Dataset Information

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

ABSTRACT:

Objective

We evaluated frequencies of T cells with high PD-1 expression (PD-1) 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-1 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-1 CD4 T cells correlated positively with viremia and negatively with CD4 T-cell count. At year 1 on-ART, %PD-1 CD4 T cells decreased but then remained stable at 4 and 6-15 years on-ART, whereas %PD-1 CD8 T cells on-ART remained similar to pre-ART. PD-1 CD4 T cells correlated positively with HIV DNA pre-ART and on-ART, and with CD4 T-cell activation on-ART. PD-1 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-1 CD8 T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV.

Conclusion

PD-1 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.

SUBMITTER: Macatangay BJC

PROVIDER: S-EPMC7313719 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Macatangay Bernard J C BJC Gandhi Rajesh T RT Jones Richard B RB Mcmahon Deborah K DK Lalama Christina M CM Bosch Ronald J RJ Cyktor Joshua C JC Thomas Allison S AS Borowski Luann L Riddler Sharon A SA Hogg Evelyn E Stevenson Eva E Eron Joseph J JJ Mellors John W JW Rinaldo Charles R CR

AIDS (London, England) 20200101 1

<h4>Objective</h4>We evaluated frequencies of T cells with high PD-1 expression (PD-1) 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.<h4>Methods</h4>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-1 T-cell frequencies at timepoints pre-ART an ...[more]

PMID: 31634201

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Project description:Although antiretroviral therapy (ART) effectively suppresses HIV replication, the latent reservoir remains the barrier to HIV eradication. It remains unknown whether long-term ART impacts levels of inducible replication-competent provirus. To address this knowledge gap, we assessed the proviral reservoir in HIV-1 perinatally infected adolescents having received ART for >13 years. We recruited 15 vertically infected adolescents living with HIV in Botswana. Historical viral load, CD4+ T cell count, and treatment data were retrieved from their outpatient medical records. Inducible replication-competent proviruses from cryopreserved peripheral blood mononuclear cells were quantified using a TZM-bl based assay (TZA). Total proviral DNA copies were quantified using droplet digital PCR. The mean age of study participants was 16 years (standard deviation = 0.7) and median CD4+ T cell count at enrollment was 784 [interquartile range (IQR) = 728.8-1,288] cells/mm3. Median age at ART initiation was 8 (IQR = 6-12) months. Fourteen (93%) participants had HIV-1 RNA <400 copies/mL at the time of enrollment in the study. A median of 19 (IQR = 18-27) HIV-1 RNA measurements were available per participant. Six (40%) participants displayed viral suppression at all clinic visits since initiating ART, whereas the remaining 9 (60%) had one or more clinic visits with detectable HIV-1 RNA. The median inducible replication-competent provirus count was 7.4 infectious units per million cells (IQR = 6.7-19.2), and did not differ significantly by either complete or incomplete viral suppression (7.2 vs. 7.4, p = .86), or by age at ART initiation (7.4 if <12 months, 11.2 if >12 months, p = .85). The median total HIV DNA count was 129.1 copies per million cells (IQR = 18.9-212.3). Our data suggest that long-term ART initiated within the 1st year in perinatally infected infants did not eliminate proviral DNA or inducible replication-competent proviruses.

Project description:BackgroundAging-associated noncommunicable comorbidities are more prevalent among human immunodeficiency virus type 1 (HIV)-infected individuals than among HIV-uninfected individuals. Residual HIV-related chronic immune activation and senescence may increase the risk of developing comorbidities.MethodsImmune phenotyping, thymic output, and telomere length were assessed in 94 HIV-infected individuals who were aged >45 years and receiving antiretroviral therapy (ART; cases) and 95 age-matched uninfected controls.ResultsCases had lower CD4(+) T-cell counts, higher CD8(+) T-cell counts, and increased levels of immune activation (ie, increased soluble CD14 [sCD14] level and increased percentages of CD38(+)HLA-DR(+) cells among both CD4(+) and CD8(+) T cells), regulatory T cells, and percentage of programmed cell death 1 (PD-1)-expressing cells among CD4(+) T cells. Immune senescence levels (ie, percentages of CD27(-)CD28(-) cells or CD57(+) cells) were comparable between cases and controls. Peripheral blood mononuclear cells from cases had shorter telomeres but increased single-joint T-cell receptor excision circle content and CD31(+) naive CD4(+) T cells. Although cytomegalovirus (CMV) antibody titers were higher in cases, CMV-specific T-cell responses were comparable between cases and controls. T-cell senescence in cases was independently associated with T-cell activation but not with CMV-specific immune responses.ConclusionsDespite long-term receipt of ART, HIV-infected adults had higher levels of immune activation, regulatory T cells, and PD-1-expressing CD4(+) cells and shorter telomeres. The increased soluble CD14 levels and percentage of CD38(+)HLA-DR(+) cells among CD4(+) T cells correlated with shorter telomeres and increased regulatory T-cell levels. This suggests that HIV influences immune function irreversibly, with several pathways that are persistently abnormal during effective ART. Therapies aimed at improving immune health during ART are needed.

Dataset Information

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

Objective

Methods

Results

Conclusion

Publications

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

Similar Datasets

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