glagov's method. Results As age of cases increased, there was a progressive increment in the frequency of atherosclerotic lesions, rising from 5% of all arteries at age 20–40, to more than 40% at age 60 or older. Stenosis also increased with age: less than 3% of the arteries in those ≤50 years had >40% stenosis, while one out of five arteries in those >80 years had >40% stenosis. In most cases (80%), atherosclerosis and stenosis were directly related. However, one out of five cases with advanced atherosclerosis had Conclusion Although intracranial atherosclerosis is typically associated with stenosis, a substantial minority of cases shows advanced atherosclerosis in the absence of stenosis >40%. Definitions based solely on stenosis may underestimate the extent and role of intracranial large artery atherosclerosis.

In recent years, HIV/AIDS populations have become older and increasingly more ethnically diverse. Concurrently, the prevalence of HIV-related neurocognitive (NC) impairment remains high. This study examined the effects of age and ethnicity on NC function in HIV-positive adults. The sample (N = 126; 84 Latina/o and 42 Non-Hispanic White) completed a comprehensive NC battery. Global NC and domain average demographically-corrected t-scores were generated. There were no significant differences between Younger (.10), with generally small effect sizes. Older Latina/os (≥50 years) were significantly more impaired than Older Non-Hispanic Whites on processing speed and learning, with trends in Global NC function and memory. Further, effect sizes fell within the medium to large range (Cohen's d's = .49–1.15). This study suggests that older Latina/os are at potentially greater risk for NC impairment, particularly in processing speed and learning, when compared to similarly-aged non-Hispanic whites.

Detectable human immunodeficiency virus (HIV) RNA in the cerebrospinal fluid (CSF) is associated with central nervous system (CNS) complications. We developed the CSF HIV risk score through prediction modeling to estimate the risk of detectable CSF HIV RNA (threshold >50 copies/mL) to help identify persons who might benefit most from CSF monitoring. We used baseline data from 1,053 participants receiving combination antiretroviral therapy who were enrolled in the 6-center, US-based CNS HIV Antiretroviral Therapy Effects Research (CHARTER) prospective cohort in 2004–2007. Plasma HIV RNA, CNS penetration effectiveness, duration of combination antiretroviral therapy, medication adherence, race, and depression status were retained correlates of CSF HIV RNA, displaying good discrimination (C statistic = 0.90, 95% confidence interval (CI): 0.87, 0.93) and calibration (Hosmer-Lemeshow P = 0.85). The CSF HIV risk score ranges from 0 to 42 points, with a mean of 15.4 (standard deviation, 7.3) points. At risk scores greater than 25, the probability of detecting CSF HIV RNA was at least 42.9% (95% CI: 36.6, 49.6). For each 1-point increase, the odds of detecting CSF HIV RNA increased by 26% (odds ratio = 1.26, 95% CI: 1.21, 1.31; P < 0.01). The risk score correlates with detection of CSF HIV RNA. It represents an advance in HIV management and monitoring of CNS effects, providing a potentially useful tool for clinicians.

OBJECTIVE:While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline). METHODS:A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7-63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood. RESULTS:The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1-3.6; p = 0.02) for SR, 5.8 (CI 3.2-10.7; p < 0.0001) for PB, and 3.2 (CI 2.0-5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not. CONCLUSIONS:This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.

Distal symmetric polyneuropathy (DSP) is common in HIV and is associated with autonomic impairment. However tools to measure HIV-DSP do not include autonomic indices. We sought to optimize the Total Neuropathy Score (TNS) and the Composite Autonomic Severity Score (CASS) for use in HIV.HIV-infected adults (n = 102) underwent neurologic examination, quantitative sensory testing (QST), nerve conduction studies, and autonomic testing. Modifications of the TNS and CASS were assessed for validity based on correlation with the original measure and internal consistency.The TNS version commonly used in HIV-DSP is valid, but it is improved by elimination of QST and addition of autonomic indices. A modified version of the CASS (M-CASS) which was designed for sensitivity to milder impairment was also valid.A modified TNS that excludes QST and includes autonomic indices is optimal for HIV-DSP. The M-CASS is a valid measure of autonomic impairment in HIV.

INTRODUCTION: Individuals with HIV live longer since the advent of antiretroviral (ARV) drugs. However, aging with HIV is now associated with vascular disease. Mechanisms underlying this association have not been fully elucidated. We explored arterial correlates that might lead the association between HIV and cerebral infarction. Methods: The Brain Arterial Remodeling Study (BARS) is a collection of 336 brains from donors in the US (69%) and Macedonia (31%) from which large brain arteries have been collected, cut, embedded and stained with H&E and van Gieson. Atherosclerosis and stenosis were graded using Glagov’s method. Cerebral infarction was identified in autopsy. For this analysis, HIV cases (n=138) were age- and sex-matched to controls without HIV. Multivariate logistic and linear regressions were used to determine odds ratios and 95% confidence intervals (OR, 95% CI) assessed associations at P< 0.05. Results: Those with HIV (mean age 48.8 ± 9.1 years, 75% men) were more likely to be black (OR 5.0, 2.4-10.4) or Hispanic (OR 2.2, 1.2-3.9), hypertensive (OR 2.2, 1.3-3.5), dyslipidemic (OR 3.5, 1.1-11.0), cocaine users (OR 10.1, 4.6-22.4) and have cardiac disease (OR 2.0, 1.2-3.5). Cerebral infarction was more common with HIV (adjusted OR 2.8, 1.1-6.8). HIV brains were less likely to have atherosclerosis (OR 0.4, 0.3-0.7) or any stenosis > 25% (OR 0.4, 0.1-1.0). Among those with HIV, after adjusting for demographic and vascular risks, cerebral infarction was more prevalent with prior opportunistic infections (5.3, 1.2-22.9), higher CD4 count (OR 1.2, 1.0-1.4 per every 50 CD4 cell increment), and in those with intimal thickening in more than 75% of the lumen circumference (OR 4.0, 1.1-14.5). Predictors of circumferential intimal thickening in the HIV group included ARV at death (Beta 0.17, P=0.007), internal elastic lamina (IEL) gaps, Beta 0.22, P=0.02), and IEL duplication (Beta 0.28, P=0.001). CONCLUSIONS: Individuals with HIV in this study have a greater prevalence of vascular risks and cerebral infarction, yet the increased infarction prevalence is not associated with atherosclerosis. Patients with HIV have a non-atherosclerotic arterial phenotype consisting of circumferential intimal thickening with disruption of the internal elastic lamina.

