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Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8⁺ T-cells.

ABSTRACT: HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac₂₅₁-infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8⁺ T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission.

SUBMITTER: Passaes C

PROVIDER: S-EPMC10784587 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8<sup>+</sup> T-cells.

Passaes Caroline C Desjardins Delphine D Chapel Anaïs A Monceaux Valérie V Lemaitre Julien J Mélard Adeline A Perdomo-Celis Federico F Planchais Cyril C Gourvès Maël M Dimant Nastasia N David Annie A Dereuddre-Bosquet Nathalie N Barrail-Tran Aurélie A Gouget Hélène H Guillaume Céline C Relouzat Francis F Lambotte Olivier O Guedj Jérémie J Müller-Trutwin Michaela M Mouquet Hugo H Rouzioux Christine C Avettand-Fenoël Véronique V Le Grand Roger R Sáez-Cirión Asier A

Nature communications 20240111 1

HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac<sub>251</sub>-infected male cynomolgus macaques receiving 2 years of therapy bef ...[more]

PMID: 38212337

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Project description:CD8+ lymphocytes play an important role in suppressing in vivo viral replication in HIV infection. However, both the extent to which and the mechanisms by which CD8+ lymphocytes contribute to viral control are not completely understood. A recent experiment depleted CD8+ lymphocytes in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) on antiretroviral treatment (ART) to study the role of CD8+ lymphocytes. CD8+ lymphocytes depletion resulted in temporary plasma viremia in all studied RMs. Viral control was restored when CD8+ lymphocytes repopulated. We developed a viral dynamic model to fit the viral load (VL) data from the CD8 depletion experiment. We explicitly modeled the dynamics of the latent reservoir and the SIV-specific effector cell population including their exhaustion and their potential cytolytic and noncytolytic functions. We found that the latent reservoir significantly contributes to the size of the peak VL after CD8 depletion, while drug efficacy plays a lesser role. Our model suggests that the overall CD8+ lymphocyte cytolytic killing rate is dynamically changing depending on the levels of antigen-induced effector cell activation and exhaustion. Based on estimated parameters, our model suggests that before ART or without ART the overall CD8 cytolytic killing rate is small due to exhaustion. However, after the start of ART, the overall CD8 cytolytic killing rate increases due to an expansion of SIV-specific CD8 effector cells. Further, we estimate that the cytolytic killing rate can be significantly larger than the cytopathic death rate in some animals during the second phase of ART-induced viral decay. Lastly, our model provides a new explanation for the puzzling findings by Klatt et al. and Wong et al. that CD8 depletion done immediately before ART has no noticeable effect on the first phase viral decay slope seen after ART initiation Overall, by incorporating effector cells and their exhaustion, our model can explain the effects of CD8 depletion on VL during ART, reveals a detailed dynamic role of CD8+ lymphocytes in controlling viral infection, and provides a unified explanation for CD8 depletion experimental data.

Dataset Information

Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8⁺ T-cells.

Publications

Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8<sup>+</sup> T-cells.

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Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8+ T-cells.

Publications

Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8&lt;sup&gt;+&lt;/sup&gt; T-cells.

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OmicsDI is part of the ELIXIR infrastructure

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Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8⁺ T-cells.

Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8<sup>+</sup> T-cells.