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Background: Cytomegalovirus (CMV) has been recognized as one of the frequently occurring opportunistic infections (OIs) reported in the patients having human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). In addition, it has been identified as the factor leading to gastrointestinal (GI) tract disorder among HIV/AIDS population. CMV exhibits broad cell tropism in different organs. This study evaluated the CMV cell tropism and clinicopathological characteristics of CMV infection in the different GI regions in HIV/AIDS cases., Methods: Using nucleic acid in situ hybridization (ISH), CMV was detected in the gastrointestinal mucosal biopsy samples. The paraffin-embedded samples were stained with hematoxylin and eosin (HE) and immunohistochemistry (IHC), respectively., Results: A total of 32 HIV/AIDS patients were enrolled in this study. Fourteen of these patients underwent gastroscopy, while the remaining eighteen received colonoscopy. CMV-infected cells were observed at 46 GI sites. Among them, the colon was the region with the highest susceptibility to GI CMV infection (n = 12, 26.1%). The CMV giant cell inclusion bodies were detected in epithelial cells and mesenchymal cells, including histiocytes, smooth muscle cells, fibroblasts, and endothelial cells. In the duodenum, there were markedly more positive epithelial cells than mesenchymal cells (p = 0.033). In contrast, in the esophagus (p = 0.030), cardia (p = 0.003), rectum (p = 0.019), colon (p < 0.001), and cecum (p < 0.001), there were notably less positive epithelial cells than mesenchymal cells. The expression levels of PDGFRα and Nrp2 in the mesenchymal cells were higher than the epithelial cells in cardia, cecum, colon, sigmoid, and rectum, especially in the areas with ulcers. However, Nrp2 in the epithelial cells was higher than that in the duodenum. Moreover, the positive CMV DNA in peripheral blood was related to the CMV-positive cell count, as well as the ulceration in GI tract (p = 0.035 and 0.036, respectively)., Conclusions: The colon has been identified as the GI site with the highest susceptibility to CMV infection. There are different CMV-infected cells in the different sites of the GI that relate to the expression level of PDGFRα and Nrp2. CMV DNA positive in the blood is related to the positive CMV cell count, as well as ulceration in the GI tract., (© 2022. The Author(s).)

Tuberculosis (TB) is the leading cause of death among HIV-1-infected individuals and Mycobacterium tuberculosis ( Mtb ) co-infection is an early precipitate to AIDS. We aimed to determine whether Mtb strains differentially modulate cellular susceptibility to HIV-1 infection ( cis - and trans -infection), via surface receptor interaction by their cell envelope lipids. Total lipids from pathogenic (lineage 4 Mtb H37Rv, CDC1551 and lineage 2 Mtb HN878, EU127) and non-pathogenic ( Mycobacterium bovis BCG and Mycobacterium smegmatis ) Mycobacterium strains were integrated into liposomes mimicking the lipid distribution and antigen accessibility of the mycobacterial cell wall. The resulting liposomes were tested for modulating in vitro HIV-1 cis - and trans -infection of TZM-bl cells using single-cycle infectious virus particles. Mtb glycolipids did not affect HIV-1 direct infection however, trans -infection of both R5 and X4 tropic HIV-1 strains were impaired in the presence of glycolipids from M. bovis , Mtb H37Rv and Mtb EU127 strains when using Raji-DC-SIGN cells or immature and mature dendritic cells (DCs) to capture virus. SL1, PDIM and TDM lipids were identified to be involved in DC-SIGN recognition and impairment of HIV-1 trans -infection. These findings indicate that variant strains of Mtb have differential effect on HIV-1 trans -infection with the potential to influence HIV-1 disease course in co-infected individuals.

HIV-1 compartmentalization in reservoir sites remains a barrier to complete HIV eradication. It is unclear whether there is variation in HIV-1 env and gag between cerebrospinal fluid (CSF) and plasma of individuals with HIV-associated cryptococcal meningitis (CM). We compared HIV-1 env characteristics and the gag cytotoxic T-lymphocyte (CTL) escape mutations from CSF and plasma samples. Employing population-based Sanger sequencing, we sequenced HIV-1 env from CSF of 25 patients and plasma of 26 patients. For gag , 15 CSF and 21 plasma samples were successfully sequenced. Of these, 18 and 9 were paired env and gag CSF/plasma samples, respectively. There was no statistically significant difference in the proportion of CCR5-using strains in the CSF and plasma, ( p = 0.50). Discordant CSF/plasma virus co-receptor use was found in 2/18 pairs (11.1%). The polymorphisms in the HIV-1 V3 loop were concordant between the two compartments. From the HIV-1 gag sequences, three pairs had discordant CTL escape mutations in three different epitopes of the nine analyzed. These findings suggest little variation in the HIV-1 env between plasma and CSF and that the CCR5-using strains predominate in both compartments. HIV-1 gag CTL escape mutations also displayed little variation in CSF and plasma suggesting similar CTL selective pressure.

Introduction: Contrasting findings have been published regarding the effect of human immunodeficiency virus (HIV) on tuberculosis (TB) drug pharmacokinetics (PK)., Objectives: The aim of this systematic review was to investigate the effect of HIV infection on the PK of the first-line TB drugs (FLDs) rifampicin, isoniazid, pyrazinamide and ethambutol by assessing all published literature., Methods: Searches were performed in MEDLINE (through PubMed) and EMBASE to find original studies evaluating the effect of HIV infection on the PK of FLDs. The included studies were assessed for bias and clinical relevance. PK data were extracted to provide insight into the difference of FLD PK between HIV-positive and HIV-negative TB patients. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and its protocol was registered at PROSPERO (registration number CRD42017067250)., Results: Overall, 27 studies were eligible for inclusion. The available studies provide a heterogeneous dataset from which consistent results could not be obtained. In both HIV-positive and HIV-negative TB groups, rifampicin (13 of 15) and ethambutol (4 of 8) peak concentration (C max ) often did not achieve the minimum reference values. More than half of the studies (11 of 20) that included both HIV-positive and HIV-negative TB groups showed statistically significantly altered FLD area under the concentration-time curve and/or C max for at least one FLD., Conclusions: HIV infection may be one of several factors that reduce FLD exposure. We could not make general recommendations with respect to the role of dosing. There is a need for consistent and homogeneous studies to be conducted.