The National NeuroAIDS Tissue Consortium (NNTC) was founded in 1998, in response to the scientific need for well-characterized central nervous system (CNS) and peripheral nervous system (PNS) tissues and fluids from HIV-infected individuals. In addition to performing the routine functions of non-transplant anatomic tissue banks, the Consortium offers a unique model for the integration of independent research entities in order to provide well-characterized tissues and fluids for the international research community. Herein, we describe the structure of the Consortium, pointing out the inherent strengths of linking together multiple independent sites for the purpose of banking HIV-infected nervous system tissues. We describe the neuropathology protocol that was adopted and successfully implemented at the four participating banks of the Consortium.

Inflammatory cytokines and enzymes such as IL-1 and inducible nitric oxide synthase (iNOS) may play an important role in the pathogenesis of AIDS dementia, a condition associated with infection of the CNS cells by the HIV-1. In this report, we investigated the expression of iNOS, IL-1, and caspase-1 (interleukin-1 converting enzyme) in HIV-1 encephalitis (HIVE) by immunocytochemistry and analyzed their expression with respect to HIV-1 infection and glial activation. In HIVE, all three molecules were expressed at high levels in areas of HIV-1 infection (microglial nodules with HIV-1 p24 immunoreactivity) and in areas of diffuse white matter gliosis. Expression was cell-type specific, with IL-1 and caspase-1 being expressed in macrophages and microglia, and iNOS in activated astrocytes. Multinucleated giant cells, a hallmark of virally infected cells, showed intense staining for both IL-1 and caspase-1, suggesting induction of these molecules by HIV-1. Double immunocytochemistry demonstrated a regional co-localization of astrocyte iNOS and microglial IL-1 and caspase-1. These results support the notion that autocrine and paracrine interactions between HIV-1 infected macrophages and microglia, activated microglia, and astrocytes lead to expression of proinflammatory and neurotoxic molecules. iNOS and caspase-1 may provide additional therapeutic targets for HIVE.

Increases in circulating CD14+/CD16+ monocytes have been associated with HIV dementia; trafficking of these cells into the CNS has been proposed to play an important role in the pathogenesis of HIV-induced neurological disorders. This model suggests that events outside the CNS leading to monocyte activation initiate the process leading to HIV dementia. To investigate the role of this activated monocyte subset in the pathogenesis of HIV dementia, we examined brain specimens from patients with HIV encephalopathy (HIVE), HIV without encephalopathy, and seronegative controls. An accumulation of perivascular macrophages was observed in HIVE. The majority of these cells identified in microglial nodules and in the perivascular infiltrate were CD14+/CD16+. P24 antigen colocalized with both CD14 and CD16 suggesting that the CD14+/CD16+ macrophage is a major reservoir of HIV-1 infection in CNS. Using CD45/LCA staining, the perivascular macrophage was distinguished from resident microglia. In addition to perivascular and nodular localizations, CD16 also stained ramified cells throughout the white matter. These cells were more ramified and abundant than cells positive for CD14 in white matter. Double staining for p24 and CD16 suggests that these cells were often infected with HIV-1. The prominent distribution of CD14+ cells in HIVE prompted our analysis of soluble CD14 levels in cerebrospinal fluid. Higher levels of soluble CD14 (sCD14) were observed in patients with moderate-to-severe HIV dementia, suggesting the utility of sCD14 as a surrogate marker. CD14+/CD16+ monocytes may play a role in other neurological disorders and sCD14 may be useful for evaluating these conditions.

Pituicytoma is a rare, poorly characterized tumor of the sella and suprasellar region that is distinct morphologically from other local tumors and is thought to be derived from neurohypophyseal pituicytes. Clinical data, neuroimaging studies, and microsections were reviewed from nine such low-grade gliomas. Immunostains for glial, neuronal, and proliferation markers were performed on all nine tumors and six control neurohypophyses. Three tumors were studied ultrastructurally. Six men and three women, age 30 to 83 years (mean, 48 years), presented with visual symptoms, headache, or hypopituitarism. Magnetic resonance images showed solid, discrete, contrast-enhancing masses, four within the sella and five in the suprasellar space. The tumors consisted of sheets and/or fascicles of plump spindle cells with slightly fibrillar cytoplasm and slightly pleomorphic, oval-to-elongate nuclei with pinpoint nucleoli. Extracellular mucin was prominent in one tumor. Rosenthal fibers, granular bodies, and Herring bodies (granular axonal dilatations characteristic of the normal neurohypophysis) were lacking. Mitoses were rare or absent. MIB-1 labeling indices were low (0.5-2%). Tumor cells were strongly reactive for vimentin and S-100 protein, variably positive for glial fibrillary acidic protein, and nonreactive for synaptophysin and neurofilament protein. Cytoplasm varied in electron density and contained intermediate filaments. Neither meningothelial nor ependymal features were noted. Two tumors recurred at 20 and 26 months after subtotal resection, but none of the six completely resected tumors have done so. Pituicytomas are discrete, largely noninfiltrative low-grade gliomas of the sellar region that occur in adults. Their histologic appearance is distinct from pilocytic and ordinary, infiltrative astrocytomas. The distinction between pituicytoma and normal neurohypophysis is aided by the latter's content of axons, Herring bodies, and perivascular anucleate zones rich in axonal terminations. Although curable by total excision, subtotal resection can be associated with recurrence.

