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The intestinal microbiome is an essential so-called human "organ", vital for the induction of innate immunity, for metabolizing nutrients, and for maintenance of the structural integrity of the intestinal barrier. HIV infection adversely influences the richness and diversity of the intestinal microbiome, resulting in structural and functional impairment of the intestinal barrier and an increased intestinal permeability. Pathogens and metabolites may thus cross the "leaky" intestinal barrier and enter the systemic circulation, which is a significant factor accounting for the persistent underlying chronic inflammatory state present in people living with HIV (PLWH). Additionally, alcohol use and abuse has been found to be prevalent in PLWH and has been strongly associated with the incidence and progression of HIV/AIDS. Recently, converging evidence has indicated that the mechanism underlying this phenomenon is related to intestinal microbiome and barrier function through numerous pathways. Alcohol acts as a "partner" with HIV in disrupting microbiome ecology, and thus impairing of the intestinal barrier. Optimizing the microbiome and restoring the integrity of the intestinal barrier is likely to be an effective adjunctive therapeutic strategy for PLWH. We herein critically review the interplay among HIV, alcohol, and the gut barrier, thus setting the scene with regards to development of effective strategies to counteract the dysregulated gut microbiome and the reduction of microbial translocation and inflammation in PLWH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yan, Ouyang, Isnard, Zhou, Harypursat, Routy and Chen.)

A 59-year-old Caucasian man infected with HIV, in remission from human herpes virus-8-positive extracavitary primary effusion lymphoma (EC-PEL), presented to a sexual health clinic with fever and rectal pain 10 weeks after a single episode of receptive anal sexual intercourse with another man. He was initially treated for a presumptive diagnosis of lymphogranuloma venereum proctitis, then for syphilis on positive serology. Rectosigmoidoscopy revealed a single ulcerated rectal mass; endoscopic biopsies confirmed the recurrence of EC-PEL. The patient received chemotherapy and went into remission. This is the first reported case of EC-PEL occurring synchronously with early syphilis, and specifically at the site of inoculation, which can be a major diagnostic challenge since both conditions may present with lymphadenopathy, mucosal involvement and constitutional symptoms. We reviewed the literature for similar cases and hypothesised that syphilis may have triggered the recurrence of this rare lymphoma., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: This review highlights current knowledge on the dichotomous role played by T helper 17 cells (Th17)-polarized CD4 T cells in maintaining mucosal immunity homeostasis versus fueling HIV/simian immunodeficiency virus (SIV) replication/persistence during antiretroviral therapy (ART), with a focus on molecular mechanisms underlying these processes., Recent Finding: Th17 cells bridge innate and adaptive immunity against pathogens at mucosal barrier surfaces. Th17 cells are located at portal sites of HIV/SIV entry, express a unique transcriptional/metabolic status compatible with viral replication, and represent the first targets of infection. The paucity of Th17 cells during HIV/SIV infection is caused by infection itself, but also by an altered Th17 differentiation, survival, and trafficking into mucosal sites. This causes major alterations of mucosal barrier integrity, microbial translocation, and disease progression. Unless initiated during the early acute infection phases, ART fails to restore the frequency/functionality of mucosal Th17 cells. A fraction of Th17 cells is long-lived and carry HIV reservoir during ART. Recent studies identified Th17-specific host factors controlling HIV transcription, a step untargeted by current ART., Summary: The identification of molecular mechanisms contributing to HIV replication/persistence in mucosal Th17 cells paves the way toward the design of new Th17-specific therapeutic strategies aimed at improving mucosal immunity in HIV-infected individuals.

