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Summary Background Few large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort. Methods We analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres—in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates. Findings At the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12–84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log10 copy per mL, 95% CI 11·3 to 28·8; p Interpretation The identified correlates of HIV RNA concentration in CSF during ART could strengthen clinical prediction of risk for failure to achieve or maintain HIV RNA suppression in CSF. Because most participants in this analysis were ART-experienced and were taking a three-drug regimen that did not include an integrase inhibitor, future research should focus on participants who are taking their first ART regimens or regimens that include integrase inhibitors or two drugs. Funding The work was supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

BACKGROUND: In clinical practice, calcifications seen on CT studies within the large brain arteries are often referred as a surrogate marker for cholesterol-mediated atherosclerosis. However, limited data exists to support the association between calcification and atherosclerosis. In this study, we examined if intracranial arterial calcifications were associated with cholesterol-mediated intracranial large artery atherosclerosis (ILAA) within the arteries of the Circle of Willis in an autopsy based sample. METHODS: We carried out a cross-sectional analysis of histopathological characteristics of brain large arteries obtained from autopsy cases. Brain large arteries were examined for evidences of calcifications, which were rated as macroscopic (coalescent) and microscopic (scattered). In addition to calcification, we also obtained measurement of the arterial wall and the presence of ILAA and non-atherosclerotic arterial fibrosis. We built hierarchical models adjusted for demographic and vascular risk factors to assess the relationship between calcification and ILAA. RESULTS: In univariate analysis, the presence of any arterial calcifications was associated with cerebral infarcts (29% v. 14%, p

Purpose HIV-associated autonomic neuropathy (HIV-AN) is common and may be associated with both sympathetic and parasympathetic dysfunction. Sympathetic nervous system (SNS) dysfunction occurs on a continuum of hyper-to hypo-adrenergic function, and may be a mediator between psychological stress and chronic inflammation. We sought to describe patterns of SNS dysfunction in people living with HIV, and to determine whether SNS dysfunction is associated with markers of systemic inflammation (focusing on IL-6 and TNF-α) and pain and anxiety. Methods Forty-seven people with well-controlled HIV and without confounding medical conditions or medications completed the Medical Outcomes Survey (MOS-HIV), quantification of a panel of 41 plasma cytokines/chemokines, and a standardized, non-invasive autonomic reflex screen (ARS). Adrenergic baroreflex sensitivity (BRSA) was calculated from the ARS as a measure of SNS function. Results Pain (46%) and anxiety (52%) were commonly reported on the MOS-HIV. BRSA was reduced in 30% of participants and elevated in 9% with the latter occurring only in participants with normal to mild HIV-AN. BRSA was significantly associated with IL-6, but not with TNF-α, pain or anxiety. Exploratory analyses also revealed positive associations of BRSA with numerous other cytokines with no significant inverse associations. Conclusion Higher BRSA, indicative of a more hyperadrenergic state, can be part of the spectrum of early HIV-AN, and may be associated with elevations in multiple cytokines including IL-6. These associations do not appear to be driven by stressors such as pain or anxiety., Highlights • Sympathetic dysfunction occurs as part of HIV-associated autonomic neuropathy. • Hypoadrenergic feature predominate, with some hyperadrenergic features early on. • Higher adrenergic baroreflex sensitivity is associated with increased IL-6. • This association is not influenced by pain or anxiety. • Adrenergic baroreflex sensitivity is also associated with many other cytokines.