Prospective memory (ProM), a form of episodic memory related to execution of future intentions, is important for everyday functioning. Among persons living with HIV (PLWH), executive dysfunction is implicated in ProM impairments. However, specific subcomponents of executive functioning involved in ProM deficits remain poorly understood. Unlike more "traditional" neurocognitive (NC) measures of executive functioning associated with dorsolateral prefrontal cortex (i.e., conceptual reasoning, abstraction), those associated with medial orbitofrontal/ventromedial prefrontal (mOF/vmP) cortex (i.e., decision making, inhibitory control, goal-oriented behavior) have yet to be examined in ProM.This study characterized ProM ability in a sample of 89 HIV-seropositive adults and examined the unique role of decision-making ability in ProM. Participants completed a standard NC battery, the Iowa Gambling Task (IGT; a decision-making measure), and the Memory for Intentions Screening Test (MIST; a ProM measure).Correlational analyses revealed that both traditional executive functioning measures and the IGT were associated with ProM. Regression analyses revealed that the IGT significantly predicted ProM, even after accounting for NC measures. Among all NC measures, only executive functioning significantly contributed to ProM.Further examination of mOF/vmP-sensitive executive dysfunction within this population is needed as PLWH may require more tailored treatment recommendations due to specific decision-making difficulties that can impact medication management.

HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p

✓ A 35-year-old man infected with human immunodeficiency virus presented with cervical myelopathy of 2 months duration. Clinical and radiographic evaluation revealed a discrete, subdural mass at C-6. At surgery, the mass proved to have a dural attachment and thus clinically, radiographically, and grossly, it resembled meningioma. Histopathological analysis revealed a leiomyosarcoma that stained diffusely for muscle-specific actin. Electron microscopy revealed basal lamina surrounding the tumor cells and intracytoplasmic bundles of myofilaments. Epstein—Barr virus (EBV) was demonstrated within tumor cell nuclei by in situ hybridization for EBER1 messenger RNA and immunohistochemical staining for EBNA2 protein. Epstein—Barr virus latent membrane protein (LMP1) was not detected. This is the first documentation of an EBV-associated smooth-muscle tumor of the dura, and the first demonstration that tumors in this location contain EBV in an unusual form of latency not seen in lymphoid cell lines. With increasing numbers of individuals being afflicted with long-term immunosuppression, EBV-associated dural leiomyoma and leiomyosarcoma may be encountered more frequently in the future.

It has been postulated that drugs of abuse act synergistically with HIV, leading to increased neurotoxicity and neurocognitive impairment. The CNS impacts of HIV and drug use converge on the mesocorticolimbic dopamine (DA) system, which contains two main receptor subtypes: dopamine receptors 1 (DRD1) and 2 (DRD2). DRD1 and DRD2 have been linked to substance dependence; whether they predict HIV-associated neurocognitive disorder (HAND) is unclear. Using an advanced-stage HIV+ population, we sought to determine if drug dependence impacts the contribution of DA receptor polymorphisms on neurocognition. We observed that both DRD1 and DRD2 polymorphisms were associated with opiate and cocaine dependence (P

Chemokine receptors CCR2 and CCR5 play a key role in immune and inflammatory responses and have been associated with several diseases, including AIDS. In order to comprehend health disparities it is important to understand the nature of genetic variation in specific genes of interest in different populations. Current studies of the CCR2 and CCR5 receptor genes are primarily focused on the CCR5-Δ32, and CCR2-V64I SNPs.Sanger sequencing was used to sequence the regions containing 16 SNPs in the adjacent CCR2 and CCR5 genes (including CCR5-Δ32, and CCR2-V64I) in 249 subjects of African, European and Hispanic ancestry. Linkage disequilibrium (LD) and haplotypes were determined using Haploview.The data revealed large differences in allele frequencies of several SNPs and LD patterns among the ethnic groups, including SNPs that were restricted to Africans or Europeans. Seven known CCR5 haplotypes and six novel CCR2 haplotypes were identified. A rare case of an HIV+ subject with the CCR5-Δ32/Δ32 was identified.These data demonstrate a LD between CCR2 and CCR5 at several loci and provide new information about CCR2 that contributes to our understanding of its population-specific genetic variability. The data indicate that in addition to CCR5-Δ32 and CCR2-V64I, other SNPs and haplotypes may be important genetic determinants of disease and should be investigated.

HIV infected people are living longer due to the success of combined antiretroviral therapy (cART). However, greater than 40-70% of HIV infected individuals develop HIV associated neurocognitive disorders (HAND) that continues to be a major public health issue. While cART reduces peripheral virus, it does not limit the low level, chronic neuroinflammation that is ongoing during the neuropathogenesis of HIV. Monocyte transmigration across the blood brain barrier (BBB), specifically that of the mature CD14(+)CD16(+) population that is highly susceptible to HIV infection, is critical to the establishment of HAND as these cells bring virus into the brain and mediate the neuroinflammation that persists, even if at low levels, despite antiretroviral therapy. CD14(+)CD16(+) monocytes preferentially migrate into the CNS early during peripheral HIV infection in response to chemotactic signals, including those from CCL2 and CXCL12. Once within the brain, monocytes differentiate into macrophages and elaborate inflammatory mediators. Monocytes/macrophages constitute a viral reservoir within the CNS and these latently infected cells may perpetuate the neuropathogenesis of HIV. This review will discuss mechanisms that mediate transmigration of CD14(+)CD16(+) monocytes across the BBB in the context of HIV infection, the contribution of these cells to the neuropathogenesis of HIV, and potential monocyte/macrophage biomarkers to identify HAND and monitor its progression.

MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79 % initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis. © 2013 Journal of NeuroVirology, Inc.

Human immunodeficiency virus-1 (HIV) is a public health issue and a major complication of the disease is NeuroAIDS. In vivo, microglia/macrophages are the main cells infected. However, a low but significant number of HIV-infected astrocytes has also been detected, but their role in the pathogenesis of NeuroAIDS is not well understood. Our previous data indicate that gap junction channels amplify toxicity from few HIV-infected into uninfected astrocytes. Now, we demonstrated that HIV infection of astrocytes results in the opening of connexin43 hemichannels (HCs). HIV-induced opening of connexin43 HCs resulted in dysregulated secretion of dickkopf-1 protein (DKK1, a soluble wnt pathway inhibitor). Treatment of mixed cultures of neurons and astrocytes with DKK1, in the absence of HIV infection, resulted in the collapse of neuronal processes. HIV infection of mixed cultures of human neurons and astrocytes also resulted in the collapse of neuronal processes through a DKK1-dependent mechanism. In addition, dysregulated DKK1 expression in astrocytes was observed in human brain tissue sections of individuals with HIV encephalitis as compared to tissue sections from uninfected individuals. Thus, we demonstrated that HIV infection of astrocytes induces dysregulation of DKK1 by a HC-dependent mechanism that contributes to the brain pathogenesis observed in HIV-infected individuals. Our studies demonstrated that HIV infection of astrocytes, despite minimal replication and a low number of infected cells, induces dysregulation of DKK1 secretion by a Cx43 hemichannel (HC)-dependent mechanism. Enhanced DKK1 secretion in response to HIV infection of glial cells compromised formation and stability of neuronal processes, similar to the synaptic compromise observed in HIV-infected individuals. In addition, analysis of human brain tissue sections obtained from encephalitic individuals also shows enhanced expression of DKK1 in astrocytes. Our data provide a novel mechanism by which HIV infection of glial cells participate in the pathogenesis of brain dysfunction observed in HIV-infected individuals. LRP5 = Low-density lipoprotein receptor-related protein 5.

HIV infection and HIV neurocognitive impairment are major global health problems. The prevalence of HIV associated neurocognitive disorders (HAND) is increasing as people with HIV are living longer due to the success of antiretroviral therapies. Our laboratory identified the soluble form of (sPrP(c)), the cellular non-pathogenic isoform of the prion protein, as a biomarker of HAND. In this review we discuss the published data addressing PrP(c) biology in normal conditions and pathologies, as well as the mechanisms of sPrP(c) shedding and secretion. Lastly, we discuss our studies that demonstrated that sPrP(c) is a biomarker of neurocognitive impairment in the HIV infected population.

Author(s): Gelman, Benjamin B; Lisinicchia, Joshua G; Morgello, Susan; Masliah, Eliezer; Commins, Deborah; Achim, Cristian L; Fox, Howard S; Kolson, Dennis L; Grant, Igor; Singer, Elyse; Yiannoutsos, Constantin T; Sherman, Seth; Gensler, Gary; Moore, David J; Chen, Tiansheng; Soukup, Vicki M | Abstract: ObjectiveReplicating HIV-1 in the brain is present in HIV encephalitis (HIVE) and microglial nodule encephalitis (MGNE) and is putatively linked with HIV-associated neurocognitive disorders (HAND). A cliniconeurovirological correlation was conducted to elucidate the relationship between brain viral load and clinical phenotype. SUBJECTS AND ASSAYS: HIV gag/pol RNA and DNA copies were quantified with reverse transcriptase-polymerase chain reaction or polymerase chain reaction in 148 HAART-era brain specimens. Comparison with HAND, HIVE, and MGNE and correlation with neuropsychological (NP) test scores were done using one-way ANOVA with Tukey-Kramer and Spearman tests, respectively.ResultsBrain HIV RNA was higher in subjects with HAND plus HIVE versus without HAND (delta = 2.48 log10 units, n = 27 versus 36, P l 0.001). In HAND without HIVE or MGNE, brain HIV RNA was not significantly different versus without HAND (P = 0.314). Worse NP scores correlated significantly with higher HIV RNA and interferon responses in brain specimens (P l 0.001) but not with HIV RNA levels in premortem blood plasma (n = 114) or cerebrospinal fluid (n = 104). In subjects with MGNE, brain HIV RNA was slightly higher versus without MGNE (P l 0.01) and much lower versus with HIVE (P l 0.001).ConclusionsBrain HIV RNA and to a lesser extent HIV DNA are correlated with worse NP performance in the 6 months before death. Linkage occurs primarily in patients with HIVE and MGNE, and these patients could obtain added NP improvement by further reducing brain HIV while on HAART. Patients not in those groups are less certain to obtain added NP benefit.

This is a cross-sectional, observational study to evaluate the hypothesis that HIV-seropositive (HIV+) apolipoprotein E4 (APOE4) carriers are at increased risk for HIV-associated neurocognitive disorders (HAND) compared to APOE4 noncarriers with HIV in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Group sample. APOE genotype was determined in 466 CHARTER participants with varying disease stages and histories of antiretroviral treatment who did not have severe psychiatric or medical comorbid conditions that preclude diagnosis of HAND. HAND diagnoses were based on results of comprehensive neurobehavioral evaluation and use of current neuroAIDS diagnostic criteria. HAND status consists of two levels: neuropsychologically normal status (i.e., no HAND) and any HAND diagnosis (i.e., asymptomatic neurocognitive impairment, minor neurocognitive disorder, HIV-associated dementia). Logistic regression analyses revealed no association between APOE4 carrier status and HAND, and there were no interactions between APOE4 carrier status and ethnicity, age, substance use disorders, duration of infection, or nadir CD4. Results did not differ when analysis was restricted to symptomatic HAND, and no APOE4 gene dose-dependent relationship to HAND emerged. APOE4 status was not associated with concurrent HAND in this large, well-characterized sample. This does not preclude emergence of an association between APOE4 status and HAND as this population ages. Prospective, longitudinal studies are needed to examine APOE4 as a risk factor for neurocognitive decline, incident HAND at older ages, and potential associations with cerebrospinal fluid amyloid.

Introduction: The pathophysiology of stroke in HIV involves alterations in vessel wall structure, both inward (stenosis) and outward remodeling (dilatation). Metalloproteinase-2 (MMP-2) has been implicated in the remodeling of large arteries, but it has not been studied in the cerebral arteries. Objectives: To assess the potential role of MMP-2 in brain arterial remodeling in HIV infection. Methods: Circle of Willis arteries were obtained from 38 brain donors with and without HIV infection, autopsied by the Manhattan HIV Brain Bank. The lumen-to-wall-ratio (LWR) was obtained from transversal Van Gieson stains and used to assess remodeling with larger ratios indicating outward remodeling. Immunohistochemistry was used to assess MMP-2 expression in the arterial wall, scored as average pixel intensity and expressed as arbitrary units (AU). Demographic and clinical variables were used as covariates of remodeling in linear regression models. Results: The sample included 38 middle cerebral arteries from 28 individuals with HIV and 10 without. Compared to non-HIV controls, the HIV group was younger (57 vs. 45 years, P=0.001), more frequently male (40 vs. 70 %, P=0.08) and African American (43 vs. 20%, P=0.18), but reported less hypertension (50 vs. 25%, P=0.14) and diabetes (66 vs. 33%, P=0.03). The expression of MMP-2 was higher in the HIV group (171 vs. 186 AU, P=0.14). After adjusting for age, sex, ethnicity, hypertension and diabetes, subjects with HIV had higher LWR (β=4.7, P=0.03, R 2 =0.22), although adjusting for MMP-2 reduced the strength of the association (β= 3.7, P=0.20, R 2 =0.52). Stratifying by HIV status, MMP-2 was the only significant predictor of outward remodeling in the HIV group (P=0.02). In this group, age >45 years (P=0.005), CD4 count Conclusion: MMP-2 may be associated with outward remodeling of cerebral arteries in HIV-infected individuals, particularly in the context of hypertension and immunosuppression. More studies are needed to better understand this arterial physiopathology given the increased cerebrovascular disease seen in the HIV-infected population.

Background Metabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but the biochemical details and underlying mechanisms of these disorders have not been defined. Methods Untargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4 counts ( Results A 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV patients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p Conclusions Lipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation, microbial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate immune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders in HIV patients.

Paraffin sections of an undifferentiated salivary gland carcinoma of lymphoepithelioma type, arising in a white (Greek) patient and confirmed by immunohistochemistry, were examined for the presence of Epstein-Barr virus (EBV), using in situ hybridization to detect EBV-specific EBER1 message. Epstein-Barr virus was detected in malignant epithelial cells, but was not found in lymphoid stroma or in residual benign salivary epithelium. These results confirm the existence of an association between EBV and tumor cells of undifferentiated carcinoma of parotid gland. This is the first demonstration of EBV in a salivary gland lymphoepithelioma arising in a non-Eskimo, white patient. This finding suggests that the association of EBV with undifferentiated salivary gland carcinoma may exist in geographic regions remote from Greenland.

Neurologic complications of HIV are well characterized in the central and peripheral nervous systems but not in the autonomic nervous system, perhaps due to the complexities of measuring autonomic function in medically ill populations. We hypothesized that autonomic dysfunction is common in HIV, can be meaningfully measured with an autonomic reflex screen, and is associated with distal symmetric polyneuropathy (DSP) but not with signs of CNS disease. We also sought to characterize immunovirologic and medical factors associated with autonomic dysfunction. We assessed 102 HIV-infected adults for autonomic dysfunction with a laboratory-based autonomic reflex screen summarized as the composite autonomic severity score (CASS). The total neuropathy score (TNS) was used to quantify DSP based on neurologic interview/examination, quantitative sensory testing, and nerve conduction studies. Autonomic dysfunction was common, with a CASS ≥ 3 in 61 % of participants, of whom 86 % were symptomatic. Greater CASS abnormalities demonstrated univariate association with increasing TNS, age, viral load, hypertension, and use of medications (particularly anticholinergics), but not with antiretrovirals, current/nadir CD(4+) count, HIV duration, metabolic factors, or signs of CNS disease. The TNS was the only significant predictor of the CASS in multivariate analysis; anticholinergic medications were marginally significant. This study demonstrates that autonomic dysfunction is common and frequently symptomatic in HIV and that an autonomic reflex screen, adjusted for anticholinergic medication, is useful in its assessment. Association of autonomic dysfunction with DSP suggests common factors in their pathogenesis, and autonomic neuropathy may be part of the spectrum of HIV-associated peripheral nerve pathologies.

