Antibody-Mediated CD4 Depletion Induces Homeostatic CD4 ⁺ T Cell Proliferation without Detectable Virus Reactivation in Antiretroviral Therapy-Treated Simian Immunodeficiency Virus-Infected Macaques

Abstract

A major barrier to human immunodeficiency virus (HIV) eradication is the long-term persistence of latently infected CD4 T cells harboring integrated replication-competent virus. It has been proposed that the homeostatic proliferation of these cells drives long-term reservoir persistence in the absence of virus reactivation, thus avoiding cell death due to either virus-mediated cytopathicity or immune effector mechanisms. Here, we conducted an experimental depletion of CD4 T cells in eight antiretroviral therapy (ART)-treated, simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) to determine whether the homeostatically driven CD4 T-cell proliferation that follows CD4 T-cell depletion results in reactivation of latent virus and/or expansion of the virus reservoir. After administration of the CD4R1 antibody, we observed a CD4 T cell depletion of 65 to 89% in peripheral blood and 20 to 50% in lymph nodes, followed by a significant increase in CD4 T cell proliferation during CD4 T cell reconstitution. However, this CD4 T cell proliferation was not associated with detectable increases in viremia, indicating that the homeostatic activation of CD4 T cells is not sufficient to induce virus reactivation from latently infected cells. Interestingly, the homeostatic reconstitution of the CD4 T cell pool was not associated with significant changes in the number of circulating cells harboring SIV DNA compared to results for the first postdepletion time point. This study indicates that, in ART-treated SIV-infected RMs, the homeostasis-driven CD4 T-cell proliferation that follows experimental CD4 T-cell depletion occurs in the absence of detectable reactivation of latent virus and does not increase the size of the virus reservoir as measured in circulating cells. Despite successful suppression of HIV replication with antiretroviral therapy, current treatments are unable to eradicate the latent virus reservoir, and treatment interruption almost invariably results in the reactivation of HIV even after decades of virus suppression. Homeostatic proliferation of latently infected cells is one mechanism that could maintain the latent reservoir. To understand the impact of homeostatic mechanisms on virus reactivation and reservoir size, we experimentally depleted CD4 T cells in ART-treated SIV-infected rhesus macaques and monitored their homeostatic rebound. We find that depletion-induced proliferation of CD4 T cells is insufficient to reactivate the viral reservoir Furthermore, the proportion of SIV DNA CD4 T cells remains unchanged during reconstitution, suggesting that the reservoir is resistant to this mechanism of expansion at least in this experimental system. Understanding how T cell homeostasis impacts latent reservoir longevity could lead to the development of new treatment paradigms aimed at curing HIV infection.

Single-cell TCR sequencing reveals phenotypically diverse clonally expanded cells harboring inducible HIV proviruses during ART

“…6d). In addition, our results indicate that HIV-infected cells have the ability to proliferate and differentiate without being eliminated, suggesting that this process can occur in the absence of HIV production as previously reported 38,39 or that these cells can escape immune-mediated killing, as recently suggested by Ren et al 40 .…”

CD8 Lymphocyte Depletion Enhances the Latency Reversal Activity of the SMAC Mimetic AZD5582 in ART-Suppressed Simian Immunodeficiency Virus-Infected Rhesus Macaques

“…Instead, several lines of evidence suggest a direct effect of CD8 depletion on latency reversal. First, we previously showed in ART-treated on May 10, 2021 by guest http://jvi.asm.org/ Downloaded from SIV-infected RMs that the strong homeostatic proliferation that follows Ab-mediated CD4 + T cell depletion did not induce on-ART viremia (28). Second, treatment of SIV-infected ARTsuppressed RMs with the IL-15 superagonist (N-803), that causes CD4 + T cell activation and proliferation, did not result in latency reversal (14).…”

In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia

“…The viral reservoir is remarkably stable, with an estimated half-life of ~44–48 months, suggesting that at least 70 years of continuous ART would be required to eliminate it completely 6 , 7 . Long-term maintenance of the reservoir can in part be explained by clonal expansion of HIV-infected cells, which is thought to be driven by three non-mutually exclusive forces: homeostatic proliferation 8 – 12 , antigenic stimulation 13 – 15 , and integration site (IS)-driven proliferation 16 – 19 . Identifying the cellular sources of viral rebound and the mechanisms that ensure their persistence during ART is needed to develop targeted strategies to eradicate or control HIV 20 , 21 .…”