Blood CXCR3+ CD4 T Cells Are Enriched in Inducible Replication Competent HIV in Aviremic Antiretroviral Therapy-Treated Individuals

Abstract

We recently demonstrated that lymph nodes (LNs) PD-1+/T follicular helper (Tfh) cells from antiretroviral therapy (ART)-treated HIV-infected individuals were enriched in cells containing replication competent virus. However, the distribution of cells containing inducible replication competent virus has been only partially elucidated in blood memory CD4 T-cell populations including the Tfh cell counterpart circulating in blood (cTfh). In this context, we have investigated the distribution of (1) total HIV-infected cells and (2) cells containing replication competent and infectious virus within various blood and LN memory CD4 T-cell populations of conventional antiretroviral therapy (cART)-treated HIV-infected individuals. In the present study, we show that blood CXCR3-expressing memory CD4 T cells are enriched in cells containing inducible replication competent virus and contributed the most to the total pool of cells containing replication competent and infectious virus in blood. Interestingly, subsequent proviral sequence analysis did not indicate virus compartmentalization between blood and LN CD4 T-cell populations, suggesting dynamic interchanges between the two compartments. We then investigated whether the composition of blood HIV reservoir may reflect the polarization of LN CD4 T cells at the time of reservoir seeding and showed that LN PD-1+ CD4 T cells of viremic untreated HIV-infected individuals expressed significantly higher levels of CXCR3 as compared to CCR4 and/or CCR6, suggesting that blood CXCR3-expressing CD4 T cells may originate from LN PD-1+ CD4 T cells. Taken together, these results indicate that blood CXCR3-expressing CD4 T cells represent the major blood compartment containing inducible replication competent virus in treated aviremic HIV-infected individuals.

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…These cells are characterized by surface expression of CXCR5 and PD-1, reside in the lymph node follicles in immediate anatomical proximity to B cells, and support the germinal center reaction essential for the generation of effective humoral immunity. Notably, the group of Matthieu Perreau, by investigating lymph node T fh (expressing CXCR5 and PD-1) and pT fh (expressing CXCR3), has shown that these subpopulations are the major sources of infectious replication-competent HIV-1 (Banga et al, 2016b(Banga et al, , 2018.…”

HIV Rebound Is Predominantly Fueled by Genetically Identical Viral Expansions from Diverse Reservoirs

“…Although different CD4+ T cell subsets have been identified as major contributors to the HIV-1 reservoir (Chomont et al, 2009;Hiener et al, 2017;Lee et al, 2017b) and different surface markers (CXCR3, CD30, and CD32a) (Banga et al, 2018;Descours et al, 2017;Henrich et al, 2017) and immune exhaustion markers (PD-1, TIGIT, and LAG-3) (Khoury et al, 2017;McGary et al, 2017) have emerged as potential biomarkers for latently infected cells, previous studies have not converged on a clear pattern or predominant subsets responsible for HIV persistence.…”

Measuring the Success of HIV-1 Cure Strategies

“…Various differentiation states of CD4 T cells appear to play important roles in the establishment and maintenance of the LR as well as viral recrudescence following ART interruption (Buzon et al, 2014;Kulpa and Chomont, 2015;Banga et al, 2016;De Scheerder et al, 2019;Falcinelli et al, 2019). As discussed above, the LR is primarily hosted in memory CD4 T cells, specifically, central (T CM ), transitional (T TM ), effector memory (T EM ), and memory stem (T SCM ) cells, although the exact contribution of each cell type to the replication competent reservoir is still to be determined (Chomont et al, 2009;Buzon et al, 2014;Soriano-Sarabia et al, 2014;Banga et al, 2016Banga et al, , 2018Kwon et al, 2020). Recently, CD32+ CD4 T cells have been proposed to be a major host of the LR, whereby selection of this cell population resulted in significant enrichment of inducible provirus (Descours et al, 2017;Darcis et al, 2020).…”