Background: The HIV Dementia Scale (HDS) was developed to screen for HIV-associated neurocognitive disorders (HAND), but concerns have persisted regarding its substandard sensitivity. This study aimed to examine the classification accuracy of the HDS using raw and norm-based cut points and to evaluate the contribution of the HDS subtests to predicting HAND. Methods: A total of 1580 HIV-infected participants from 6 US sites completed the HDS, and a gold standard neuropsychological battery, on which 51% of participants were impaired. Results: Sensitivity and specificity to HAND using the standard raw HDS cut point were 24% and 92%, respectively. The raw HDS subtests of attention, recall, and psychomotor speed significantly contributed to classification of HAND, whereas visuomotor construction contributed the least. A modified raw cut point of 14 yielded sensitivity of 66% and specificity of 61%, with cross-validation. Using norms also significantly improved sensitivity to 69% with a concomitant reduction of specificity to 56%, whereas the positive predictive value declined from 75% to 62% and negative predictive value improved from 54% to 64%. The HDS showed similarly modest rates of sensitivity and specificity among subpopulations of individuals with minimal comorbidity and successful viral suppression. Conclusions: Findings indicate that while the HDS is a statistically significant predictor of HAND, particularly when adjusted for demographic factors, its relatively low diagnostic classification accuracy continues to hinder its clinical utility. A raw cut point of 14 greatly improved the sensitivity of the previously established raw cut score, but may be subject to ceiling effects, particularly on repeat assessments.

Stella E Panos,1,2 Charles H Hinkin,1,2 Elyse J Singer,3 April D Thames,1,2 Sapna M Patel,1,2 Janet S Sinsheimer,4 AC Del Re,5 Benjamin B Gelman,6 Susan Morgello,7 David J Moore,8 Andrew J Levine31Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, David Geffen School of Medicine, 2VA Greater Los Angeles Healthcare System; 3National Neurological AIDS Bank, UCLA Department of Neurology, 4Departments of Biomathematics and Human Genetics, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 5Department of Psychiatry, Stanford University, Menlo Park, CA, 6Department of Pathology, University of Texas Medical Branch, Galveston, TX, 7Departments of Neurology, Neuroscience, and Pathology, The Mount Sinai School of Medicine, New York, NY, 8Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USABackground: The apolipoprotein-E (APOE) ε4 allele is a risk factor for vascular dementia and Alzheimer’s disease. Recent studies are equivocal with regards to whether or not the ε4 allele confers increased risk for the development of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), but suggest that age and/or disease severity may be modulating factors. The aim of this study was to assess the interactions and contributions of APOE genotype, age, and HIV disease severity as risk factors for HAND in HIV-infected adults.Methods: Participants were 259 HIV-positive individuals who underwent APOE genotyping, a standardized neurological evaluation, a comprehensive neuropsychological evaluation, and laboratory testing.Results: Older ε4 carriers showed a higher frequency of HAND compared with age-matched non-ε4 carriers. Analysis by discrete neurocognitive domain revealed that advanced age modulated the effect of the ε4 allele, such that older ε4 allele carriers showed reduced executive functioning and information processing speed. Exploratory analyses assessing the relationship between ε4 and disease severity in the overall sample revealed that disease severity modulated the effect of the ε4 allele on cognition. Lower absolute CD4+ cell count among ε4 allele carriers was associated with poorer working memory ability.Conclusion: Advancing age and degree of immunosuppression may influence the association between APOE ε4 allele status and HAND. These two factors need to be taken into account in future research.Keywords: apolipoprotein-E, human immunodeficiency virus, aging, neurocognition

As HIV infected individuals live longer, the prevalence of HIV associated neurocognitive disorders is increasing, despite successful antiretroviral therapy. CD14(+)CD16(+) monocytes are critical to the neuropathogenesis of HIV as they promote viral seeding of the brain and establish neuroinflammation. The mechanisms by which HIV infected and uninfected monocytes cross the blood brain barrier and enter the central nervous system are not fully understood. We determined that HIV infection of CD14(+)CD16(+) monocytes resulted in their highly increased transmigration across the blood brain barrier in response to CCL2 as compared to uninfected cells, which did not occur in the absence of the chemokine. This exuberant transmigration of HIV infected monocytes was due, at least in part, to increased CCR2 and significantly heightened sensitivity to CCL2. The entry of HIV infected and uninfected CD14(+)CD16(+) monocytes into the brain was facilitated by significantly increased surface JAM-A, ALCAM, CD99, and PECAM-1, as compared to CD14(+) cells that are CD16 negative. Upon HIV infection, there was an additional increase in surface JAM-A and ALCAM on CD14(+)CD16(+) monocytes isolated from some individuals. Antibodies to ALCAM and JAM-A inhibited the transmigration of both HIV infected and uninfected CD14(+)CD16(+) monocytes across the BBB, demonstrating their importance in facilitating monocyte transmigration and entry into the brain parenchyma. Targeting CCR2, JAM-A, and ALCAM present on CD14(+)CD16(+) monocytes that preferentially infiltrate the CNS represents a therapeutic strategy to reduce viral seeding of the brain as well as the ongoing neuroinflammation that occurs during HIV pathogenesis.

There is controversy as to whether zidovudine (ZDV) induces a mitochondrial myopathy that is distinguishable from human immunodeficiency virus (HIV)-associated myopathy in ZDV-naive patients. Mitochondrial abnormalities were evaluated in skeletal muscle obtained from 18 HIV-positive, ZDV-exposed patients, and 9 who were drug naive. All patients had clinical myopathy, and underwent neuromuscular evaluation with information recorded on timing and dosage of ZDV. All underwent muscle biopsies and samples were examined without knowledge of clinical history or ZDV status. Biopsy samples were evaluated by light and electron microscopy. Mitochondrial abnormalities were seen in ZDV-treated and -naive groups, and did not correlate with ZDV exposure or cumulative ZDV dosage. Mitochondrial abnormalities displayed significant correlation with the presence and severity of myofiber degeneration on biopsy, regardless of ZDV status. As mitochondrial abnormalities reflect myofiber degeneration, present in both patient groups, they may not be used as evidence of primary mitochondrial dysfunction. The etiology of myofiber degeneration in patients with HIV infection, whether ZDV-exposed or -naive, remains unclear.