Objectives: To observe relationships between oral Candida status and salivary human beta-defensin 2 and 3 (hBD-2 and hBD-3) levels in HIV/AIDS patients of Guangxi, China during the first year of antiretroviral therapy (ART) dynamically, and to understand the influence of ART on oral Candida status and salivary hBDs expressions., Methods: A prospective self-controlled study was carried to observe the dynamic changes of CD4 + T cell counts, oral Candida carriages and salivary hBD-2,3 expressions in HIV/AIDS patients during the first year of ART. A total of 90 HIV/AIDS patients were enrolled and were examined at the baseline, 3rd, 6th, 12th month of ART. Thirty healthy individuals were enrolled as control. Peripheral blood, oral rinse sample, and unstimulated whole saliva were collected to test CD4 + T cell counts, oral Candida carriages, and hBD-2,3 expressions., Results: In the first year of ART, CD4 + T cell counts increased significantly. However, oral Candida carriages and oral candidiasis decreased significantly, and salivary hBD-2 expressions in HIV/AIDS patients decreased gradually, salivary hBD-3 levels were highly variable. Salivary hBD-2 concentrations were positively related to oral Candida carriages., Conclusions: The incidence of oral candidiasis among HIV/AIDS patients gradually decreased due to the immune reconstruction of ART. Salivary defensins might play an important role in Candida-host interaction in HIV/AIDS patients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Background: Tuberculosis (TB) is the major cause of death in Human Immunodeficiency Virus (HIV)-infected individuals. However, diagnosis of TB in HIV remains challenging particularly when HIV infection is advanced. Several gene signatures and serum protein biomarkers have been identified that distinguish active TB from latent infection. Our study was designed to assess if gene expression signatures and cytokine levels would distinguish active TB in advanced HIV., Methods: We conducted a case-control study of whole blood RNA-Seq and plasma cytokine/chemokine analysis in HIV-infected with CD4 + T cell count of ≤ 100 cells/μl, with and without active TB. Next, the overlap of the differentially expressed genes (DEG) with the published signatures was performed and then receiver operator characteristic (ROC) analysis was done on small gene discriminators to determine their performance in distinguishing TB in advanced HIV. ELISA was performed on plasma to evaluate cytokine and chemokine levels., Results: Hierarchical clustering of the transcriptional profiles showed that, in general, HIV-infected individuals with TB (TB-HIV) clustered separately from those without TB. IPA indicated that the TB-HIV signature was characterized by an increase in inflammatory signaling pathways. Analysis of overlaps between DEG in our data set with published TB signatures revealed that significant overlap was seen with one TB signature and one TB-IRIS signature. ROC analysis revealed that transcript levels of FcGR1A (AUC = 0.85) and BATF2 (AUC = 0.82), previously reported as consistent single gene classifiers of active TB irrespective of HIV status, performed successfully even in advanced HIV. Plasma protein levels of IFNγ, a stimulator of FcGR1A and BATF2, and CXCL10, also up-regulated by IFNγ, accurately classified active TB (AUC = 0.98 and 0.91, respectively) in advanced HIV. Neither of these genes nor proteins distinguished between TB and TB-IRIS., Conclusions: Gene expression of FcGR1A and BATF2, and plasma protein levels of IFNγ and CXCL10 have the potential to independently detect TB in advanced HIV. However, since other lung diseases were not included in this study, these final candidates need to be validated as specific to TB in the advanced HIV population with TB.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS). It is endemic in a number of sub-Saharan African countries with infection rate of >50%. The high prevalence of HIV-1 coupled with late presentation of advanced cancer staging make KS the leading cancer in the region with poor prognosis and high mortality. Disease markers and cellular functions associated with KS tumorigenesis remain ill-defined. Several studies have attempted to investigate changes of the gene profile with in vitro infection of monoculture models, which are not likely to reflect the cellular complexity of the in vivo lesion environment. Our approach is to characterize and compare the gene expression profile in KS lesions versus non-cancer tissues from the same individual. Such comparisons could identify pathways critical for KS formation and maintenance. This is the first study that utilized high throughput RNA-seq to characterize the viral and cellular transcriptome in tumor and non-cancer biopsies of African epidemic KS patients. These patients were treated anti-retroviral therapy with undetectable HIV-1 plasma viral load. We found remarkable variability in the viral transcriptome among these patients, with viral latency and immune modulation genes most abundantly expressed. The presence of KSHV also significantly affected the cellular transcriptome profile. Specifically, genes involved in lipid and glucose metabolism disorder pathways were substantially affected. Moreover, infiltration of immune cells into the tumor did not prevent KS formation, suggesting some functional deficits of these cells. Lastly, we found only minimal overlaps between our in vivo cellular transcriptome dataset with those from in vitro studies, reflecting the limitation of in vitro models in representing tumor lesions. These findings could lead to the identification of diagnostic and therapeutic markers for KS, and will provide bases for further mechanistic studies on the functions of both viral and cellular genes that are involved.

HIV- and highly active antiretroviral therapy (HAART)-associated elevations in oxidative stress likely play a role in incomplete immune reconstitution, opportunistic infections and non-AIDS co-morbidities. We aimed to test the hypothesis that children living with HIV exhibit elevated markers of oxidative stress and reduced antioxidant profiles and that HAART-therapy will exacerbate these differences. HIV-positive HAART-naïve (n = 50) and HAART-treated (n = 50) and HIV-negative control (n = 50) participants, 3-15 years of age, were recruited from Black Lion Hospital in Ethiopia. Serum malondialdehyde (MDA) and bilirubin were higher and vitamin C and zinc were lower in HAART-naïve and HAART-treated compared with HIV-negative subjects and higher in HAART-treated compared with HAART-naïve subjects. Uric acid was higher in HAART-naïve compared with HAART-treated and HIV-negative subjects. Differences in MDA and several antioxidants were also observed across treatment regimens. Thus, children living with HIV exhibited systemic elevations in oxidative stress and reduction in antioxidants, which are exacerbated with HAART therapy., (© The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Opportunistic infections (OIs) are common among human immunodeficiency virus (HIV) patients; however, genetic susceptibility to these infections has not been studied. Recent studies have shown that interleukin-8 (IL-8) A/T genotype carriers are more susceptible to a variety of diseases. In this study, we showed the effects of IL-8 gene polymorphisms on OIs and symptoms such as sexually transmitted diseases (STDs), tuberculosis (TB), diarrhea, shortness of breath, weight loss, and viral load, in HIV and acquired immunodeficiency syndrome patients. Genomic DNA was purified from mouthwash samples collected from patients attending HIV centers in the Vhembe district. The IL-8 (-251) A/T locus was genotyped using allele-specific polymerase chain reaction followed by agarose gel electrophoresis. The results showed a weak association between the IL-8 AA genotype and OIs such as STDs (P = 0.143), diarrhea (P = 0.906), and TB (P = 0.762). Significant associations were found between the IL-8 AT genotype and weight loss (P = 0.019), shortness of breath (P = 0.043), and skin problems (P = 0.003). Low viral load was also found to be significantly associated with IL-8 AA genotype (P = 0.009). The present study suggests that different IL-8 genotypes are associated with resistance to various OIs. However, further studies using larger samples sizes are needed to confirm this hypothesis.

Positron emission tomography (PET) has been used to aid in diagnosis of inflammatory and infectious disease. We describe the case of a patient with early latent syphilis with increased metabolic activity along the aorta detected via PET, suggesting probable aortitis. Three months after treatment, the PET showed apparent resolution of the aortitis.

Mycobacterium tuberculosis (Mtb) is the most common co-infection in HIV patients and a serious co-epidemic. Apart from increasing the risk of reactivation of latent tuberculosis (TB), HIV infection also permits opportunistic infection of environmental non-pathogenic mycobacteria. To gain insights into mycobacterial survival inside host macrophages and identify mycobacterial proteins or processes that influence HIV propagation during co-infection, we employed proteomics approach to identify differentially expressed intracellular mycobacterial proteins during mono- and HIV co-infection of human THP-1 derived macrophage cell lines. Of the 92 proteins identified, 30 proteins were upregulated during mycobacterial mono-infection and 40 proteins during HIV-mycobacteria co-infection. We observed down-regulation of toxin-antitoxin (TA) modules, up-regulation of cation transporters, Type VII (Esx) secretion systems, proteins involved in cell wall lipid or protein metabolism, glyoxalate pathway and branched chain amino-acid synthesis during co-infection. The bearings of these mycobacterial factors or processes on HIV propagation during co-infection, as inferred from the proteomics data, were validated using deletion mutants of mycobacteria. The analyses revealed mycobacterial factors that possibly via modulating the host environment, increased viral titers during co-infection. The study provides new leads for investigations towards hitherto unknown molecular mechanisms explaining HIV-mycobacteria synergism, helping address diagnostics and treatment challenges for effective co-epidemic management.

Antiretroviral therapy (ART) has led to dramatic improvements in the lives of HIV-infected persons. However, residual immune activation, which persists despite ART, is associated with increased risk of non-AIDS morbidities. Accumulating evidence shows that disruption of the gut mucosal epithelium during SIV/HIV infections allows translocation of microbial products into the circulation, triggering immune activation. This disruption is due to immune, structural and microbial alterations. In this review, we highlighted the key findings of gut mucosa studies of SIV-infected macaques and HIV-infected humans that have revealed virus-induced changes of intestinal CD4, CD8 T cells, innate lymphoid cells, myeloid cells, and of the local cytokine/chemokine network in addition to epithelial injuries. We review the interplay between the host immune response and the intestinal microbiota, which also impacts disease progression. Collectively, these studies have instructed clinical research on early ART initiation, modifiers of microbiota composition, and recombinant cytokines for restoring gut barrier integrity.