The phenotypic characterization of the cells in which HIV persists during antiretroviral therapy (ART) remains technically challenging. We developed a simple flow cytometry-based assay to quantify and characterize infected cells producing HIV proteins during untreated and treated HIV infection. By combining two antibodies targeting the HIV capsid in a standard intracellular staining protocol, we demonstrate that p24-producing cells can be detected with high specificity and sensitivity in the blood from people living with HIV. In untreated individuals, the frequency of productively infected cells strongly correlated with plasma viral load. Infected cells preferentially displayed a transitional memory phenotype and were enriched in Th17, peripheral Tfh and regulatory T cells subsets. These cells also preferentially expressed activation markers (CD25, HLA-DR, Ki67), immune checkpoint molecules (PD-1, LAG-3, TIGIT, Tim-3) as well as the integrins α4β7 and α4β1. In virally suppressed individuals on ART, p24-producing cells were only detected upon stimulation (median frequency of 4.3 p24+ cells/106 cells). These measures correlated with other assays assessing the size of the persistent reservoir including total and integrated HIV DNA, Tat/rev Induced Limiting Dilution Assay (TILDA) and quantitative viral outgrowth assay (QVOA). In ART-suppressed individuals, p24-producing cells preferentially displayed a transitional and effector memory phenotype, and expressed immune checkpoint molecules (PD-1, TIGIT) as well as the integrin α4β1. Remarkably, α4β1 was expressed by more than 70% of infected cells both in untreated and ART-suppressed individuals. Altogether, these results highlight a broad diversity in the phenotypes of HIV-infected cells in treated and untreated infection and suggest that strategies targeting multiple and phenotypically distinct cellular reservoirs will be needed to exert a significant impact on the size of the reservoir., Competing Interests: The authors have declared that no competing interests exist.

Background: The lungs were historically identified as one of the major anatomic sites for HIV replication in the pre-antiretroviral therapy (ART) era. However, their contribution to HIV persistence in individuals under suppressive ART remains understudied., Design: We assessed HIV persistence and comprehensively characterized pulmonary mucosal CD4 T cells in HIV-infected (HIV) individuals receiving long-term suppressive ART versus uninfected participants., Methods: Bronchoalveolar lavage (BAL), bronchial biopsies, and matched peripheral blood were obtained from n = 24 HIV-infected adults receiving long-term suppressive ART (median: 9 years) and n = 8 healthy volunteers without respiratory symptoms. HIV-DNA and cell-associated HIV-RNA were quantified by ultra-sensitive PCR, and lung mucosal CD4 T-cell subsets were characterized by multiparameter flow cytometry., Results: The levels of HIV-DNA were 13-fold higher in total BAL cells compared to blood. Importantly, FACS-sorted CD4 T cells from BAL contained greater levels of HIV-DNA compared to peripheral CD4 T cells. BAL CD4 T cells in HIV individuals were characterized mostly by an effector memory phenotype, whereas naive and terminally differentiated cells were underrepresented compared to blood. Furthermore, BAL CD4 T cells expressed higher levels of immune activation (HLA-DR/CD38) and senescence (CD57) markers. Importantly, BAL was enriched in T-cell subsets proposed to be preferential cellular HIV reservoirs, including memory CD4CCR6, Th1Th17 (CD4CCR6CCR4CXCR3), CD4CCR6CXCR3CCR4, and CD4CD32a T cells., Conclusion: The pulmonary mucosa represents an important immunological effector site highly enriched in activated and preferential CD4 T-cell subsets for HIV persistence during long-term ART in individuals without respiratory symptoms. Our findings raise new challenges for the design of novel HIV eradication strategies in mucosal tissues.

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Although there is discordance between human immunodeficiency virus (HIV) blood plasma and seminal plasma viral loads (VL), little is known about the dynamics of VL rebound in these compartments upon discontinuation of highly active antiretroviral therapy (HAART). Therefore, we sought to examine the relationship between blood and semen VL rebound after discontinuation of HAART. Participants in this substudy were men enrolled from two centers of a multicenter, placebo-controlled randomized trial of HIV therapeutic vaccination using ALVAC with or without Remune. With at least 2 years of sustained virologic suppression and following a 20-week vaccination course, subjects underwent structured HAART interruption. Fourteen men provided semen samples. Seven to 12 weeks after HAART interruption, all 14 men had detectable blood VLs whereas 8 of 14 had detectable seminal VLs. There was a significant correlation between blood and seminal VLs (Spearman r=0.58, p=0.03) at the time of semen collection. An earlier time to detectable blood VL after HAART interruption was associated with higher seminal VL (Spearman r=-0.64, p=0.02). These findings support the compartmentalization of HIV and underscore the importance of understanding the genital tract as an HIV reservoir in the quest to minimize HIV transmission.