This study examined the association between trauma exposure, PTSD, suicide attempts, and other psychopathology among 316 racially/ethnically diverse HIV-infected men and women who underwent semi-structured psychiatric assessment. In addition, the role of psychological resilience in trauma exposure was examined in the context of neurological symptoms and functional status. Nearly half (47.8%; 151/316) of the participants reported trauma exposure, of which 47.0% (71/151) developed PTSD. Among trauma-exposed individuals, those with a current psychiatric diagnosis reported more neurological symptoms and lower functional status. Trauma exposure without PTSD was associated with a higher rate of panic disorder and substance-induced mental disorders. Trauma-exposed individuals who did not develop PTSD were less likely than those who reported no trauma exposure to meet criteria for major depressive disorder (MDD). Trauma exposure, MDD, borderline personality disorder, and substance-induced mental disorders were independently associated with increased odds of suicide attempt. These results indicate that co-morbid psychiatric disorders are common among trauma exposed individuals with a history of PTSD, but those with trauma exposure who do not develop PTSD are less likely to experience MDD. The role of other co-morbid psychopathologies in the genesis of suicidal behavior among individuals living with HIV deserves further study.

It is hypothesized that outward remodeling in systemic arteries is a compensatory mechanism for lumen area preservation in the face of increasing arterial stenosis. Large brain arteries have also been studied, but it remains unproven if all assumptions about arterial remodeling can be replicated in the cerebral circulation.The sample included 196 autopsied subjects with a mean age of 55 years; 63 % were men, and 74 % non-Hispanic whites. From each of 1396 dissected cadaveric large arteries of the circle of Willis, the areas of the lumen, intima, media, and adventitia were measured. Internal elastic lamina (IEL) area was defined as the area encircled by this layer. Stenosis was calculated by dividing the plaque area by the IEL area and multiplying by 100.Plotting stenosis against lumen area or stratified by arterial size showed no preservation of the lumen in the setting of growing stenosis. We could not find an association between greater IEL proportion and stenosis (B = 0.44, P = 0.86). Stratifying arteries by their size, we found that smaller arteries have greater lumen reduction at any degree of stenosis (B = -23.65, P ≤ 0.0001), and although larger arteries show a positive association between IEL proportion and stenosis, this was no longer significant after adjusting for covariates (B = 6.0, P = 0.13).We cannot confirm the hypothesis that large brain arteries undergo outward remodeling as an adaptive response to increasing degrees of stenosis. We found that the lumen decreases proportionally to the degree of stenosis.

Objectives To test a strategy for minimizing ischemic spinal cord injury after extensive thoracoabdominal aneurysm (TAAA) repair, we occluded a small number of segmental arteries (SAs) endovascularly 1 week before simulated aneurysm repair in an experimental model. Methods Thirty juvenile Yorkshire pigs (25.2 ± 1.7 kg) were randomized into 3 groups. All SAs, both intercostal and lumbar, were killed by a combination of surgical ligation of the lumbar SAs and occlusion of intercostal SAs with thoracic endovascular stent grafting. Seven to 10 days before this simulated TAAA replacement, SAs in the lower thoracic/upper lumbar region were occluded using embolization coils: 1.5 ± 0.5 SAs in group 1 (T13/L1), and 4.5 ± 0.5 SAs in group 2 (T11-L3). No SAs were coiled in the controls. Hind limb function was evaluated blindly from daily videotapes using a modified Tarlov score (0 = paraplegia, 9 = full recovery). After death, each segment of spinal cord was graded histologically using the 9-point Kleinman score (0 = normal, 8 = complete necrosis). Results Hind limb function remained normal after coil embolization. After simulated TAAA repair, paraplegia occurred in 6 of 10 control pigs, but in only 2 of 10 pigs in group 1; no pigs in group 2 had a spinal cord injury. Tarlov scores were significantly better in group 2 (control vs group 1, P = .06; control vs group 2, P = .0002; group 1 vs group 2, P = .05). A dramatic reduction in histologic damage, most prominently in the coiled region, was seen when SAs were embolized before simulated TAAA repair. Conclusions Endovascular coiling of 2 to 4 SAs prevented paraplegia in an experimental model of extensive hybrid TAAA repair, and helped protect the spinal cord from ischemic histopathologic injury. A clinical trial in a selected patient population at high risk for postoperative spinal cord injury may be appropriate.

Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and 2 disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment.

