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HIV-1 signalling remodels nuclear pores to licence infection

ABSTRACT: HIV-1 is readily-detected in resting CD4+ T-cells in vivo1-4. However, resting T-cells are highly-refractory to cell-free virus infection in vitro5-7 and require mitogenic activation to become permissive. This paradox raises the fundamental question of what makes a T-cell permissive for HIV-1. Here we address this and show that HIV-1 capsid nuclear import at the nuclear pore complex (NPC) is a bottleneck to resting T-cell infection, but that HIV-1 overcomes this by triggering receptor-mediated signalling during cell-cell spread to drive nuclear import and licence infection. Coupling viral and cellular assays with super-resolution imaging we show that contact between HIV-1 infected and uninfected T-cells triggers CD4-Lck signalling that activates CDK1, independent of cell-cycle entry, phosphorylating nucleoporins and priming the NPC to promote HIV-1 nuclear import. Critically, cell-cell contact also accelerates nuclear import in activated T-cells, providing a new paradigm for why cell-cell spread dominates infection. By contrast, HIV-1 virions do not trigger this response, explaining why resting T-cells cannot be efficiently infected by cell-free virus. We propose that HIV-1 has evolved to activate CD4 signalling during cell-cell spread to regulate infection at the step of the NPC, thereby bypassing the need for T-cell activation and offering an explanation for how resting T-cells can be infected in vivo.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: riccardo zenezini chiozzi

LAB HEAD: Thalassinos, Konstantinos

PROVIDER: PXD062217 | Pride | 2026-05-01

REPOSITORIES: Pride

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			Action	DRS
	06032025_P26_STP0126_Dejan_DIA_phos_sample_01.htrms	Other
	06032025_P26_STP0126_Dejan_DIA_phos_sample_01.raw	Raw
	06032025_P26_STP0126_Dejan_DIA_phos_sample_02.htrms	Other
	06032025_P26_STP0126_Dejan_DIA_phos_sample_02.raw	Raw
	06032025_P26_STP0126_Dejan_DIA_phos_sample_03.htrms	Other

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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.

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HIV-1 signalling remodels nuclear pores to licence infection

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