Background: HIV reservoirs represent the major obstacles for eradication and are defined as a cell type that allows persistence of replication-competent HIV in patients on optimal long-term antiretroviral therapy (HAART). Several pilot clinical trials have been implemented to assess the value of experimental therapy to reduce reservoir size or eradicate HIV. In order to eradicate HIV, valproic acid was used as a new strategy to increase viral gene expression in the nucleus of infected cells with the expectation of generating a direct cell death or destruction by nearby cytotoxic cells. Previous pilot studies using VPA have showed conflicting results on the ability of VPA to reduce the size of HIV reservoirs., Purpose: As the role of VPA on HIV reservoirs remains unclear, we conducted a multicenter clinical trial with a specific study design to obtain optimal information on reservoir changes while exposing the smallest number of individuals to the experimental medication., Method: To this aim, a randomized, crossover design with 2 different treatment durations was implemented. By doubling the therapeutic period in one study arm, we were in a position to assess the impact of an extended duration of VPA on the size of the HIV reservoir and to evaluate the duration of treatment effects upon VPA withdrawal in the other arm. However, limitations for this type of study design included the logistical complexity of 2 uneven study arms and longer study duration., Conclusion: Despite the absence of demonstrable impact of VPA on reservoir size, such crossover study design should be considered in the early stage testing of novel HIV therapeutics targeted to reduce reservoir size or eradicate HIV.

Persistent exposure to cognate Ag leads to the functional impairment and exhaustion of HIV-specific CD8 T cells. Ag withdrawal, attributable either to antiretroviral treatment or the emergence of epitope escape mutations, causes HIV-specific CD8 T cell responses to wane over time. However, this process does not continue to extinction, and residual CD8 T cells likely play an important role in the control of HIV replication. In this study, we conducted a longitudinal analysis of clonality, phenotype, and function to define the characteristics of HIV-specific CD8 T cell populations that persist under conditions of limited antigenic stimulation. Ag decay was associated with dynamic changes in the TCR repertoire, increased expression of CD45RA and CD127, decreased expression of programmed death-1, and the emergence of polyfunctional HIV-specific CD8 T cells. High-definition analysis of individual clonotypes revealed that the Ag loss-induced gain of function within HIV-specific CD8 T cell populations could be attributed to two nonexclusive mechanisms: 1) functional improvement of persisting clonotypes; and 2) recruitment of particular clonotypes endowed with superior functional capabilities.

Expression of major histocompatibility complex (MHC) class I alleles such as B*57 and B*27 are associated with slow HIV disease progression. HIV-specific immune responses in slow progressors (SP) are characterized by a poly-functional profile. We previously observed within infected subjects that HIV peptide-specific responses could differ from each other in their functional composition. We investigate here whether responses restricted by MHC class I alleles associated with slow disease progression have a more poly-functional profile than responses restricted by other alleles. We stimulated peripheral blood mononuclear cells (PBMCs) isolated from 36 chronically HIV-infected individuals with a panel of optimal peptides restricted by the HLA alleles expressed by each subject, and assessed the contribution of single IL-2-, single IFN-γ-, and IFN-γ/IL-2-secreting lymphocytes to the total response measured using a dual color ELISPOT assay. The contribution of functional subsets to responses restricted by HLA B*57/B*27 was similar in SP and progressors. For responses restricted by other MHC class I alleles, dual IFN-γ/IL-2-secreting lymphocytes contributed significantly more to the total response in SP than progressors. Within SP subjects, peptides restricted by both B*57/B*27 and other alleles stimulated responses with similar functional profiles. In progressors, peptides restricted by B*57/B*27 stimulated responses composed of a significantly greater proportion of IFN-γ/IL-2-secreting cells than peptides restricted by other alleles. Within progressors, the contribution of IFN-γ/IL-2-secreting lymphocytes was greater to epitopes restricted by protective HLA alleles compared with responses restricted by other alleles. HLA haplotypes influence the relative functional composition of HIV-specific responses.

Several combinations of genes encoding KIR3DL1 alleles and their HLA‐Bw4 ligands have been linked with favorable outcomes upon exposure to or infection with human immunodeficiency virus (HIV). Some protective KIR3DL1/HLA‐Bw4 combinations confer elevated natural killer (NK) cell functional potential. The K562‐stimulated functionality of NK cells from KIR3DL1*004/HLA‐Bw4 and control genotype carriers was assessed by flow cytometry and found to be higher in KIR3DL1*004/HLA‐Bw4 carriers. However, a comparison of the frequency of this combined genotype among HIV‐exposed uninfected and HIV‐infected subjects revealed no between‐group differences. Thus, despite its ability to license NK cells, KIR3DL1*004/HLA‐Bw4 is not associated with a reduced risk of infection.

