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Evaluation of HIV-specific T-cell responses in HIV-infected older patients with controlled viremia on long-term antiretroviral therapy.

ABSTRACT: HIV-infected older individuals may have a diminished immune response because of exhaustion/immune aging of T-cells. Therefore, we have investigated HIV-specific CD4 and CD8 T-cell responses in 100 HIV-infected patients (HIV+) who have aged on long-term antiretroviral therapy (ART) and achieved controlled viremia (mostly undetectable viral load; 92 patients with <20 to <40 HIV RNA copies/mL and 8 <60 to <100) and improved CD4 T-cell counts. We show that the median frequencies of HIV-specific CD4+ and CD8+ IFN-? T-cells were higher in HIV+ than uninfected individuals (HIV-), including increasing levels of IFN-?produced by CD4+ T-cells and decreasing levels by CD8+ T-cells with increasing CD4 T-cell counts in HIV+. No correlation was found between T-cell responses and varying levels of undetectable viremia. HIV-specific TNF-? made by CD8+ T-cells was higher in HIV+ than HIV-, including decreasing levels with increasing CD4 T-cell counts in HIV+. Furthermore, the CD8+ T-cell mediators, CD107a and Granzyme-B, were higher in HIV+ than HIV-, and decreased with increasing CD4 T-cell counts in HIV+. Remarkably, HIV-specific CD8 T-cells produced decreasing levels of IFN-?with increasing age of HIV+, including decreased levels of CD107a and Granzyme-B in older HIV+. However, HIV-specific CD8+ T-cells produced increasing levels of TNF-? with increasing age of the HIV+, suggesting continued inflammation. In conclusion, HIV+ with controlled viremia on long-term ART and with higher CD4 T-cell counts showed reduced HIV-specific CD8 T-cell responses as compared to those with lower CD4 T-cell counts, and older HIV+ exhibited decreasing levels of CD8 T-cell responses with increasing age.

SUBMITTER: Behrens NE

PROVIDER: S-EPMC7498024 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Evaluation of HIV-specific T-cell responses in HIV-infected older patients with controlled viremia on long-term antiretroviral therapy.

Behrens Nicole E NE Wertheimer Anne A Love Maria B MB Klotz Stephen A SA Ahmad Nafees N

PloS one 20200917 9

HIV-infected older individuals may have a diminished immune response because of exhaustion/immune aging of T-cells. Therefore, we have investigated HIV-specific CD4 and CD8 T-cell responses in 100 HIV-infected patients (HIV+) who have aged on long-term antiretroviral therapy (ART) and achieved controlled viremia (mostly undetectable viral load; 92 patients with <20 to <40 HIV RNA copies/mL and 8 <60 to <100) and improved CD4 T-cell counts. We show that the median frequencies of HIV-specific CD4+ ...[more]

PMID: 32941433

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Project description:Background: Disease progression monitoring through CD4 counts alone can be inadequate in HIV infection as ongoing immune activation may result in Serious non-AIDS events (SNAEs). SNAEs involve monocyte activation driven chronic inflammation with significant sequelae observed even during HAART. Here, we attempted to delineate functional monocyte based signatures across stages of HIV disease progression. Methods: Participants spanning four cohorts were recruited-pre-ART (PA; <7 years of infection; n = 20), long-term non-progressors (LTNP; >7 years of infection, CD4 > 350 cells/μL, n = 20), individuals on therapy (ART; n = 18) and seronegative controls (SN; n = 15). Immunophenotyping of monocyte subsets and evaluation of expression of HIV-binding receptors-CD4 and CCR5, marker of immune activation- HLA-DR and M2 phenotype-mannose receptor (CD206) was followed by association of monocyte-specific parameters with conventional markers of disease progression such as absolute CD4 count, CD4/CD8 ratio, viral load, and T cell activation. Results: A significant expansion of intermediate monocytes (CD14++CD16+) with a concomitant decline in classical subset (CD14++CD16-) was observed in all infected cohorts compared to seronegative controls. In addition, an expansion of the non-classical subset (CD14+CD16++) was observed in long-term non-progressors. Dysregulation in monocyte subsets associated with CD4 count and CD4/CD8 ratio in PAs but not in LTNPs. We report for the first time that expression of CD206 is most prominent on intermediate monocytes which also have the highest expression of CD4, CCR5, and HLA-DR. Despite preserved CD4 counts, LTNPs had similar immune activation profiles to PAs, as evidenced by elevated HLA-DR expression across monocyte subsets. HLA-DR expression, similar to that in SNs, observed in the ART group indicated partial immune restoration within the monocyte compartment. Increased CD206 expression on monocytes together with frequency of activated CD4+ T lymphocytes (HLA-DR+CD38+) showed significant and positive association with viral load in LTNPs, but not PAs. Conclusion: Our results describe for the first time the presence of monocyte dysregulation involving increased activation in LTNPs, who, in spite of preserved CD4 counts, may remain susceptible to prolonged effects of systemic inflammation and highlight CD206, as a unique non-T correlate of viremia, in viremic non-progression.