Background: Other than Kaposi sarcoma (KS)-associated herpesvirus and CD4 T-cell lymphopenia, the mechanisms responsible for KS in the context of HIV are poorly understood. One recently explored pathway of HIV pathogenesis involves induction of the enzyme indoleamine 2,3-dioxygenase-1 (IDO), which catabolizes tryptophan into kynurenine and several other immunologically active metabolites that suppress T-cell proliferation. We investigated the role of IDO in the development of KS in HIV disease., Methods: In a case-control study among untreated HIV-infected Ugandans, cases were adults with KS and controls were without KS. IDO activity was assessed by the ratio of plasma kynurenine to tryptophan levels (KT ratio), measured by liquid chromatography-tandem mass spectrometry., Results: We studied 631 HIV-infected subjects: 222 KS cases and 409 controls. Non-KS controls had a higher median plasma KT ratio (130, interquartile range: 90 to 190 nM/μM) than KS cases (110, interquartile range: 90 to 150 nM/μM) (P = 0.004). After adjustment for age, sex, CD4 count, and plasma HIV RNA level, subjects with the highest (fourth quartile) plasma KT ratios had a 59% reduction (95% confidence interval: 27% to 77%) in the odds of KS compared with those with the lowest (first quartile) levels. KS was also independently associated with lower CD4 count, higher plasma HIV RNA, and men., Conclusions: Among HIV-infected individuals, greater activity of the kynurenine pathway of tryptophan catabolism, as evidenced by higher levels of plasma KT ratio, was associated with lower occurrence of KS. Some consequences of immune activation in HIV infection might actually suppress certain cancers.

γδ T cells expressing the Vδ1 TCR are expanded in patients with HIV infection. We show in this article that circulating Vδ1 T cell numbers are particularly high in patients with HIV and candidiasis, and that these cells expand and produce IL-17 in response to Candida albicans in vitro. Although C. albicans could directly stimulate IL-17 production by a subset of Vδ1 T cells, fungus-treated dendritic cells (DCs) were required to expand C. albicans-responsive Vδ1 T cells to generate sufficient numbers of cells to release IL-17 at levels detectable by ELISA. C. albicans induced the release of IL-1β, IL-6, and IL-23 by DCs, but addition of these cytokines or supernatants of C. albicans-treated DCs to Vδ1 T cells was not sufficient to induce proliferation. We found that direct contact with DCs was required for Vδ1 T cell proliferation, whereas IL-23R-blocking studies showed that IL-23 was required for optimal C. albicans-induced IL-17 production. Because IL-17 affords protection against both HIV and C. albicans, and because Vδ1 T cells are not depleted by HIV, these cells are likely to be an important source of IL-17 in HIV-infected patients with candidiasis, in whom CD4(+) Th17 responses are impaired. These data show that C. albicans stimulates proliferation and IL-17 production by Vδ1 T cells by a mechanism that involves IL-23 release by DCs., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Background: Cell-mediated immunity plays a crucial role in resistance to intracellular infection. We previously reported antibodies against interferon-gamma (IFN-γ) in HIV- negative (HIV-) patients with acquired immunodeficiency presenting with repeated episodes of disseminated infection caused by uncommon opportunistic intracellular fungal, bacterial, and viral pathogens. This follow-up study aimed to investigate cellular immune responses in these unusual patients., Methods: Twenty HIV- patients presenting with ≥2 episodes of culture- or histopathologic-proven opportunistic infections were enrolled along with age- and sex-matched controls comprised of 20 HIV+ patients plus 20 healthy adults. Monocyte phenotyping and intracellular cytokine production were determined by staining with specific antibodies followed by flow cytometry. Anti-interferon-γ antibodies were measured by enzyme-linked immunosorbent assay, and inducible nitric oxide synthase by reverse-transcription polymerase chain reaction., Results: There were no differences among cases, HIV+, and healthy controls in the percentage of monocytes, or CD68 and HLA-DR expression on their surfaces. FcR1 (CD119) expression on monocytes was significantly higher in cases than in HIV+ (p<0.05) and healthy controls (p<0.01), suggesting the presence of activated monocytes in the circulation. Interleukin (IL)-2 and tumor necrosis factor (TNF)-α production in CD4 cells were significantly lower in cases than in healthy controls (p<0.01 and p<0.001, respectively). CD8 production of TNF-α among cases was significantly lower than that of healthy controls (p<0.05)., Conclusion: Immunodeficiency in HIV- individuals with repeated infections with intracellular pathogens may be associated with one or more of the abnormal immune responses reflected by the reduced production of both IL-2 by CD4 T cells and TNF-α by CD4 T cells and CD8 T cells, as well as presence of anti-IFN-γ antibody, as previously reported.

The increase in immunosuppressed patient populations has correlated with a rise in clinical fungal infections, including cryptococcosis. Patient outcome following Cryptococcus infection is linked to initial fungal burden in cerebrospinal fluid (CSF) and fungal clearance following treatment; however, the role of the pathogen in disease prognosis is poorly defined. In this issue of the JCI, Sabiiti and colleagues have directly correlated phenotypic traits of Cryptococcus neoformans with clinical outcome of infected patients. A better understanding of both the host and pathogen contributions to disease etiology will provide more options for targeted treatment strategies.

Background: Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis., Methods: Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis., Results: High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003)., Conclusion: These findings underscore the contribution of cryptococcal-phagocyte interactions and laccase-dependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM., Funding: This work was made possible by funding from the Wellcome Trust (WT088148MF), the Medical Research Council (MR/J008176/1), the NIHR Surgical Reconstruction and Microbiology Research Centre and the Lister Institute for Preventive Medicine (to R.C. May), and a Wellcome Trust Intermediate fellowship (089966, to T. Bicanic). The C. neoformans isolates were collected within clinical trials funded by the British Infection Society (fellowship to T. Bicanic), the Wellcome Trust (research training fellowships WT069991, to A.E. Brouwer and WT081794, to J.N. Jarvis), and the Medical Research Council, United Kingdom (76201). The funding sources had no role in the design or conduct of this study, nor in preparation of the manuscript.

Galactofuranose (Galf) is the five-membered ring form of galactose. Although it is absent from mammalian glycans, it occurs as a structural and antigenic component of important cell surface molecules in a variety of microbes, ranging from bacteria to parasites and fungi. One such organism is Cryptococcus neoformans, a pathogenic yeast that causes lethal meningoencephalitis in immunocompromised individuals, particularly AIDS patients. C. neoformans is unique among fungal pathogens in bearing a complex polysaccharide capsule, a critical virulence factor reported to include Galf. Notably, how Galf modification contributes to the structure and function of the cryptococcal capsule is not known. We have determined that Galf is β1,2-linked to an unusual tetrasubstituted galactopyranose of the glucuronoxylomannogalactan (GXMGal) capsule polysaccharide. This discovery fills a longstanding gap in our understanding of a major polymer of the cryptococcal capsule. We also engineered a C. neoformans strain that lacks UDP-galactopyranose mutase; this enzyme forms UDP-Galf, the nucleotide sugar donor required for Galf addition. Mutase activity was required for the incorporation of Galf into glucuronoxylomannogalactan but was dispensable for vegetative growth, cell integrity, and virulence in a mouse model.

