Dataset Information

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8⁺ T cells.

ABSTRACT:

Background

Harnessing CD8⁺ T cell responses is being explored to achieve HIV remission. Although HIV-specific CD8⁺ T cells become dysfunctional without treatment, antiretroviral therapy (ART) partially restores their function. However, the extent of this recovery under long-term ART is less understood.

Methods

We analyzed the differentiation status and function of HIV-specific CD8⁺ T cells after long-term ART initiated in acute or chronic HIV infection ex vivo and upon in vitro recall.

Findings

ART initiation in any stage of acute HIV infection promoted the persistence of long-lived HIV-specific CD8⁺ T cells with high expansion (P<0·0008) and cytotoxic capacity (P=0·02) after in vitro recall, albeit at low cell number (P=0·003). This superior expansion capacity correlated with stemness (r=0·90, P=0·006), measured by TCF-1 expression, similar to functional HIV-specific CD8⁺ T cells found in spontaneous controllers. Importanly, TCF-1 expression in these cells was associated with longer time to viral rebound ranging from 13 to 48 days after ART interruption (r =0·71, P=0·03). In contrast, ART initiation in chronic HIV infection led to more differentiated HIV-specific CD8⁺ T cells lacking stemness properties and exhibiting residual dysfunction upon recall, with reduced proliferation and cytolytic activity.

Interpretation

ART initiation in acute HIV infection preserves functional HIV-specific CD8⁺ T cells, albeit at numbers too low to control viral rebound post-ART. HIV remission strategies may need to boost HIV-specific CD8⁺ T cell numbers and induce stem cell-like properties to reverse the residual dysfunction persisting on ART in people treated after acute infection prior to ART release.

Funding

U.S. National Institutes of Health and U.S. Department of Defense.

SUBMITTER: Takata H

PROVIDER: S-EPMC9471490 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8<sup>+</sup> T cells.

Takata Hiroshi H Kakazu Juyeon C JC Mitchell Julie L JL Kroon Eugene E Colby Donn J DJ Sacdalan Carlo C Bai Hongjun H Ehrenberg Philip K PK Geretz Aviva A Buranapraditkun Supranee S Pinyakorn Suteeraporn S Intasan Jintana J Tipsuk Somporn S Suttichom Duanghathai D Prueksakaew Peeriya P Chalermchai Thep T Chomchey Nitiya N Phanuphak Nittaya N de Souza Mark M Michael Nelson L NL Robb Merlin L ML Haddad Elias K EK Crowell Trevor A TA Vasan Sandhya S Valcour Victor G VG Douek Daniel C DC Thomas Rasmi R Rolland Morgane M Chomont Nicolas N Ananworanich Jintanat J Trautmann Lydie L

EBioMedicine 20220908

<h4>Background</h4>Harnessing CD8<sup>+</sup> T cell responses is being explored to achieve HIV remission. Although HIV-specific CD8<sup>+</sup> T cells become dysfunctional without treatment, antiretroviral therapy (ART) partially restores their function. However, the extent of this recovery under long-term ART is less understood.<h4>Methods</h4>We analyzed the differentiation status and function of HIV-specific CD8<sup>+</sup> T cells after long-term ART initiated in acute or chronic HIV infec ...[more]

PMID: 36088683

Similar Datasets

Project description:BackgroundFor people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain.MethodsThe Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021.ResultsThrough December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference).ConclusionsAmong adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Dataset Information

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8⁺ T cells.

Background

Methods

Findings

Interpretation

Funding

Publications

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8+ T cells.

Background

Methods

Findings

Interpretation

Funding

Publications

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8⁺ T cells.