Project description:ObjectiveThis study aims to analyze the efficacy of anti-syphilis treatment and the impact of syphilis events on HIV virology and immunology in HIV/syphilis co-infected patients on long-term antiretroviral therapy (ART) and to investigate the incidence and factors of syphilis recurrence/re-infection/serofast state. The insights derived from this investigation can potentially guide strategies for preventing and managing syphilis and AIDS.MethodsA retrospective case-control study was conducted at the AIDS clinic of Peking Union Medical College Hospital from January 2003 to December 2022. The study involved 86 HIV/syphilis co-infected patients and 86 HIV mono-infected patients matched based on age, baseline CD4 + T cell counts, and viral load. We examined the clinical characteristics of HIV/syphilis co-infected patients, evaluated the efficacy of anti-syphilis treatment, and analyzed the dynamic changes in HIV virology and immunology. The Generalized Estimating Equations (GEE) model investigated the factors associated with HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state.ResultsSyphilis serofast state was observed in 11.6% (10/86) of HIV/syphilis co-infected patients after treatment, and 33.7% (29/86) had syphilis recurrence or re-infection. The overall effectiveness of syphilis treatment stood at 76.8% (63/82). Notably, the effectiveness of syphilis treatment displayed a significant correlation with baseline syphilis titers exceeding 1:128 (p = 0.003). Over the 10-year follow-up period on ART, the HLA-DR + CD8+/CD8 + % levels in the HIV/syphilis co-infected group were markedly higher than those in the HIV mono-infected group (p < 0.05). However, no significant differences were observed between the two groups regarding HIV viral load, CD4+ T cell counts, CD8+ T cell counts, CD4/CD8 ratio, and CD38 + CD8+/CD8 + % (p > 0.05). GEE analysis model revealed that elevated HLA-DR + CD8+/CD8 + % levels were associated with HIV/syphilis co-infection (OR = 1.026, 95% CI = 1.007-1.046; p = 0.007) and syphilis recurrence/reinfection/serofast state (OR = 1.036, 95% CI = 1.008-1.065; p = 0.012).ConclusionWhile HIV/syphilis co-infected patients typically receive adequate treatment, the incidence of syphilis recurrence and reinfection remain notably elevated. A heightened HLA-DR + CD8+/CD8+ % is a notable risk factor for HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state. Therefore, it is advisable to reinforce health education efforts and ensure regular follow-ups for people living with HIV undergoing ART to monitor syphilis infection or increased risk of syphilis infection.

Project description:Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients. Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median -0.2 and -0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus -44 cells/mm(3), p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood. In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection. ClinicalTrials.gov NCT00515827

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Evaluation of HIV-specific T-cell responses in HIV-infected older patients with controlled viremia on long-term antiretroviral therapy.

Publications

Evaluation of HIV-specific T-cell responses in HIV-infected older patients with controlled viremia on long-term antiretroviral therapy.

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