Kaposi sarcoma (KS) is a low-grade vascular tumor associated with Kaposi sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) infection. Kaposi sarcoma lesions predominantly present at mucocutaneous sites, but may involve all organs and anatomic locations. Recognized epidemiologic-clinical forms of KS include classic, African (endemic), AIDS-associated (epidemic), and iatrogenic KS. New clinical manifestations have been described, such as antiretroviral therapy-related KS regression or flares. Kaposi sarcoma lesions evolve from early (patch stage) macules into plaques (plaque stage) that grow into larger nodules (tumor stage). Newer histologic variants include anaplastic, hyperkeratotic, lymphangioma-like, bullous, telangiectatic, ecchymotic, keloidal, pyogenic granuloma-like, micronodular, intravascular, glomeruloid and pigmented KS, as well as KS with sarcoidlike granulomas and KS with myoid nodules. Latency-associated nuclear antigen (HHV8) is the most specific immunohistochemical marker available to help distinguish KS from its mimics. Since KS remains one of the most common AIDS-defining malignancies, it is important that pathologists be able to recognize KS and its contemporary manifestations.

Drug abuse and HIV infection are interlinked. From the onset of the HIV/AIDS epidemic, the impact of illicit drug use on HIV disease progression has been a focus of many investigations. Both laboratory-based and epidemiological studies strongly indicate that drug abuse may exacerbate HIV disease progression and increase mortality and morbidity in these patients. Increase susceptibility to opportunistic infection has been implicated as one of the major causes for this detriment. Furthermore, opioids are known to elicit prevalence of neurodegenerative disorders in HIV-infected patients. Numerous authors have delineated various molecular as well as cellular mechanisms associated with neurological complications in these patients. This review gives an overview of these findings. Understanding the mechanisms will allow for the development of targeted therapies aimed at reducing the progression of neurocognitive decline in the drug abusing HIV infected individuals.

Molluscum contagiosum is a cutaneous poxviral infection that is rarely associated with other skin diseases, such as cutaneous neoplasms. Such associations are likely to be coincidental, except in immunocompromised patients. Kaposi sarcoma, an angioproliferative neoplasm derived from lymphatic endothelium, is mediated by human herpes virus-8 infection and occurs with increased frequency in immunocompromised individuals. We report an unusual case of molluscum contagiosum with underlying cutaneous Kaposi sarcoma diagnosed in a single skin biopsy of a human immunodeficiency virus-positive patient. Our case highlights the importance of adequate sampling to avoid missing secondary diagnoses in histopathologic sections and alerts pathologists and dermatologists to the possibility of coinfection in high-risk patients by 2 virally-mediated skin conditions.

Introduction: Among opportunistic pathogens associated with acquired immunodeficiency syndrome (AIDS), Mycobacterium tuberculosis is distinguished by its relative virulence and potential for person-to-person transmission. Oxidative stress is associated with TB infection with a high level in patients with HIV-TB co-infection. However, the comparative level of oxidative stress in HIV patients on highly active anti-retroviral therapy (HAART) and naïve (untreated) HIV patients is not clear., Methodology: This study is aimed to determine the level of oxidative stress and haematological parameters in HIV patients (naïve), HIV patients undergoing HAART, and HIV-TB co-infected patients. In total, 100 consenting subjects were recruited from the AIDS Prevention Iniative in Nigeria (APIN) Clinic. For controls, normal male healthy volunteers were recruited from the blood donor clinic and females from the APIN clinic staff members, both of the Lagos University Teaching Hospital. Measurements of antioxidant enzyme activity and lipid peroxidation were performed according to standard procedures. Haematological parameters were determined using a fully automated hematology analyzer., Results: Red blood cells significantly decreased (P ≤ 0.001) in all patients when compared with control subjects. The lipid peroxidation (MDA) was significantly high (P ≤ 0.05) in naive patients when compared to HIV patients on HAART. The decrease in the levels of GSH in both naive and HIV-TB co-infected patients (P ≤ 0.001) and HIV patients on HAART (P < 0.05) were significant when compared to control patients., Conclusion: There is lower antioxidant level and higher MDA in naive and HIV-TB co-infected patients as compared to HIV patients on HAART and the seronegative patients.

Pegylated liposomal doxorubicin (Caelyx™, Doxil®) represents an improved formulation of conventional doxorubicin, with reduced cardiotoxicity and an improved pharmacokinetic profile. This article reviews the efficacy and tolerability of pegylated liposomal doxorubicin in metastatic breast cancer, progressive ovarian cancer, relapsed or refractory multiple myeloma and AIDS-related Kaposi's sarcoma, as well as summarizing its pharmacological properties. In three randomized, open-label, multicentre trials, monotherapy with pegylated liposomal doxorubicin was as effective as doxorubicin or capecitabine in the first-line treatment of metastatic breast cancer, and as effective as vinorelbine or combination mitomycin plus vinblastine in taxane-refractory metastatic breast cancer. Pegylated liposomal doxorubicin alone was as effective as topotecan or gemcitabine alone in patients with progressive ovarian cancer resistant or refractory to platinum- or paclitaxel-based therapy, according to the results of three randomized multicentre trials. In addition, in patients with progressive ovarian cancer who had received prior platinum-based therapy, progression-free survival was significantly longer with pegylated liposomal doxorubicin plus carboplatin than with paclitaxel plus carboplatin, according to the results of a randomized, open-label multicentre trial. Combination therapy with pegylated liposomal doxorubicin plus bortezomib was more effective than bortezomib alone in patients with relapsed or refractory multiple myeloma, according to the results of a randomized, open-label, multinational trial. Randomized multinational trials also demonstrated the efficacy of pegylated liposomal doxorubicin in patients with advanced AIDS-related Kaposi's sarcoma. Pegylated liposomal doxorubicin exhibited a relatively favourable safety profile compared with conventional doxorubicin and other available chemotherapy agents. The most common treatment-related adverse events included myelosuppression, palmar-plantar erythrodysesthesia and stomatitis, although these are manageable with appropriate supportive measures. To conclude, pegylated liposomal doxorubicin is a useful option in the treatment of various malignancies, including metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma.

Energy intake recommendations for adults should be based preferably on direct measurements of total daily energy expenditure (TDEE) in corresponding populations who are maintaining healthy body weight and satisfactory physical activity levels. During adolescence, pregnancy, and lactation, energy requirements should be based on TDEE plus the additional energy required to advance these physiologic states. With illness, energy expenditure and energy intake change, but nutritional intervention is not necessarily beneficial. This article reviews data on energy expenditure in HIV infection with a focus on adults, adolescents aged ≥14 y, and pregnant and lactating women. Resting energy expenditure (REE) in adults with untreated asymptomatic HIV is ~ 10% higher than in healthy control subjects. In asymptomatic adults receiving antiretroviral therapy, REE may be similarly increased. HIV wasting and secondary infections are also associated with increased REE. In contrast, TDEE is typically normal in asymptomatic HIV and decreased in HIV wasting and secondary infection. No direct measurements of REE or TDEE are available in adolescents or in pregnant or lactating women with HIV. On the basis of current data, energy intake may need to increase by ~ 10% in adults with asymptomatic HIV to maintain body weight. In adolescents and in pregnant and lactating women with asymptomatic HIV, energy requirements should approximate recommendations for their uninfected counterparts until further data are available. In the resource-rich world, the energy expenditure changes associated with HIV are unlikely to contribute to significant weight loss. More data are needed on energy expenditure in HIV-infected populations from developing nations, where concurrent malnutrition and coinfections are common.

