Hide and seek: for HIV-infected CD4+ T cells, playing well comes with maturity

Abstract

Antiretroviral therapy suppresses HIV replication but leaves a population of infected CD4+ T cells with integrated proviruses. While most of these proviruses contain defects, such as deletions, some intact proviruses persist and can reinitiate viral replication. In this issue of the JCI, Duette, Hiener, and colleagues performed a tour de force proviral landscape analysis on clinical samples collected over many years with in vitro functional assays. The researchers showed that effector memory CD4+ T cells provide partial sanctuary to intact proviruses from CD8+ T cells and this was associated with superior Nef-mediated MHC-I downregulation relative to less mature CD4+ T cell populations. This finding implicates differential immunoevasion as a cell-intrinsic property, influencing proviral persistence, and highlights Nef as a therapeutic target.

Figure 1. Interactions between HIV-infected cells of different maturational phenotypes and CTLs from participants on ART.

Viral latency is a substantial but imperfect barrier to CTL engagement. Effector memory and naive CD4⁺ T cells possess the additional barriers of superior Nef-mediated immunoevasion and cell-intrinsic CTL resistance, respectively, which allow for higher frequencies of intact proviruses to persist in Tem and Tn cells. Additional layers of diversity exist within these maturational subsets (depicted by cell membrane shading), and further dissecting each subset in relation to immunoevasion/resistance is a key frontier.