HIV persistence: clonal expansion of cells in the latent reservoir

Abstract

While antiretroviral therapy (ART) can reduce HIV-1 to undetectable levels, the virus generally reappears if treatment is stopped. Resurgence of the virus is due to the reactivation of T cells harboring latent integrated provirus, and recent studies indicate that proliferation of these latently infected cells helps maintain the HIV-1 reservoir. In this issue of the JCI, Lee et al. evaluated CD4+ T cell subsets to determine whether certain populations are more likely to harbor full-length, replication-competent provirus. The authors identified an enrichment of clonally expanded Th1 cells containing intact HIV-1 proviruses, suggesting that this polarized subset contributes to the persistence of the reservoir. Strategies to target these provirus-harboring cells need to be considered for future therapies aimed toward HIV-1 cure.

Figure 1. Intact, clonally expanded HIV-1 proviruses in Th1 subpopulation.

(A) CD4⁺ T cells differentiate into functional subsets, each of which is characterized by a defining transcription factor (TF) and a set of cytokines produced following activation. In this issue, Lee et al. sorted peripheral blood mononuclear cells from 3 cART-treated patients into CD4⁺ T cell subpopulations based on production of 4 signature cytokines (blue). Subsets not examined are labeled as such. Cellular activation induces virus production from latently infected CD4⁺ T cells (B). Differentiated T cell subsets carrying replication-competent (C) or defective (D) proviruses can also be stimulated to proliferate. In the patients studied by Lee et al., clonally expanded, intact proviral sequences were predominantly in the largest subset, Th1 cells. See Supplemental Table 3 in ref. 23. Tfh, T follicular helper.