Introduction: To describe 2 unusual cases of hypercalcemia due to granulomatous diseases with normal vitamin D metabolites and no other ready explanation for the hypercalcemia., Methods: We present the clinical, laboratory and pathologic findings of 2 patients with hypercalcemia and review previous reports of hypercalcemia in granulomatous diseases without elevated vitamin D metabolites., Results: Hypercalcemia was described in various granulomatous diseases including sarcoidosis, tuberculosis, berylliosis, leprosy and, rarely, in fungal infections. Elevated serum level of vitamin D or its metabolites was linked to the pathogenesis of hypercalcemia in these disorders. The authors present the clinical, laboratory and pathologic findings in 2 patients who presented with hypercalcemia and normal vitamin D metabolites with no other ready explanation for the hypercalcemia. The first patient was diagnosed with Mycobacterium avium, whereas the second patient was found to have sarcoidosis., Conclusion: Although hypercalcemia in granulomatous diseases has been attributed to be mediated by elevated vitamin D metabolites, there have been several case reports that documented normal values of active vitamin D metabolites. This report illustrates the regulatory feedback mechanisms of vitamin D synthesis and introduces the term "inappropriately normal" vitamin D metabolites levels in light of low levels of parathyroid hormone.

Background: In the SMART study, HIV-viral-hepatitis-coinfected persons were, compared with HIV-monoinfected persons, at higher risk of non-AIDS death if randomized to the antiretroviral therapy (ART) interruption strategy. We hypothesized that a marker of liver fibrosis, hyaluronic acid (HA), would be predictive of development of non-AIDS-related outcomes in coinfected participants in the SMART study., Methods: All participants positive for HCV RNA or hepatitis B surface antigen (HBsAg) and with stored plasma samples were included (n=675). Plasma samples were tested for HA (normal range 0-75 ng/ml) at baseline and months 6, 12 and 24 during follow-up in the drug conservation (DC; interrupt ART until CD4(+) T-cell count <250) group and the viral suppression (VS; continued use of ART) group. Time to non-AIDS death was investigated using Kaplan-Meier analysis., Results: Overall, 52 (31 in DC and 21 in VS) coinfected participants died during follow-up. Coinfected participants who were randomized to the DC group with baseline HA>75 ng/ml had a cumulative risk of non-AIDS death of 24.6% after 36 months of follow-up compared with 9.3% for participants randomized to the VS group (P=0.005), while the cumulative risk for coinfected participants with HA ≤ 75 ng/ml was 4.1% (DC) and 4.7% (VS; P=0.76). The change in HA from baseline to month 24 was 8.3 ng/ml and 4.7 ng/ml in the DC and VS group (P=0.56), respectively., Conclusions: Interruption of ART was particularly unsafe in HIV-hepatitis-coinfected individuals if plasma HA was increased. HA changed very little during follow-up and was not influenced by differences in CD4(+) T-cell count or HIV viral load.

Purpose: The population pharmacokinetics (PK) of lopinavir in tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected South African children taking super-boosted lopinavir (lopinavir/ritonavir ratio 1:1) as part of antiretroviral treatment in the presence of rifampicin were compared with the population PK of lopinavir in HIV-infected South African children taking standard doses of lopinavir/ritonavir (ratio 4:1)., Methods: Lopinavir concentrations were measured in 15 TB/HIV-co-infected paediatric patients who were sampled during and after rifampicin-based TB treatment and in 15 HIV-infected children without TB. During TB therapy, the dose of ritonavir was increased to lopinavir/ritonavir 1:1 in order to compensate for the induction of rifampicin. The children received median (interquartile range=IQR) doses of lopinavir 292 mg/m(2) (274, 309) and ritonavir 301 mg/m(2) (286, 309) twice daily. After TB treatment completion the children received standard doses of lopinavir/ritonavir 4:1 (median [IQR] lopinavir dose 289 mg/m(2) [286, 303] twice daily) as did those without TB (median [IQR] lopinavir dose 265 mg/m(2) [249, 289] twice daily)., Results: Lopinavir oral clearance (CL/F) was about 30% lower in children without TB than in co-infected children treated with super-boosted lopinavir. However, the predicted lopinavir C(min) was above the recommended minimum therapeutic concentration during TB/HIV co-treatment in the 15 children. Lopinavir CL/F increased linearly during the dosing interval., Conclusions: Increasing the ritonavir dose to achieve a lopinavir/ritonavir ratio of 1:1 when given in combination with rifampicin-based TB treatment did not completely compensate for the enhancement of lopinavir CL/F caused by rifampicin. The time-dependent lopinavir CL/F might be due to a time-dependent recovery from ritonavir inhibition of lopinavir metabolism during the dosing interval.

Background: Although the use of antiretroviral therapy has led to dramatic declines in AIDS-associated mortality, Pneumocystis pneumonia (PCP) remains a leading cause of death in HIV-infected patients., Objectives: To measure mortality, identify predictors of mortality at time of illness presentation and derive a PCP mortality prediction rule that stratifies patients by risk for mortality., Methods: An observational cohort study with case note review of all HIV-infected persons with a laboratory diagnosis of PCP at San Francisco General Hospital from 1997 to 2006., Results: 451 patients were diagnosed with PCP on 524 occasions. In-hospital mortality was 10.3%. Multivariate analysis identified five significant predictors of mortality: age (adjusted odds ratio (AOR) per 10-year increase, 1.69; 95% CI 1.08 to 2.65; p = 0.02); recent injection drug use (AOR 2.86; 95% CI 1.28 to 6.42; p = 0.01); total bilirubin >0.6 mg/dl (AOR 2.59; 95% CI 1.19 to 5.62; p = 0.02); serum albumin <3 g/dl (AOR 3.63; 95% CI 1.72-7.66; p = 0.001); and alveolar-arterial oxygen gradient >or=50 mm Hg (AOR 3.02; 95% CI 1.41 to 6.47; p = 0.004). Using these five predictors, a six-point PCP mortality prediction rule was derived that stratifies patients according to increasing risk of mortality: score 0-1, 4%; score 2-3, 12%; score 4-5, 48%., Conclusions: The PCP mortality prediction rule stratifies patients by mortality risk at the time of illness presentation and should be validated as a clinical tool.

Myopericytoma is an uncommon, benign perivascular myoid cell tumor that occurs almost exclusively in somatic soft tissues. We report 2 cases occurring in patients with acquired immunodeficiency syndrome who show unusual clinical and biologic features. One patient presented with a bronchial mass and the other developed mass lesions of the tongue, vocal cord, and brain. Histologically, oval to plump spindly tumor cells with uniform nuclei and scanty cytoplasm formed sheets or cuffs around gaping or narrow vascular spaces. Focally, these areas merged into fascicles of more elongated cells with eosinophilic cytoplasm. The tumor cells were immunoreactive for actin but not desmin, and showed uniform labeling for Epstein-Barr virus (EBV) encoded RNAs on in-situ hybridization. Both patients were alive 5 years after incomplete excision of the lesions. In conjunction with another case reported in the literature, myopericytoma occurring in acquired immunodeficiency syndrome patients exhibits several features distinct from sporadic myopericytoma: presentation in anatomic sites other than somatic soft tissues, frequent presence of multifocal disease, and association with EBV. This tumor type therefore also broadens the spectrum of neoplasms associated with EBV.

Background: Tuberculosis (TB) occurs in more than 50% of human immunodeficiency virus (HIV) infected Indian patients. This study was carried out to determine the immunophenotypic and intracellular cytokine profile of patients with HIV-TB co-infection., Patients and Methods: Fifteen patients with HIV-TB co-infection and 15 each with TB alone and healthy individuals were studied. Immunophenotypic analysis and intracellular cytokines were measured using appropriate antibodies on a flowcytometer., Results: Percentage of CD3+ did not differ significantly in the three groups. The ratio of CD4+ : CD8+ was reversed among patients with TB and HIV-TB. CD19+ and CD25+ were present on fewer cells of healthy individuals but this was not statistically significant. Significantly higher percentage of cells of patients with TB and HIV-TB were CD69 positive. Interferon-gamma (INF-gamma) and tumour necrosis factor-alpha (TNF-alpha) levels are significantly reduced in the CD4+ cells of patients with HIV-TB when compared with those with TB and healthy individuals. In CD8+ cells of patients with HIV-TB, levels of TNF-alpha are higher when compared with the other two groups. Interleukin-2 (IL-2) producing cells were not significantly different in any of the above subsets. Monocytes in individuals with HIV-TB had significantly higher interleukin-6 (IL-6) and TNF-alpha., Conclusions: T-helper cells among patients with HIV-TB have significantly lower cytokine production. T-suppressor cells and monocytes produce more TNF-alpha. These findings may be significant in view of recent attempts to treat HIV-TB coinfected patients with anti-TNF therapy.