Background: Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART). Method: Participants (n = 1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n = 981) were classified into five categories: 1) no thoughts of death or suicide (n = 352); 2) thoughts of death (n = 224); 3) thoughts of suicide (n = 99); 4) made a suicide plan (n = 102); and 5) attempted suicide (n = 204). Results: Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p < 0.0001), and higher rates of current major depressive disorder (p = 0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p = 0.02) and current use of psychotropic medications (p = 0.01) than non-attempters. Limitations: Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt. Conclusions: High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggest that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era. © 2011 Elsevier B.V. All rights reserved.

Of the 33 million people infected with the human immunodeficiency virus (HIV) worldwide, 40-60% of individuals will eventually develop neurocognitive sequelae that can be attributed to the presence of HIV-1 in the central nervous system (CNS) and its associated neuroinflammation despite antiretroviral therapy. PrP(C) (protease resistant protein, cellular isoform) is the nonpathological cellular isoform of the human prion protein that participates in many physiological processes that are disrupted during HIV-1 infection. However, its role in HIV-1 CNS disease is unknown. We demonstrate that PrP(C) is significantly increased in both the CNS of HIV-1-infected individuals with neurocognitive impairment and in SIV-infected macaques with encephalitis. PrP(C) is released into the cerebrospinal fluid, and its levels correlate with CNS compromise, suggesting it is a biomarker of HIV-associated neurocognitive impairment. We show that the chemokine (c-c Motif) Ligand-2 (CCL2) increases PrP(C) release from CNS cells, while HIV-1 infection alters PrP(C) release from peripheral blood mononuclear cells. Soluble PrP(C) mediates neuroinflammation by inducing astrocyte production of both CCL2 and interleukin 6. This report presents the first evidence that PrP(C) dysregulation occurs in cognitively impaired HIV-1-infected individuals and that PrP(C) participates in the pathogenesis of HIV-1-associated CNS disease.

HIV infection of the central nervous system results in neurological dysfunction in a large number of individuals. NeuroAIDS is characterized by neuronal injury and loss, yet there is no evidence of HIV-infected neurons. Neuronal damage and dropout must therefore be due to indirect effects of HIV infection of other central nervous system cells through elaboration of inflammatory factors and neurotoxic viral proteins, including the viral transactivator, tat. We previously demonstrated that HIV-tat-induced apoptosis in human primary neurons is dependent on N-methyl-d-aspartate receptor (NMDAR) activity. NMDAR activity is regulated by various mechanisms including NMDAR phosphorylation, which may lead to neuronal dysfunction and apoptosis in pathological conditions. We now demonstrate that tat treatment of human neurons results in tyrosine (Y) phosphorylation of the NMDAR subunit 2A (NR2A) in a src kinase–dependent manner. In vitro kinase assays and in vivo data indicated that NR2A Y1184, Y1325, and Y1425 are phosphorylated. Tat treatment of neuronal cultures enhanced phosphorylation of NR2A Y1325, indicating that this site is tat sensitive. Human brain tissue sections from HIV-infected individuals with encephalitis showed an increased phosphorylation of NR2A Y1325 in neurons as compared with uninfected and HIV-infected individuals without encephalitis. These findings suggest new avenues of treatment for HIV-associated cognitive impairment.

With prolonged survival and aging of the HIV-infected population in the era of antiretroviral therapy, biopsy series have found a broad spectrum of HIV-related and co-morbid kidney disease in these patients. Our study describes the variety of renal pathology found in a prospective cohort of antiretroviral-experienced patients (the Manhattan HIV Brain Bank) who had consented to postmortem organ donation. Nearly one-third of 89 kidney tissue donors had chronic kidney disease, and evidence of some renal pathology was found in 75. The most common diagnoses were arterionephrosclerosis, HIV-associated nephropathy and glomerulonephritis. Other diagnoses included pyelonephritis, interstitial nephritis, diabetic nephropathy, fungal infection and amyloidosis. Excluding 2 instances of acute tubular necrosis, slightly over one-third of the cases would have been predicted using current diagnostic criteria for chronic kidney disease. Based on semi-quantitative analysis of stored specimens, pre-mortem microalbuminuria testing could have identified an additional 12 cases. Future studies are needed to evaluate the cost-effectiveness of more sensitive methods for defining chronic kidney disease, in order to identify HIV-infected patients with early kidney disease who may benefit from antiretroviral therapy and other interventions known to delay disease progression and prevent complications.

