Initiation of Antiretroviral Therapy Restores CD4 ⁺ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

Abstract

Treatment of human immunodeficiency virus (HIV) infection with antiretroviral therapy (ART) has significantly improved prognosis. Unfortunately, interruption of ART almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. Based on their longevity and proliferative potential, CD4؉ T memory stem cells (T SCM ) have been proposed as an important site of HIV persistence. In a previous study, we found that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RM), CD4؉ T SCM are preserved in number but show (i) a decrease in the frequency of CCR5 ؉ cells, (ii) an expansion of the fraction of proliferating Ki-67 ؉ cells, and (iii) high levels of SIV DNA. To understand the impact of ART on both CD4؉ T SCM homeostasis and virus persistence, we conducted a longitudinal analysis of these cells in the blood and lymph nodes of 25 SIV-infected RM. We found that ART induced a significant restoration of CD4 ؉ CCR5 ؉ T SCM both in blood and in lymph nodes and a reduction in the fraction of proliferating CD4؉ Ki-67 ؉ T SCM in blood (but not lymph nodes). Importantly, we found that the level of SIV DNA in CD4؉ transitional memory (T TM ) and effector memory (T EM ) T cells declined ϳ100-fold after ART in both blood and lymph nodes, while the level of SIV DNA in CD4؉ T SCM and central memory T cells (T CM-) did not significantly change. These data suggest that ART is effective at partially restoring CD4 ؉ T SCM homeostasis, and the observed stable level of virus in T SCM supports the hypothesis that these cells are a critical contributor to SIV persistence. IMPORTANCE Understanding the roles of various CD4؉ T cell memory subsets in immune homeostasis and HIV/SIV persistence during antiretroviral therapy (ART) is critical to effectively treat and cure HIV infection. T memory stem cells (T SCM ) are a unique memory T cell subset with enhanced self-renewal capacity and the ability to differentiate into other memory T cell subsets, such as central and transitional memory T cells (T CM and T TM , respectively). CD4 ؉ T SCM are disrupted but not depleted during pathogenic SIV infection. We find that ART is partially effective at restoring CD4 ؉ T SCM homeostasis and that SIV DNA harbored within this subset contracts more slowly than virus harbored in shorter-lived subsets, such as T TM and effector memory (T EM ). Because of their ability to persist long-term in an individual, understanding the dynamics of virally infected CD4 ؉ T SCM during suppressive ART is important for future therapeutic interventions aimed at modulating immune activation and purging the HIV reservoir. Infection with pathogenic lentiviruses such as human and simian immunodeficiency viruses (HIV and SIV, respectively) significantly perturbs the homeostasis of the CD4 ϩ T cell compartment through preferential infection and depletion of memory CD4 ϩ T cells, which is the hallmark of progression to AIDS. While the availability of antiretroviral therapy (ART) has significantly reduced the mortality and ...

Simian Immunodeficiency Virus Persistence in Cellular and Anatomic Reservoirs in Antiretroviral Therapy-Suppressed Infant Rhesus Macaques

“…Following ART initiation at week 5 after infection, we observed a 2 to 3 log reduction in plasma viral loads within 2 weeks and levels below the limit of detection of our assay (60 copies/ml plasma) after 4 to 22 weeks of treatment. Consistent with prior studies of SIV infection in adult RMs (17,23), the absolute number of peripheral CD4 ϩ T cells was significantly decreased following infection (1,644 Ϯ 203 preinfection versus 916 Ϯ 101 pre-ART; P ϭ 0.006) ( Fig. 1B) and was partially restored on ART (916 Ϯ 101 pre-ART versus 1,441 Ϯ 81 on ART; P ϭ 0.0003) (Fig.…”

Antiretroviral Therapy in Simian Immunodeficiency Virus-Infected Sooty Mangabeys: Implications for AIDS Pathogenesis

“…The main findings of the current study are that administration of ART in SIV-infected SMs was well tolerated overall and resulted in a rapid decline of viremia to levels below the limit of detection of our standard assay in all but one treated animal. The level of viremia decline observed in the current study is comparable overall to what we observed in similar studies conducted on SIV-infected RMs (19,44). In addition, we found that ART initiation was followed by an increase in the percentage of CD4 ϩ T CM cells in peripheral blood, an increase of CD4 ϩ T cells in the rectal mucosa, and a decline in the levels of activated CD8 ϩ HLA-DR ϩ T cells in both blood and the rectum.…”

Multimodal profiling of lung granulomas reveals cellular correlates of tuberculosis control

“…These cells may represent a "stemlike" population of T cells, which are described as an early differentiating memory phenotype, distinct from naïve T cells, that are long-lived and possess a unique ability to proliferate and self-renew (Ahmed et al, 2016;Caccamo et al, 2018;Gattinoni et al, 2011). Similar cells have been reported in human and animal models of viral infection (Cartwright et al, 2016;Fuertes Marraco et al, 2015) and tumors (Ando et al, 2020;Brummelman et al, 2018;Wu et al, 2019), and in humans with Chagas disease (Mateus et al, 2015). In the tumor microenvironment, stem-like T cells have been described as expressing inhibitory receptors such as PD-1 (Siddiqui et al, 2019).…”