Background: Activation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human immunodeficiency virus (HIV)-positive patients were examined., Methods: Inflammatory (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], amyloid-A, and amyloid-P) and coagulation (D-dimer and prothrombin-fragment 1+2) markers were determined. Conditional logistic regression analyses were used to assess associations between these biomarkers and risk of OD., Results: The 91 patients who developed an OD were matched to 182 control subjects. Patients with an hsCRP level > or =5 microg/mL at baseline had a 3.5 higher odds of OD (95% confidence interval [CI], 1.5-8.1) than did those with an hsCRP level <1 microg/mL (P=.003, by test for trend) and patients with an IL-6 level > or =3 pg/mL at baseline had a 2.4 higher odds of OD (95% CI, 1.0-5.4) than did those with an IL-6 level <1.5 pg/mL (P=.02, by test for trend). No other baseline biomarkers predicted development of an OD. Latest follow-up hsCRP level for those with an hsCRP level > or =5 microg/mL (compared with a level <1 microg/mL; odds ratio [OR], 7.6; 95% CI, 2.0-28.5; [P=.002, by test for trend), latest amyloid-A level for those with an amyloid-A level > or =6 mg/L (compared with a level <2 mg/L; OR, 3.8; 95% CI, 1.1-13.4; P=.03, by test for trend), and latest IL-6 level for those with an IL-6 level > or =3 pg/mL (compared with a level <1.5 pg/mL; OR 2.4; 95% CI, 0.7-8.8; P=.04, by test for trend) were also associated with development of an OD., Conclusions: Higher IL-6 and hsCRP levels independently predicted development of OD. These biomarkers could provide additional prognostic information for predicting the risk of OD.

Tuberculosis (TB) is a prominent opportunistic infection in HIV-1-infected subjects and enhances HIV-1 replication. TB is associated with excess monocyte chemoattractant protein (MCP)-1 and tumour necrosis factor (TNF)-alpha activity in situ, both of which are implicated in transcriptional activation of HIV-1. The role of MCP-1 and TNF-alpha in activation of HIV-1 during TB and by Mycobacterium tuberculosis (MTB) in mononuclear cells from HIV-1/TB subjects with pleural TB was examined here. Extremely high levels of MCP-1 (as compared with TNF-alpha) protein and mRNA were found in pleural fluid and pleural fluid mononuclear cells. Levels of MCP-1 mRNA were sustained during in vitro culture of pleural fluid mononuclear cells. Neutralization of MCP-1 (but not TNF-alpha), resulted in inhibition of MTB induced HIV-1 gag/pol mRNA. Neutralization of both MCP-1 and TNF-alpha, however, abrogated the effect of anti-MCP-1 antibody on HIV-1 mRNA. LMP-420, a small molecular transcriptional inhibitor of both TNF-alpha and MCP-1 expression, did not reduce MTB-induced HIV-1 expression. These data imply that MCP-1 activity may be critical to activation of HIV-1 at sites of TB. An interplay of MCP-1 and TNF-alpha is also suggested.

The urokinase plasminogen activator receptor (uPAR) and its ligand (uPA) play an important role in cell migration and extracellular proteolysis. We previously described uPAR/uPA overexpression in the cerebrospinal fluid (CSF) and brain tissues of patients with human immunodeficiency virus (HIV)-related cerebral diseases. In this study, we examined uPAR/uPA expression by immunohistochemistry (IHC) in brains of HIV patients with opportunistic cerebral lesions and in HIV-positive/negative controls. uPAR was found in macrophages/microglia with the highest levels in cytomegalovirus (CMV) encephalitis, toxoplasmosis, and lymphomas; in cryptococcosis and progressive multifocal leukoencephalopathy (PML) cases, only a few positive cells were found and no positivity was observed in controls. uPA expression was demonstrated only in a few macrophages/microglia and lymphocytes in all the cases and HIV-positive controls without different pattern of distribution; no uPA immunostaining was found in cryptococcosis and HIV-negative controls. The higher expression of uPAR/uPA in most of the opportunistic cerebral lesions supports their role in these diseases, suggesting their contribution to tissue injury.

We aimed to evaluate the frequency of Kaposi sarcoma (KS)-associated herpesvirus (KSHV) infection in KS lesions in patients from Brazil. In addition, expression of human bcl-2, cleaved caspase-3, and KSHV latency-associated nuclear antigen (LANA)-1 in tumors was evaluated using immunohistochemical analysis. We studied 64 KS cases, classified as follows: classical, 20 (31%); iatrogenic, 2 (3%); AIDS-associated, 25 (39%); and not otherwise specified (lack of information about HIV status), 17 (27%). KSHV was detected by polymerase chain reaction (PCR) in 61 cases (95%); 40 cases (63%) were KSHV+ by PCR and immunohistochemical analysis for LANA-1. Immunoexpression of bcl-2 was detected in 47 cases (73%). Only a few cells in 15 cases (23%) of KS had demonstrable immunostaining for cleaved caspase-3. These results further support the association of KSHV with all KS forms. Cleaved caspase-3 in KS tumors was infrequent, which may reflect the inhibition of apoptosis owing to bcl-2 overexpression observed in the majority of KS tumors.

Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research-not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed., ((c) 2006 Wiley-Liss, Inc.)

Objective: Pneumocystis pneumonia (PCP) is a severe infection of the immunocompromised host, resulting in diffuse alveolar damage and life-threatening respiratory failure. We analyzed pulmonary surfactant composition and function in bronchoalveolar lavage fluid (BALF) from ventilated and spontaneously breathing HIV-positive patients with PCP., Design: Prospective clinical trial., Setting: University hospital intensive care unit., Patients: Thirty-four spontaneously breathing (SB-PCP) and 20 ventilated HIV-positive patients with PCP (V-PCP), ten patients with acute respiratory distress syndrome (ARDS), 11 spontaneously breathing patients with bacterial pneumonia (PNEU), and 22 healthy volunteers., Interventions: None., Measurements and Main Results: Total phospholipid in BALF did not differ between any category vs. controls, whereas total protein increased approximately 14-fold in V-PCP and five-fold in SB-PCP compared with controls (p < .001). The relative content of large surfactant aggregates (LA) was reduced in SB-PCP and V-PCP compared with controls (p < .05). The phospholipid and fatty acid profiles showed a significant reduction in the relative content of phosphatidylcholine (PC), phosphatidylglycerol, and palmitic acid in PC in all patient categories compared with controls, with more in V-PCP (p < .001) compared with SB-PCP (p < .05). The neutral lipid-to-phospholipid ratio in LA was three-fold elevated in V-PCP (p < .01 compared with control) but not in SB-PCP. Analysis of neutral lipid classes showed a significant increase in the relative content of triglycerides and a reduction in free fatty acids in V-PCP compared with controls. BALF surfactant protein (SP)-A and SP-D significantly increased in V-PCP and SB-PCP, but not in ARDS and PNEU, compared with controls (p < .05). SP-B and SP-C content in LA remained unchanged in PCP compared with controls but decreased significantly in ARDS and PNEU. The minimum surface tension of LA was impaired (p < .001) in V-PCP more than in SB-PCP and was strongly correlated with the reduction in palmitic acid levels in PC LA (r = -.81). Reductions in phosphatidylglycerol strongly correlated with decreased Pao2/Fio2 values (r = .72)., Conclusions: We conclude that severe alterations in surfactant function and composition occur in patients with PCP and are even more pronounced in ventilated patients than in nonventilated patients. Surfactant lipid changes in PCP, but not surfactant protein profiles, closely resemble those found in ARDS.

