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HIV-1 Vpr targets PU.1 to vastly alter the antiviral machinery of HIV infected primary human macrophages

ABSTRACT: HIV-1 accessory protein, Vpr, is required for efficient HIV-1 infection of macrophages. Here we show that Vpr reprograms macrophage gene expression by altering the activity of master transcriptional regulator, PU.1, which is responsible for regulating the expression of host immune response genes and is necessary for normal hematopoiesis. In HIV-infected primary macrophages, Vpr-dependent changes in PU.1 levels result in suppression of known anti-viral targets of Vpr including IFITM3 and MRC1. Moreover, we find that PU.1 and its co-factor TET2 are co-recruited to DCAF1 by Vpr and targeted for accelerated degradation. Downmodulation of PU.1 is a highly conserved function of Vpr that is maintained across primate lentiviruses including HIV-2 and several SIVs. In contrast, this activity is not shared by the evolutionarily related accessory protein Vpx. Our findings demonstrate how Vpr dramatically enhances HIV spread in macrophages by targeting a myeloid-specific transcription factor needed for expression of multiple viral restriction factors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220574 | GEO | 2024/04/30

REPOSITORIES: GEO

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Project description:Although HIV-1 can directly infect resting CD4+ T cells, virus replication in resting CD4+T cells is very inefficient owing to the different host restriction factors blocking viral replication. The accessory protein Vpx from the major simian immunodeficiency virus (SIV) of rhesus macaque (mac) and HIV-2 lineage could degrade a host restriction factor, SAM and HD domain containing protein 1 (SAMHD1), to facilitate HIV reverse transcription. Interestingly, Vpx proteins from a second SIV lineage, the SIV of redcapped mangabeys or mandrills (SIVrcm/nmd-2), had no effect on SAMHD1 and did not affect the dNTP pool, but strongly increased HIV-1 infection in resting CD4+ T cells although not in primary macrophages. This indicates that Vpx, in addition to SAMHD1,can overcome a previously unexplored restriction factor for lentiviruses. Here to identify this potential restriction factor, we examined Vpxrcm-interacting cellular proteins and found that keratin 72 (KRT72), an intermediate filament protein that is exclusively expressed in resting CD4+ T cells, is a new host antiviral factor targeted by Vpx. Other than Vpx from SIV mac and HIV-2, the Vpxrcm/nmd-2 lineage, which had no effect on the SAMHD1 protein, could strongly promote the degradation of KRT72, resulting in enhanced HIV-1 infection in resting CD4+ T cells. Furthermore, we discovered that KRT72 restricts HIV-1 replication by sequestering incoming HIV-1 capsids in cytoplasmic intermediate filaments (IFs). In the presence of KRT72, HIV-1 capsid cores become attached to the IF and their trafficking toward the nucleus is inhibited. In contrast, in the absence of KRT72, HIV-1 capsids are transported into the nucleus,leading to high levels of integrated HIV-1 DNA. In addition, KRT72 expression was substantially higher in resting CD4+ T cells than in activated CD4+ T cells, and it was rapidly reduced by T cell activation. Collectively, the results show that KRT72 is a new Vpx-counteracted host antiviral factor that acts to tether incoming capsids to the cytoplasmic IF, thereby restricting HIV-1 infection in resting CD4+ T cells.