Interleukin-18 is a proinflammatory, proapoptotic, and proatherogenic cytokine belonging to the interleukin-1 family of cytokines. The cytokine exerts many unique immunologic and biological effects. It is produced as a biologically inactive and leaderless precursor protein, which must be cleaved into its mature form by caspase-1. The caspase-1 also exists in an inactive precursor in the cytosol and needs proteolytic auto-cleavage, which is catalyzed by the assembly of a multi-protein complex called inflammasome. Inside the circulation, interleukin-18 is bound to its naturally occurring antagonist called interleukin-18 binding protein. The antagonist is induced as a negative feedback to increased interleukin-18 production. It protects body cells and tissues from the potentially destructive and harmful proinflammatory effects of the cytokine. Several researchers have reported that the concentrations and biological activities of the cytokine are increased in the circulation of HIV-infected patients. Unlike interleukin-18, the concentrations of its antagonist, interleukin-18 binding protein, are decreased in these persons. The cytokine may play a major role in the development and pathogenesis of AIDS in HIV-infected persons. Insufficient/lack of interleukin-12 and related cytokines may compromise the ability of interleukin-18 to induce interferon-gamma production from natural killer and T-cells. By inducing production of T-helper 2-type cytokines like interleukin-4, -5, -9, and -13 from basophils and mast cells, interleukin-18 promotes the development and differentiation of CD4+ naive T-cells into T-helper 2-type effector cells, which blunt anti-HIV immunity. The effect may be more pronounced in HIV-infected persons with compromised production of interleukin-12. Interleukin-18 also directly enhances viral replication. Because of its proapoptotic effects, the cytokine decreases survivability and promotes the death of various immune and nonimmune cells. It has also been documented to play a role in the depletion and wasting of subcutaneous fat from the limbs and face. The wasting is a characteristic feature of HIV-associated lipodystrophy. The cytokine is also likely to be involved in the higher incidence of atherosclerotic plaques and systemic insulin resistance in these patients. Finally, increased production of the cytokine in the brain may lead to motor and cognitive dysfunctions, leading to the development of HIV-associated dementia. In conclusion, increased interleukin-18 concentrations in HIV-infected persons are likely to play an important role in the development and progression of the infection toward AIDS and associated clinical conditions. Therefore, its neutralization may represent an appropriate and useful immunotherapeutic strategy in these patients. It may delay AIDS progression and improve the immune status of infected persons. The best way to achieve this goal may be using exogenous interleukin-18 binding protein.

During chronic infection, HIV-specific CD8 T cells exhibit progressive signs of functional impairment, attributed to persistent antigenic stimulation, up-regulation of the inhibitory receptor PD-1, and declining T cell help. Strategies that directly improve CD8 T cell function offer the potential of restoring immune control of HIV. Although PD-1 expression has been identified as a cause of functional impairment in HIV, in this study, PD-1 expression was observed on only a subfraction of HIV-specific CD8 T cells in a subfraction of donors, whereas HIV-specific CTL from all donors exhibited a limited repertoire of effector functions. CD137L (4-1BBL) is emerging as an important stimulator of antiviral CD8 T cell responses. Regardless of the PD-1 status of the donors, here we show that 4-1BBL, when combined with CD80 or CD70, expands a population of Ag-specific CD8 T cells expressing multiple markers of effector function, from the functionally impaired starting population. In contrast, CD70 in combination with CD80 was insufficient for these effects and the related TNF family ligand, LIGHT, had negligible activity. The unique contribution of 4-1BBL correlated with down-regulation of the proapoptotic molecule Bim in activated CD8 T cells. Decreasing the level of TNFR-associated factor 1 in T cells using small interfering RNA resulted in increased levels of Bim in the 4-1BBL-stimulated T cells. Thus, costimulation via 4-1BBL leads to TNFR-associated factor 1-dependent Bim down-modulation in T cells, resulting in increased T cell expansion. These studies identify 4-1BBL as a critical component in therapeutic strategies aimed at improving CD8 T cell function.

Using a dual color ELISPOT assay able to detect HIV-specific IFN-gamma, IL-2 and dual IFN-gamma/IL-2 secreting lymphocytes we screened for HIV peptide-specific responses directed against the entire HIV proteome in two groups of untreated HIV-infected individuals, slow progressors (SP) and progressors. We found that the three functional lymphocyte subsets contributed differentially to individual HIV peptide-specific responses within a study subject. Among the identified stimulatory peptides, a higher proportion induced dual IFN-gamma/IL-2 secretion in SP than progressors. While the magnitude of single IFN-gamma secreting lymphocytes is similar between groups, the magnitude of peptide-specific dual IFN-gamma/IL-2 secreting lymphocytes is significantly more intense in SP. Neither single nor total IFN-gamma secreting cell magnitude and breadth measurements correlated with CD4 cell count or viral load whereas both parameters of dual IFN-gamma/IL-2 secreting responses correlated positively with CD4 counts and negatively with viremia.

