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We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Some human immunodeficiency virus (HIV)-infected individuals are not able to achieve a normal CD4(+) T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size., Methods: Thirty treated subjects with CD4(+) T cell counts of <350 cells/mm(3) despite viral suppression for ≥ 1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38(+)HLA-DR(+)CD8(+) T cells in peripheral blood mononuclear cells (PBMCs)., Results: The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue., Conclusions: Low-level viremia is not likely to be a significant cause of suboptimal CD4(+) T cell gains during HIV treatment., Clinical Trials Registration: NCT00631449.

Background: The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP., Methods: HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation., Results: Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus., Conclusions: As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

Background: The central nervous system (CNS) is a recognized target for human immunodeficiency virus type 1 (HIV-1). CD8(+) T cells may mediate viral clearance from the CNS but also may contribute to immune-mediated neuronal damage., Methods: Using 4- and 6-color flow cytometry, we investigated the role of adhesion molecules (very late antigen [VLA]-4 [ alpha 4 beta 1 integrin] and leukocyte function antigen [LFA]-1 [ alpha L beta 2 integrin]) and chemokine receptors (CXCR3 and CCR5) in CD8(+) T cell migration to cerebrospinal fluid (CSF) during HIV-1 infection., Results: CD8(+) T cells trafficking to CSF were uniformly VLA-4(high), LFA-1(high). CCR5 expression was significantly enhanced in T cells from CSF, compared with those from blood (P<.001), including HIV-1-specific CD8(+) T cells, and most T cells from CSF expressed both CXCR3 and CCR5. Interferon-inducible protein (IP)-10 (CXCL10) levels in CSF were significantly increased in HIV-1-positive individuals, relative to IP-10 levels in control subjects (P=.007), and a positive correlation was found between IP-10 levels and virus load in CSF (r2=.777; P=.0007)., Conclusions: These findings suggest that LFA-1, CCR5 and CXCR3, and IP-10 play an important role in lymphocyte trafficking to CSF during HIV-1 infection. These observations suggest a "push-pull" model, in which lymphocyte extravasation is driven by lymphocyte activation, expression of adhesion molecules, and increased vascular permeability and is coupled with chemokine-mediated trafficking to inflammatory sites in the CNS.

Much scientific effort has been directed towards elucidating the complexities of cell-mediated immune responses to HIV-1(reviewed in [1,2]). These studies have attempted to explain the immune system's ultimate failure to contain viral replication, leading to development of AIDS disease, and to identify immune responses that will be useful in developing immunomodulatory therapies and novel vaccine strategies. Although many of the complex interactions involved in AIDS pathogenesis remain unsolved, great progress has been made in characterizing the kinetics, specificity and functional dynamics of HIV-1-specific T cell responses. These investigations have come at a time when advances in virology, cellular immunology and molecular biology have converged to provide a variety of methodological approaches not available at the onset of the AIDS pandemic. Application of these tools to other infectious diseases and immunopathological conditions will provide a fertile area of research for future years. This review focuses on recent developments in the assessment of HIV-1-specific T cell responses in peripheral blood and tissues, with a particular emphasis on flow cytometry-based approaches.

Seventeen women who were persistently uninfected by human immunodeficiency virus type 1 (HIV-1), despite repeated sexual exposure, and 12 of their HIV-positive male partners were studied for antiviral correlates of non-transmission. Thirteen women had > or = 1 immune response in the form of CD8 cell noncytotoxic HIV-1 suppressive activity, proliferative CD4 cell response to HIV antigens, CD8 cell production of macrophage inflammatory protein-1 beta, or ELISPOT assay for HIV-1-specific interferon-gamma secretion. The male HIV-positive partners without AIDS had extremely high CD8 cell counts. All 8 male partners evaluated showed CD8 cell-related cytotoxic HIV suppressive activity. Reduced CD4 cell susceptibility to infection, neutralizing antibody, single-cell cytokine production, and local antibody in the women played no apparent protective role. These observations suggest that the primary protective factor is CD8 cell activity in both the HIV-positive donor and the HIV-negative partner. These findings have substantial implications for vaccine development.