Brief Report: HIV Antibodies Decline During Antiretroviral Therapy but Remain Correlated With HIV DNA and HIV-Specific T-Cell Responses

Background: In people with HIV on antiretroviral therapy (ART), the relationship between HIV-specific immune responses and measures of HIV persistence is uncertain. Methods: We evaluated 101 individuals on suppressive ART in the AIDS Clinical Trials Group A5321 cohort. Cell-associated (CA) HIV DNA and RNA levels and HIV antibody concentrations and avidity to Env/p24 were measured longitudinally at years 1, 4, and 6-15 after ART initiation. Plasma HIV RNA by single copy assay and T-cell responses (IFN-γ ELISPOT) against multiple HIV antigens were measured at the last time point. Results: HIV antibody levels declined significantly with increasing time on ART (19%/year between year 1 and 4). HIV antibody levels correlated with T-cell responses to HIV Pol (r = 0.28, P = 0.014) and to Nef/Tat/Rev (r = 0.34; P = 0.002). HIV antibody and T-cell responses were positively associated with HIV DNA levels; for example, at the last time point (median 7 years on ART), r = 0.35 for antibody levels and HIV DNA (P < 0.001); r = 0.23 for Nef/Tat/Rev-specific T-cell responses and HIV DNA (P = 0.03). Neither antibody nor T-cell responses correlated with cell-associated HIV RNA or plasma RNA by single copy assay. Conclusions: In individuals on long-term ART, HIV-specific antibody and T-cell responses correlate with each other and with HIV DNA levels. The positive correlation between HIV immune responses and HIV DNA implies that the immune system is sensing, but not clearing, infected cells, perhaps because of immune dysfunction. Measuring immune responses to HIV antigens may provide insight into the impact of reservoir-reducing strategies

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy

Objective: We evaluated frequencies of T cells with high PD-1 expression (PD-1HI) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses.Methods:We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for at least 4 years (N=99). We assessed PD-1HI T-cell frequencies at timepoints pre-ART and on-ART using flow cytometry, and evaluated how frequencies on-ART are associated with measures of HIV persistence, HIV-specific immune responses, and immune activation levels.Results:Pre-ART, PD-1HI CD4+ T cells correlated positively with viremia and negatively with CD4+ T-cell count. At year 1 on-ART, %PD-1HI CD4+ T cells decreased but then remained stable at 4 and 6-15 years on-ART, whereas %PD-1HI CD8+ T cells on-ART remained similar to pre-ART. PD-1HI CD4+ T cells correlated positively with HIV DNA pre-ART and on-ART, and with CD4+ T-cell activation on-ART. PD-1HI CD4+ T cells negatively correlated with HIV Gag-specific and Env-specific T-cell responses but not with CMV-specific or EBV-specific responses. PD-1HI CD8+ T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV.Conclusion:PD-1HI T cells persist in blood despite prolonged suppression on ART, correlate with HIV DNA levels, and are associated with lower HIV-specific T-cell responses but not CMV-specific or EBV-specific responses, suggesting that these cells are HIV-specific. The findings support evaluating PD-1 blockade strategies for their effect on HIV persistence and HIV-specific immunity

Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

BACKGROUND. Persistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART. METHODS. Participants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321) underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment. Cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) were measured by quantitative PCR (qPCR). in peripheral blood mononuclear cells (PBMCs) and in cell pellets from CSF. In CSF supernatant and blood plasma, cell-free HIV RNA was quantified by qPCR with single copy sensitivity, and inflammatory biomarkers were measured by enzyme immunoassay. RESULTS. Sixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm3, plasma HIV RNA &lt;100 copies/mL) were assessed after a median 8.6 years of ART. In CSF, cell-free RNA was detected in 4%, CA-RNA in 9%, and CA-DNA in 48% of participants (median level 2.1 copies/103 cells). Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = 0.007). CSF inflammatory biomarkers did not correlate with HIV persistence measures. Detection of CSF CA-DNA HIV was associated with worse neurocognitive outcomes including global deficit score (P = 0.005), even after adjusting for age and nadir CD4 count. CONCLUSION. HIV-infected cells persist in CSF in almost half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance