Single-cell transcriptomics identifies prothymosin α restriction of HIV-1 in vivo

Abstract

Host restriction factors play key roles in innate antiviral defense, but it remains poorly understood which of them restricts HIV-1 in vivo. Here, we used single-cell transcriptomic analysis to identify host factors associated with HIV-1 control during acute infection by correlating host gene expression with viral RNA abundance within individual cells. Wide sequencing of cells from one participant with the highest plasma viral load revealed that intracellular viral RNA transcription correlates inversely with expression of the gene PTMA , which encodes prothymosin α. This association was genome-wide significant ( P adjusted < 0.05) and was validated in 28 additional participants from Thailand and the Americas with HIV-1 CRF01_AE and subtype B infections, respectively. Overexpression of prothymosin α in vitro confirmed that this cellular factor inhibits HIV-1 transcription and infectious virus production. Our results identify prothymosin α as a host factor that restricts HIV-1 infection in vivo, which has implications for viral transmission and cure strategies.

HIV-1–infected T cell clones are shared across cerebrospinal fluid and blood during ART

“…The gene expression of these infected cells in the CSF showed upregulation in key pathways, highlighting potential cellular mechanisms of HIV persistence and immune evasion. We extend prior studies in blood that have shown that single-cell technologies can identify transcriptionally active HIV-infected cells ( 33 , 34 ).…”

AP-1/c-Fos supports SIV and HIV-1 latency in CD4 T cells infected in vivo

“…These analyses have culminated in novel revelations about the properties of infected cells in PWH on and off suppressive ART, such as preferential infection of Th1-polarized, cytotoxic effector memory cells during early infection 37 ; enrichment of specific transcription factor motifs 38 ; upregulation of pro-survival and immune checkpoint markers 39 ; increased cell proliferation and HIV-1 silencing signatures 40 ; phenotypically distinct T cell subsets targeted in blood and lymph nodes 41 ; and differential expression of host restriction factors. 42 Despite these gains, a knowledge gap remains regarding the cellular environment conducive to latency establishment in vivo , which requires detailed viral transcriptional activity information to distinguish productive versus non-productive infection combined with the host transcriptome. This is supported by findings from in vitro models in which latently infected cells exhibit distinct transcriptomic profiles from virus-expressing cells.…”