Background : During HAART, HIV RNA can be detectable (>50 cop/mL) in CSF when it is undetectable in plasma, a condition termed CSF viral escape (CVE). The aim of the current analysis was to determine the prevalence and risk factors for CVE in two large US cohorts. Methods : 1,264 volunteers enrolled in CHARTER or HNRP at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was undetectable while on stable HAART (>6 months) and if they had CSF collected. Potential risk factors were identified using univariable and multivariable analysis. Odds ratios for detected risk factors were calculated. Results : Mean age was 46 years, 82% were men, 70% had AIDS, 22% were HCV+, 49% were Caucasians, median CD4 nadir was 129, and 38% were cognitively impaired. CVE was present in 55 (4.35%) with a median HIV RNA in CSF of 155 (IQR 80-283). The table summarizes the main analysis results. CVE was associated with longer durations of HIV disease, higher platelet count, higher total serum protein, and higher CSF white blood cells (WBCs). CVE was also associated with treatment-associated factors, including use of boosted PIs and unboosted atazanavir. Conclusions: In this large, cross-sectional analysis, CVE was uncommon in subjects on effective HAART. A combination of disease and treatment factors were associated with CVE. The associations with higher levels of CSF WBCs, blood platelets, and serum total protein may reflect greater immune activation. Treatment with PI-based HAART was particularly associated with CVE, especially if unboosted atazanavir was part of the regimen. CVE was not associated with neurocognitive impairment. Prospective analyses are needed for better characterization of CVE. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Perez Valero I et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18189 http://www.jiasociety.org/index.php/jias/article/view/18189 | http://dx.doi.org/10.7448/IAS.15.6.18189

Author(s): Soontornniyomkij, Virawudh; Moore, David J; Gouaux, Ben; Soontornniyomkij, Benchawanna; Tatro, Erick T; Umlauf, Anya; Masliah, Eliezer; Levine, Andrew J; Singer, Elyse J; Vinters, Harry V; Gelman, Benjamin B; Morgello, Susan; Cherner, Mariana; Grant, Igor; Achim, Cristian L | Abstract: ObjectiveThe apolipoprotein E (APOE) e4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer's disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE e4 genotype and cerebral Aβ deposition.DesignClinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium.MethodsWe used multivariable logistic regressions to model outcomes [Aβ plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE e4 (allelic discrimination assay), older age (≥50 years), Aβ plaques, and their two-way interactions] and comorbid factors.ResultsIsocortical Aβ deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE e4 and older age were independently associated with the presence of Aβ plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 - 35.76 and 1.91-17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of Aβ plaques among APOE e4 carriers (adjusted OR 30.00, 95% CI 1.41-638.63, P = 0.029, n = 15), but not in non-e4 carriers (n = 57).ConclusionThe APOE e4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally, Aβ plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimer's disease brains. Nonetheless, Aβ plaques were associated with HAND among APOE e4 carriers. The detection of APOE e4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND patients who could benefit from Aβ-targeted therapies.

BACKGROUND Providers treating chronic pain must attempt to relieve suffering, while minimizing problematic prescription opioid use, including addiction and diversion. Previously described risk factors for problematic use include history of substance use, younger age, male sex, psychiatric comorbidity, and lower education level. METHODS We examined these risk factors in HIV-infected individuals, using cross-sectional and longitudinal data from the Manhattan HIV Brain Bank. Problematic use was defined as illicit substance use (documented by urine toxicology or structured psychiatric interview), while receiving prescription opioids. RESULTS Among 173 participants prescribed opioids, 62% had problematic use, the majority of which was discovered by urine toxicology. Problematic use was associated with past substance use, current psychiatric disorder, and poorer adherence to antiretrovirals. However, when participants without problematic use at baseline were followed longitudinally, these factors were not predictive. Furthermore, the cumulative incidence of problematic use behaviors was no greater than in a similar group of participants who were not prescribed opioids. CONCLUSIONS Problematic prescription opioid use is common among HIV-infected individuals and is associated with history of substance use, current psychiatric disorder, and poor adherence to antiretrovirals. However, these factors do not predict future problematic use in those who are not currently using illicit substances, and the prescription of an opioid does not seem to predispose patients toward a future substance use disorder. Rather than attempting to assess risk for problematic prescription opioid use in HIV-infected individuals, we recommend baseline and follow-up urine toxicology.