Background: Human herpesvirus 8 (HHV-8) DNA has been detected in semen and prostatic tissues in some, but not all reports. We have analyzed prostate tissues from HHV-8 seropositive men for the expression of viral proteins and determined if expression of these proteins are associated with increased inflammation., Methods: Paraffin sections of non-cancerous prostates from HHV-8 seropositive (n = 16) and seronegative (n = 2) men who died with AIDS were screened for expression of three viral proteins by immunohistochemistry. Levels of inflammation were determined by expression of CD68 and CD20. Cellular proliferation was determined by expression of Ki67., Results: Among the 16 HHV-8 seropositive cases, 68.9% (11/16) (95% C.I. = 0.41-0.89) were positive for HHV-8 protein expression, while the 2 seronegative patients showed no HHV-8 protein expression. There was increased inflammation among HHV-8 positive prostates., Conclusions: These results demonstrate that HHV-8 is present in normal prostates of HIV-infected men and the expression of viral proteins is associated with increased localized inflammation., ((c) 2006 Wiley-Liss, Inc.)

Purpose: Systemic chemotherapy is the treatment of choice for AIDS-related advanced Kaposi sarcoma. One principal schedule combines adriamycin (doxorubicin), bleomycin, and vincristine (ABV). We analysed the plasma concentrations of low-dose doxorubicin (Dx) and its metabolites doxorubicinol, 7-deoxydoxorubicinone, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinolone in AIDS-patients to define patient-group and dose-specific pharmacokinetic parameters., Materials and Methods: A previously described high-performance liquid chromatographic (HPLC) method and a population approach with non-linear mixed effects modelling (NONMEM) were used for analysis and subsequent modelling of the time-concentration data of low-dose Dx and metabolites in seven patients with AIDS-related advanced Kaposi sarcoma. Patients received Dx 20 mg m(-2), bleomycin 15 U m(-2) and vincristine 2 mg as a 30-min intravenous infusion each. Blood samples were collected up to 72 h after the start of Dx treatment. WinNonlin software version 4.1 was used for non-compartmental analysis and NONMEM software version V for compartmental analysis. Covariate analysis was performed for various clinical and laboratory parameters., Results: Non-compartmental analysis yielded an area under the plasma concentration-time curve (AUC) for Dx of 566 mug h L(-1), a maximum plasma concentration (c(max)) of 599 mug L(-1) and an elimination half-life (t(1/2)) of 30.8 h. Compartmental analysis resulted in a two-compartment model with first-order elimination, which best fitted the concentration-time data. Model estimate for Dx clearance was 61.8 L h(-1), for intercompartmental clearance (Q) 112 L h(-1), for the volume of the central compartment (V(1)) 23.3 L, and for the volume of the peripheral compartment (V(2)) 1,130 L. Metabolite data could adequately be estimated by NONMEM using single-compartment models. Graphical plots of residuals versus time for all metabolites yielded no evidence of non-linear pharmacokinetic behaviour. Laboratory parameters of liver and renal function were all in the normal range and their inclusion in the pharmacokinetic model did not improve data fit. A final jack-knife analysis was performed., Conclusions: Concentration-time data for low-dose Dx and metabolites in the ABV-regimen are best described by a two-compartment model with first-order elimination. The results confirm that the aglycones doxorubicinone, 7-deoxydoxorubicinone, and doxorubicinolone can be reliably detected in the studied patient group and implemented into a common metabolic model. Model estimates suggest that pharmacokinetic parameters are similar for low-dose Dx and higher-dosed Dx. As the role of the aglycones is still poorly understood, despite their potential clinical relevance, their analysis should be implemented in future pharmacokinetic and pharmacodynamic studies of Dx.

The clearance of cytomegalovirus viraemia in HIV-1-infected patients may partly result from the inhibition of cytomegalovirus protease by HIV-1 protease inhibitors contained in highly active antiretroviral therapy. We used a computational method to calculate the binding affinity of six HIV-1 protease inhibitors to cytomegalovirus protease based on its X-ray crystallography structure. The calculations showed that amprenavir and indinavir occupy the substrate-binding site of the cytomegalovirus protease with high affinity, and may be implicated in alleviating cytomegalovirus infection.

The objective of the present study was to evaluate human immunodeficiency virus (HIV) levels in the aqueous humor and vitreous fluid in patients with and those without ocular involvement due to AIDS-related cryptococcosis. We also assessed whether cryptococcosis infection in the central nervous system (CNS) was associated with elevated HIV levels in the cerebrospinal fluid (CSF). From 1993 to 2003, we obtained 16 CSF samples from 9 AIDS patients with cryptococcal meningitis and 7 AIDS patients without CNS opportunistic infection. Samples of intraocular fluids were obtained from all 9 patients with cryptococcal meningitis. Five cases presented with ocular involvement in patients with meningitis. By using the method of reverse transcriptase-polymerase chain reaction, we detected higher HIV loads in aqueous humor (27,244+/-4,123 copies/ml) and vitreous fluid (84,930+/-5,071 copies/ml) in patients with concomitant CNS and ocular involvement due to AIDS-related cryptococcosis (p<0.05). HIV levels in the vitreous fluid were correlated with levels in CSF (r=0.77). Mean HIV level in the CSF (209,761+/-18,787 copies/ml) was significantly elevated in AIDS patients with cryptococcoal meningitis (p<0.05). To our knowledge, this is the first report to study the level of HIV loads in the CSF and intraocular fluid simultaneously in AIDS patients with cryptococcosis. Our results revealed the intrathecal and intraocular HIV replication in patients with cryptococcosis., (Copyright (c) 2005 S. Karger AG, Basel.)

Oropharyngeal candidiasis, typically caused by Candida albicans, is the most common oral disease associated with human immunodeficiency virus type 1 (HIV-1) infection. Secretory leukocyte protease inhibitor (SLPI), a 12-kDa antiprotease, suppresses the growth of C. albicans in vitro. To determine whether the mucosal protein plays a role in protecting oral tissues against fungal infection, we conducted a cross-sectional study investigating the oral and systemic health and salivary SLPI levels in 91 dentate HIV-1-infected adults receiving medical care in the southeastern United States. Participants with a self-reported history of clinical oropharyngeal candidiasis during the previous 2 years constituted the test group (n = 52), while the comparison group (n = 39) had no oropharyngeal candidiasis during that period. Data collected from medical records, oral examination, and SLPI enzyme-linked immunosorbent assay quantitation of whole saliva were analyzed by t test, analysis of variance, linear regression, and unconditional logistic regression. The test group had a significantly higher mean salivary SLPI level than the comparison group (1.9 microg/ml versus 1.1 microg/ml, P < 0.05). Linear regression modeling identified CD4 cell count and history of oropharyngeal candidiasis as key predictors of salivary SLPI and revealed a significant interaction (P < 0.05) between immunosuppression (CD4 cell count below 200 cells/ microl) and positive history of oropharyngeal candidiasis in predicting salivary SLPI level. By logistic regression modeling, a salivary SLPI level exceeding 2.1 microg/ml, low CD4 count, antiretroviral monotherapy, and smoking were key predictors of oropharyngeal candidiasis. These data support a key role for SLPI in the oral mucosal defense against C. albicans. The antimicrobial mucosal protein may serve as an indicator of previous oropharyngeal candidiasis infection among immunosuppressed persons.