Human immunodeficiency virus (HIV) infection is associated with accelerated atherosclerosis and vasculopathy, although the mechanisms underlying these findings have not been determined. Hypotheses for these observations include: 1) an increase in the prevalence of established cardiac risk factors observed in HIV-infected individuals who are currently experiencing longer life expectancies; 2) the dyslipidemia reported with certain HIV anti-retroviral therapies; and/or 3) the proinflammatory effects of infiltrating HIV-infected monocytes/macrophages. An unexplored possibility is whether HIV itself can infect vascular smooth muscle cells (SMCs) and, by doing so, whether SMCs can accelerate vascular disease. Our studies demonstrate that human SMCs can be infected with HIV both in vivo and in vitro. The HIV protein p24 was detected by fluorescence confocal microscopy in SMCs from tissue sections of human atherosclerotic plaques obtained from HIV-infected individuals. Human SMCs could also be infected in vitro with HIV by a mechanism dependent on CD4, the chemokine receptors CXCR4 or CCR5, and endocytosis, resulting in a marked increase in SMC secretion of the chemokine CCL2/MCP-1, which has been previously shown to be a critical mediator of atherosclerosis. In addition, SMC proliferation appeared concentric to the vessel lumen, and minimal inflammation was detected, unlike typical atherosclerosis. Our data suggest that direct infection of human arterial SMCs by HIV represents a potential mechanism in a multifactorial paradigm to explain the exacerbated atherosclerosis and vasculopathy reported in individuals infected with HIV.

Human immunodeficiency virus-associated distal-symmetric neuropathy (HIV-DSP) is the most common neurological complication of HIV infection. The pathophysiology of HIV-DSP is poorly understood and no treatment is available for this entity. The dorsal root ganglia (DRG) are the principal sites of neuronal damage and are associated with reactive mononuclear phagocytes as well as HIV-infected macrophages. To determine the role of HIV-infected macrophages in the pathogenesis of HIV-DSP, we developed a technique for culturing human DRG's. When the dissociated DRG neurons were exposed to supernatants from macrophages infected with CXCR4 or CCR5 tropic HIV-1 strains axonal retraction was observed without neuronal cell death but there was mitochondrial dysfunction in the neuronal cell body. Even though CXCR4 and CCR5 were expressed on the DRG neurons, the effects were independent of these receptors. Antioxidants rescued the neuronal cell body but not the axon from the toxic effects of the culture supernatants. Further, peripheral nerves of HIV-infected patients obtained at autopsy did not show evidence of increased oxidative stress. These observations suggest a differential effect on the axon and cell body. Different mechanisms of injury may be operative in these two structures.

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.

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.

Macrophages are essential for normal wound repair and many of their effects on healing wounds are likely to be mediated by the secretion of cytokines. This study examines the appearance of messenger RNA (mRNA) for cachectin/tumor necrosis factor (TNF), IL 1, and macrophage inflammatory proteins 1 and 2 (MIP-1 and MIP-2), as well as the mature peptides, in a model of wound healing using wound chambers. RNA for all four cytokines can be detected in wound inflammatory cells by polymerase chain reaction amplification throughout the first 7 days. Cachectin/TNF and IL 1 protein levels peaked on the first day after wound chamber implantation, and MIP-1 and MIP-2 were detected only on day 3. The data suggest that these cytokines participate in the early inflammatory response to wounding.