Tissue memory CD4+T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection

Abstract

The primary reservoir for HIV is within memory CD4+ T cells residing within tissues, yet the features that make some of these cells more susceptible than others to infection by HIV is not well understood. Recent studies demonstrated that CCR5-tropic HIV-1 efficiently enters tissue-derived memory CD4+ T cells expressing CD127, the alpha chain of the IL7 receptor, but rarely completes the replication cycle. We now demonstrate that the inability of HIV to replicate in these CD127-expressing cells is not due to post-entry restriction by SAMHD1. Rather, relative to other memory T cell subsets, these cells are highly prone to undergoing latent infection with HIV, as revealed by the high levels of integrated HIV DNA in these cells. Host gene expression profiling revealed that CD127-expressing memory CD4+ T cells are phenotypically distinct from other tissue memory CD4+ T cells, and are defined by a quiescent state with diminished NF kappa B, NFAT, and Ox40 signaling. However, latently-infected CD127+ cells harbored unspliced HIV transcripts and stimulation of these cells with anti-CD3/CD28 reversed latency. These findings identify a novel subset of memory CD4+ T cells found in tissue and not in blood that are preferentially targeted for latent infection by HIV, and may serve as an important reservoir to target for HIV eradication efforts. Author summary Although the primary targets of HIV are CD4+ T cells that reside in tissues, to date most studies characterizing HIV-infected cells have used cells isolated from blood. We recently demonstrated that although HIV can enter a diverse array of CD4+ T cells present in lymphoid tissues, only a limited subset of these cells support completion of the full viral life cycle. Here, we identified a subset of lymphoid tissue CD4+ T cells that express a surface protein called CD127. These cells efficiently support early stages of the viral life cycle up to the point where the virus has integrated its DNA into the human genome, but suppress the later stages of viral gene expression. Relative to other types of CD4+ T cells, the CD127+ cells exist in a more quiescent state, which may be inadequate for HIV protein expression and results in latency. This latency, however, can be reversed following T cell stimulation. Better characterizing the mechanisms that promote latency in tissue cells, using CD127 as a biomarker or this specific subset of cells as a model system, promises to help identify new approaches for eliminating or controlling these cells thus contributing to achieving a functional cure for HIV/AIDS.