Background: Pneumocystis jerovici pneumonia (PJP) remains a frequent opportunistic infection in HIV infected patients which markedly upregulates HIV replication by mechanisms so far poorly elucidated. PJP triggers the production of proinflammatory mediators with activating effects on HIV. However, anti-inflammatory factors with inhibiting effects on HIV are normally produced in parallel. We postulated that an imbalance of mediators normally controlling HIV replication could underlie its marked increase during PJP., Methods: The production of tumour necrosis factor alpha (TNFalpha), interleukins IL-6 and IL-10, and beta-chemokine by bronchoalveolar lavage (BAL) cells recovered from HIV infected patients with and without PJP was compared. The pulmonary viral load was determined and correlations with cytokine and chemokine production were examined., Results: TNFalpha and IL-6 release was similar in patients with and without PJP but IL-10 and beta-chemokine release was markedly lower in the PJP group (IL-10: p<10(-2), RANTES, MIP-1alpha and MIP-1beta: p<0.001). The pulmonary viral load was markedly higher in patients with PJP (p<0.001) and correlated negatively with levels of MIP-1alpha, RANTES and IL-10 in BAL fluid cells (p<0.05)., Conclusion: Pulmonary IL-10 and beta-chemokine production is markedly defective in HIV infected patients with PJP, while pulmonary TNFalpha and IL-6 levels are normal. The resulting excess of these latter factors, which are known to upregulate HIV replication, might contribute to the increase in pulmonary viral load and to the more rapid HIV disease progression observed in patients with PJP.

The anatomic distribution and rate of progression vary significantly between acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (KS) and classic KS. The reasons are unclear, but cyclin D1 overexpression is associated with tumor progression in other malignancies. Cyclin D has an important regulatory role in the progression of cell cycle at the G1-S phase due to its effect in phosphorylating the retinoblastoma gene product. Forty-one paraffin-embedded surgical specimens (31 AIDS-related, 10 classic) were examined using streptavidin-biotin-peroxidase immunohistochemistry with monoclonal antibody to cyclin D1. A scoring system based on the intensity and extent of staining was used. The correlations among cyclin D1 expression and clinicopathologic parameters were statistically analyzed. Cyclin D1 overexpression was found in 29% (12/41) of all KS cases. There was a strong correlation between cyclin D1 overexpression and pathologic stage (0% in patch stage, 13% in plaque stage, 50% in nodular stage; P = 0.0017). Classic KS lesions had a higher incidence of cyclin D1 overexpression than AIDS-related lesions (70% vs 16%, P = 0.001). Cyclin D1 overexpression was detected in 78% of the classic nodular lesions and 31% of the AIDS-related nodular lesions (P = 0.03). On multivariate analysis, negative human immunodeficiency virus status (P = 0.001) and nodular lesions (P = 0.007) were strong predictors of cyclin D1 overexpression. Age, gender, recurrence of the tumor, multiplicity, and site of the lesions hold no statistically significant association with cyclin D1 expression on multivariate analysis. In summary, cyclin D1 overexpression was more prevalent in classic lesions and more advanced nodular stage. These findings raise the possibility of a different pathogenetic mechanism in the progression of AIDS-related KS and classic KS.

With strict reference to how AIDS dementia somehow evolves from HIV infection through stages of initial monocyte-macrophage stimulation via a series of transendothelial and infiltrative events, it is perhaps significant to consider systemic body involvement by the HIV-associated processes to culminate in a concerted series of effects involving cascades and amplifications of action of cytokines and chemokines. Indeed, in terms that would implicate neurons only secondarily in AIDS dementia, one might perhaps consider HIV-1-dementia as an effective result of ongoing inflammation in the brain dependent not only on macrophage-microglial activation and replication, but also on glial participation in an overall process particularly conducive to increasing the brain HIV-1 load. In effect, perhaps, HIV encephalitis would constitute a system of mutually self-enhancing series of events ranging from macrophage-monocyte activation and replication on the one hand, and also HIV-1-induced cellular effects on the other that would result in progressively amplifying neuronal injury induced by cytokines and chemokines in AIDS patients suffering from repetitive opportunistic infections.

Background: Tuberculosis (TB) and HIV infection are wasting diseases that frequently occur together and have severe consequences on nutritional status., Objective: The objective was to determine the effects of TB and HIV, separately and together, on protein metabolism., Design: Protein metabolism was determined in the fed state in 11 healthy control subjects, in 10 patients with HIV infection without TB or other active infection (HIV group), in 10 patients with active TB without HIV infection (TB group), and in 8 patients with HIV infection and active TB (HIVTB group) with the use of oral [(15)N]glycine and measurement of enrichment in urinary urea and ammonia., Results: Whole-body protein flux and degradation were lower in the HIV group than in the control group (mean flux: 3.53 +/- 0.40 compared with 4.75 +/- 0.97 g. kg lean body mass(-1). 12 h(-1); P = 0.002). Protein flux, synthesis, and degradation were not significantly different between the control group and the TB and HIVTB groups. Net protein balance was strongly anabolic in the control, HIV, and TB groups but was neutral in the HIVTB group (P < 0.001 for comparison between groups)., Conclusions: HIV infection was associated with a significant down-regulation of whole-body protein flux. TB alone was not associated with abnormal protein metabolism, but net anabolism in the fed state was impaired in the HIVTB group.

Cytomegalovirus (CMV) encephalitis is well documented in immunosuppressed persons, but its pathogenesis has received little investigative attention. The examination of brain tissue from 2 patients with acquired immunodeficiency syndrome who had CMV encephalitis showed colocalization of CMV inclusions and transforming growth factor (TGF)-beta in cells that contained astrocyte-specific glial filaments. To investigate the relationship between CMV and TGF-beta in the brain, an ex vivo murine model of CMV-infected astrocytes was established. Cultures of primary murine (strain FVB/N) astrocytes inoculated with murine (Smith strain) CMV expressed, over time, increasing amounts of infectious CMV in parallel with increasing levels of TGF-beta mRNA and peptide. Astrocyte release of CMV declined in the presence of antibody to TGF-beta and increased substantially after the addition of exogenous TGF-beta. These findings suggest that CMV infection of astrocytes induces the production of TGF-beta, which in turn enhances productive CMV expression.

To reduce possible nephrotoxicity, intravenous prehydration with normal saline and administration of probenecid must be used with each infusing of the antiviral cidofovir. The recommended standard-dose probenecid (SDP) regimen is 2 g at 3 hours before cidofovir, then 1 g at 2 and 8 hours after cidofovir (total 4 g). A new regimen of reduced-dose probenecid (RDP), 2 g at 1 hour before cidofovir without additional probenecid administrations after infusion (total 2 g), was compared with SDP using a randomized, open-label, parallel design. A single dose of cidofovir (5 mg/kg) was given as a 1-hour infusion after saline prehydration to 24 HIV-infected patients (11 males, 13 females) with cytomegalovirus retinitis and good renal function. Blood was sampled for 48 hours and urine for 24 hours after the start of the cidofovir infusion. Cidofovir pharmacokinetics did not differ significantly between groups. Average key pharmacokinetic parameters (Cmax, tmax, lambda z, AUC0-infinity, Vss, CL, CLR, fe, ER) for RDP differed by less than 17% from SDP and were consistent with previously reported SDP data. Renal function parameters, other safety endpoints, and adverse events were similar between the groups. Therefore, the reduced-dose regimen of probenecid provided renal protection after a single dose of cidofovir and did not alter the pharmacokinetics of cidofovir in patients with moderately good renal function. Although the overall pharmacokinetic results do not show a significant difference in cidofovir exposure with the new probenecid regimen, the main issue of safety of the new dose regimen, both relating to renal toxicity and probenecid-related adverse events, is not adequately addressed in a small study.

A review of Kawasaki disease (KD)-like syndromes (KDLS) in patients with human immunodeficiency virus (HIV) raised the question whether vasculitis in children and KDLS in immunocompromised adults might be etiologically related. We describe a 42-year-old white man with AIDS and Kaposi sarcoma who presented with KDLS, which was diagnosed on the basis of clinical criteria for KD. Analysis of a conjunctival tissue sample revealed endothelial cell damage with fibrin deposition and infiltration of immunoglobulin A-secreting plasma cells.