HIV-specific CD8 T cell responses are defective in chronic HIV infection. In this study, we report that costimulation with either CD137L (4-1BBL) or CD80 (B7.1) enhanced the Ag-specific expansion and acquisition of effector function by HIV-specific memory CD8 T cells. Ag-specific T cells from recently infected donors showed maximal expansion with single costimulatory molecules. Dual costimulation of T cells from recently infected donors or from healthy donors responding to influenza epitopes led to enhanced responses when the accumulation of cytokines was measured. However, accumulation of regulatory cytokines, particularly IFN-gamma, led to inhibition of further Ag-specific CD8 T cell expansion in the cultures. This inhibition was relieved by neutralization of IFN-gamma or of IFN-gamma, TNF, and IL-10. Thus, strong costimulation of T cells in vitro can lead to induction of regulatory cytokines at levels that limit further T cell expansion. In marked contrast, T cells from long-term (>4 years) infected HIV+ donors exhibited reduced Ag-specific CD8 T cell expansion, reduced CD4 T cell responses, and minimal cytokine accumulation. Dual costimulation with both 4-1BBL and B7.1 enhanced responses of T cells from long-term infected subjects to a level similar to that obtained with T cells from early in HIV infection. Experiments with purified CD8 T cells showed that B7.1 and 4-1BBL could act directly and synergistically on CD8 T cells. Taken together, these data suggest that 4-1BBL and B7.1 have additive or synergistic effects on HIV-specific CD8 T cell responses and represent a promising combination for therapeutic vaccination for HIV.

The interferon-gamma ELISPOT assay was used to assess and compare the magnitude and breadth of human immunodeficiency virus (HIV)-specific CD8 T cell responses in treatment-naive subjects during the first year of HIV primary infection and during the chronic phase of infection. Twenty-five subjects tested within a year of exposure to HIV resulting in seroconversion and 20 subjects with chronic infection were screened for HIV peptide-specific activity by stimulating peripheral blood mononuclear cells with a panel of 5-21 HLA class I-restricted HIV peptides (mean, 11.2 +/- 3.5 HIV peptides). There was a significant correlation between the magnitude and breadth of HIV-specific effector responses and time elapsed from exposure (r=0.63 for magnitude vs. time and r=0.64 for breadth vs. time; P<.02, paired t test). Maximal breadth of the HIV gene product reactivity was achieved within 2 months of exposure for Nef-specific responses and by 4 months of exposure for responses directed to Env, Gag, and reverse transcriptase.

The search to identify HIV-associated molecules with superantigenic properties has focussed on demonstration of T cell receptor V beta subset-specific perturbations in HIV-infected patients. In this report, the V beta repertoire of two HIV patients was studied in lymph nodes, where HIV-1 replication is the most intense, and compared to the repertoire found in peripheral blood. Use of this fully MHC-compatible system has allowed identification of a small, partly overlapping set of V beta determinants which appear significantly perturbed in HIV-1 infection. These results are consistent with the presence of an HIV-associated superantigen.

Objectives: The reported prevalence of chronic obstructive pulmonary disease (COPD) in people living with HIV (PLWHIV) varies widely. Our objective was to estimate the prevalence of airflow obstruction and COPD in unselected PLWHIV and identify characteristics that increase the risk of nonreversible airflow obstruction in order to guide case finding strategies for COPD. Methods: All adults attending the Chronic Viral Illness Service were invited to participate in the study, regardless of smoking status or history of known COPD/asthma. Individuals underwent spirometric testing both before and after use of a salbutamol bronchodilator. Airflow obstruction was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < 0.7 post‐bronchodilation, whereas COPD was defined as FEV1/FVC < 0.7 post‐bronchodilation and Medical Research Council (MRC) score > 2. Multivariate logistic regression was used to evaluate risk factors associated with airflow obstruction, reported as adjusted odds ratios (aORs). Results: Five hundred and three participants successfully completed spirometry testing. The median (Q1; Q3) age was 52 (44; 58) years. The median (Q1; Q3) CD4 count was 598 (438; 784) cells/μL and the median (Q1; Q3) nadir CD4 count was 224 (121; 351) cells/μL. There were 119 (24%) current smokers and 145 (29%) former smokers. Among those screened, 54 (11%) had airflow obstruction whereas three (1%) of the participants had COPD. Factors that were associated with airflow obstruction included a history of smoking [aOR 2.2; 95% confidence interval (CI) 1.1; 4.7], older age (aOR 1.6; 95% CI 1.2; 2.2), and lower CD4 count (aOR 0.8; 95% CI 0.7; 1.0). Conclusions: Airflow obstruction was relatively uncommon. Our findings suggest that PLWHIV who are ≥50 years old, smokers and those with nadir CD4 counts ≤ 200 cells/μL could be targeted to undergo spirometry to diagnose chronic airflow obstruction. [ABSTRACT FROM AUTHOR]