Background Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive impairment. While the cause remains unclear, recent gene expression studies have identified genes whose transcription is dysregulated in individuals with HIV-association neurocognitive disorder (HAND). However, the methods for interpretation of such data have lagged behind the technical advances allowing the decoding genetic material. Here, we employ systems biology methods novel to the field of NeuroAIDS to further interrogate extant transcriptome data derived from brains of HIV + patients in order to further elucidate the neuropathogenesis of HAND. Additionally, we compare these data to those derived from brains of individuals with Alzheimer’s disease (AD) in order to identify common pathways of neuropathogenesis. Methods In Study 1, using data from three brain regions in 6 HIV-seronegative and 15 HIV + cases, we first employed weighted gene co-expression network analysis (WGCNA) to further explore transcriptome networks specific to HAND with HIV-encephalitis (HIVE) and HAND without HIVE. We then used a symptomatic approach, employing standard expression analysis and WGCNA to identify networks associated with neurocognitive impairment (NCI), regardless of HIVE or HAND diagnosis. Finally, we examined the association between the CNS penetration effectiveness (CPE) of antiretroviral regimens and brain transcriptome. In Study 2, we identified common gene networks associated with NCI in both HIV and AD by correlating gene expression with pre-mortem neurocognitive functioning. Results Study 1: WGCNA largely corroborated findings from standard differential gene expression analyses, but also identified possible meta-networks composed of multiple gene ontology categories and oligodendrocyte dysfunction. Differential expression analysis identified hub genes highly correlated with NCI, including genes implicated in gliosis, inflammation, and dopaminergic tone. Enrichment analysis identified gene ontology categories that varied across the three brain regions, the most notable being downregulation of genes involved in mitochondrial functioning. Finally, WGCNA identified dysregulated networks associated with NCI, including oligodendrocyte and mitochondrial functioning. Study 2: Common gene networks dysregulated in relation to NCI in AD and HIV included mitochondrial genes, whereas upregulation of various cancer-related genes was found. Conclusions While under-powered, this study identified possible biologically-relevant networks correlated with NCI in HIV, and common networks shared with AD, opening new avenues for inquiry in the investigation of HAND neuropathogenesis. These results suggest that further interrogation of existing transcriptome data using systems biology methods can yield important information.

Despite the successes of combination antiretroviral therapy, HIV-associated neurocognitive disorders persist in many infected individuals. Earlier studies showed that neurocognitive impairment was associated with glutamate toxicity and synaptodendritic damage. We examined alterations in expression of four ephrin genes that are involved in synapse formation and recruitment of glutamate receptors to synapses, in the caudate and anterior cingulate in postmortem brain of cognitively characterized HIV-infected subjects, along with expression of neuronal and astroglial/macroglial markers. Postmortem tissues of HIV-infected and control subjects were obtained from the Manhattan HIV Brain Bank. HIV-infected subjects underwent neurocognitive assessment prior to death. Quantification of mRNA of genes of chemokine receptors and chemokines (CCR5, CXCR4, CCL2), astroglial/microglial markers (GFAP, CD163, CD68), the neuronal marker SNAP25, ephrin receptors EPHA4 and EPHB2, and ephrin ligands EFNB1 and EFNB2 was performed using SYBR Green RT-PCR. Proinflammatory chemokine and glial/macrophage mRNA levels in both regions were significantly greater in HIV+ than in HIV- subjects. Levels of EPHA4 and EFNB2 mRNA in the caudate, and EPHB2 mRNA in anterior cingulate were significantly lower in HIV+ subjects (p < 0.002, p < 0.02, p < 0.05, respectively). These transcripts also showed correlations with immune status and cognitive function within the HIV-infected group. Decreased levels of EFNB2 mRNA in the caudate correlated with lower CD4 counts (P < 0.05). Cognitive associations were limited to the cingulate, where decreased levels of EPHB2 mRNA were associated with better global cognitive status. Decreased cingulate expression of EPHB2 may represent a compensatory mechanism minimizing excitotoxic injury in the face of chronic inflammation.

To investigate the independent and interactive effects of opiate addiction and HIV on neuroinflammation, we measured microglial/macrophage activation and astrogliosis in multiple regions of human brain. Samples of thalamus, frontal gray matter, and frontal white matter were obtained from 46 individuals categorized as: HIV negatives, HIV-negative opiate addicts, HIV positives, HIV-positive opiate addicts, HIV encephalitis (HIVE), and HIVE opiate addicts. Activated brain microglia/macrophages and astrocytosis were quantified by morphometric analysis of immunohistochemical stains for CD68, HLA-D, CD163, and GFAP. The effects of HIV grouping, opiate addiction, and their interaction on expression of the markers were examined in a series of two-way ANOVAs. In opiate addicts, there was generally higher baseline expression of CD68 and HLA-D in HIV negatives, and lower expression in HIV and HIVE, compared to individuals without opiate abuse. Thus, for these markers, and for GFAP in frontal gray, opiates were associated with attenuated HIV effect. In contrast, for CD163, opiates did not significantly alter responses to HIV, and HIV effects were variably absent in individuals without opiate abuse. The divergent impact that opiate addiction displays on these markers may suggest a generally immunosuppressive role in the CNS, with decreased HIV-associated activation of markers CD68 and HLA-D that potentially reflect neurotoxic pathways, and preservation of CD163, thought to be an indicator of neuroprotective scavenger systems. These results suggest a complex impact of opiates on neuroinflammation in baseline and virally stimulated states.

Because HIV-related neurocognitive impairment is usually mild and variable, clinical ratings (CR) and global deficit scores (GDS) are recommended for detecting HIV-associated neurocognitive disorders (HAND). The CR approach requires impairment in at least two ability domains while the GDS considers number and severity of impairments across all measures. We examined classification agreement and clinical correlates of the two methods. Neurocognitive functioning of 1574 HIV-infected participants was assessed via a comprehensive, seven-domain neuropsychological battery. Global neurocognitive impairment was defined for each participant independently by CR and GDS. Participants were classified into four categories (Dually-normal, [impaired by] CR-only, [impaired by] GDS-only, or Dually-impaired). There was 83% concordance between CR and GDS classifications; in total, 56% of participants were deemed impaired by CR and 41% were classified as impaired by GDS. Impairment by GDS virtually guaranteed CR impairment, but 16% of participants were additionally classified as impaired only by CR. As compared to Dually-normal participants, those classified as Dually and CR-only impaired were more likely to have AIDS, have more severe co-occurring conditions, have more severe depressive symptoms, be unemployed, and have more everyday functioning complaints (ps