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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 (Padjusted < 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. Editor's summary: Identifying factors that restrict human immunodeficiency virus (HIV)–1 replication in vivo may inform potential cure strategies for people living with HIV-1. Here, Geretz et al. analyzed transcripts from both the host and virus within the same single cells to identify host transcripts associated with lower HIV-1 RNA. Using samples from a person living with HIV-1, the authors identified prothymosin α as one such host restriction factor, which they validated in 28 additional participants. Further, overexpression of prothymosin α was sufficient to restrict HIV-1 replication in vitro. These data demonstrate that prothymosin α is a host restriction factor and suggest that it may represent a target for HIV-1 cure strategies. —Courtney Malo [ABSTRACT FROM AUTHOR]

Putting pressure on HIV: Type 1 interferons provide early host immune defense against viruses, including HIV-1, by promoting expression of proteins that have direct or indirect antiviral activity. It remains unclear how viruses that persist long term, such as HIV-1, escape type 1 interferon–mediated pressure. Gondim et al. characterize interferon resistance in HIV-1 isolates acquired from HIV-1–infected individuals over several years. The authors found that HIV-1 isolates acquired at the time of initial infection or during interruption of antiretroviral therapy were the most resistant to type 1 interferons. These findings underpin the importance of type 1 interferons in controlling HIV-1 infection in the host. Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4+ T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC50) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant. [ABSTRACT FROM AUTHOR]