Objectives: The aim was to determine the effectiveness of the serum cryptococcal antigen (CrAg) test in the diagnosis of concurrent cryptococcal meningitis (CM) and as a predictor of mortality in HIV‐infected patients. Methods: In this retrospective study, all HIV‐infected patients admitted to Shanghai Public Health Clinical Center from 1 January 2014 to 31 August 2016 were screened for serum CrAg using the latex agglutination test. Serum CrAg‐positive patients underwent lumbar puncture to confirm CM prior to the initiation of appropriate antifungal therapy and were followed up for at least 6 months. Results: One hundred and four (7.1%) of the total of 1474 HIV‐infected patients screened were serum CrAg‐positive. CM was diagnosed in the majority of serum CrAg‐positive patients (71.3%; 67 of 94) and was confirmed in all (46 of 46) of the patients with headache or coma and in 43.8% (21 of 48) of patients without neurological symptoms. CrAg titres ≥ 1:1024 showed a sensitivity of 82.5% and a specificity of 86.7% for the diagnosis of concurrent CM (P < 0.001). The positive predictive value for CM in this population was 94.3%. A total of 13 serum CrAg‐positive patients [13.8%; 95% confidence interval (CI) 7.5–22.4%] died (11 as a result of CM and two others as a result of bacterial pneumonia) despite early antifungal treatment initiation. Serum CrAg titres ≥ 1:1024 predicted all‐cause mortality (hazard ratio 3.69; P = 0.03). Conclusions: Serum CrAg titres ≥ 1:1024 not only were associated with concurrent CM but also predicted mortality. HIV‐infected patients with a positive serum CrAg test during screening should receive lumbar punctures regardless of symptoms to rule out CM and patients with serum CrAg titres ≥ 1:1024 should be offered immediate care. [ABSTRACT FROM AUTHOR]

Objectives Conflicting results have been reported regarding the ability of valproic acid ( VPA) to reduce the size of HIV reservoirs in patients receiving suppressive highly active antiretroviral therapy ( HAART). In a randomized multicentre, cross-over study, we assessed whether adding VPA to stable HAART could potentially reduce the size of the latent viral reservoir in CD4 T cells of chronically infected patients. Methods A total of 56 virologically suppressed patients were randomly assigned either to receive VPA plus HAART for 16 weeks followed by HAART alone for 32 weeks (arm 1; n = 27) or to receive HAART alone for 16 weeks and then VPA plus HAART for 32 weeks (arm 2; n = 29). VPA was administered at a dose of 500 mg twice a day (bid) and was adjusted to the therapeutic range. A quantitative culture assay was used to assess HIV reservoirs in CD4 T cells at baseline and at weeks 16 and 48. Results No significant reductions in the frequency of CD4 T cells harbouring replication-competent HIV after 16 and 32 weeks of VPA therapy were observed. In arm 1, median (range) values of IU per log10 billion ( IUPB) cells were 2.55 (range 1.20-4.20), 1.80 (range 1.0-4.70) and 2.70 (range 1.0-3.90; P = 0.87) for baseline, week 16 and week 48, respectively. In arm 2, median values of IUPB were 2.55 (range 1.20-4.65), 1.64 (range 1.0-3.94) and 2.51 (range 1.0-4.48; P = 0.50) for baseline, week 16 and week 48, respectively. Conclusions Our study demonstrates that adding VPA to stable HAART does not reduce the latent HIV reservoir in virally suppressed patients. [ABSTRACT FROM AUTHOR]