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Structural bases for integrase-RNA binding and retention of viral RNA within HIV-1 capsid cores

ABSTRACT: HIV-1 integrase (IN) promotes encapsulation of viral genomic RNA into mature viral cores, and this function is a target for ongoing antiretroviral drug development efforts. We determined a cryo-EM structure of a primate lentiviral IN complexed with RNA, which revealed a linear filament made of IN octamer repeat units, each comprising a pair of asymmetric homotetramers. The assembly is stabilized through IN-RNA interactions primarily involving the IN C-terminal domains and RNA backbone. Remarkably, the spacing and orientation of the IN filament repeat units closely matched those of consecutive capsid (CA) hexamers within the mature CA lattice. Using cryo-EM images of native purified HIV-1 cores, we refined the structure of the IN filament as it propagates along the luminal side of the CA lattice. Each IN tetramer within the filament nestled in a CA hexamer, engaging closely with the major homology regions. Substitutions of residues involved in IN-CA contacts yielded eccentric virions with RNA nucleoids located outside of the cores. Collectively, our results establish the structural basis for the HIV 1 IN-RNA interaction and reveal that IN forms an RNA-binding module on the luminal side of the mature CA lattice.

INSTRUMENT(S):

ORGANISM(S): Simian Immunodeficiency Virus

TISSUE(S): Blood Cell

SUBMITTER: Mark Skehel

LAB HEAD: Peter Cherepanov

PROVIDER: PXD070910 | Pride | 2025-12-04

REPOSITORIES: Pride

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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.

			Action	DRS
	HIV-1_IN_HDX.csv	Csv
	HIV-1_IN_HDX.zip	Other
	SIVtal_IN_HDX.csv	Csv
	SIVtal_IN_HDX.zip	Other
	checksum.txt	Txt

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Structural bases for integrase-RNA binding and retention of viral RNA within HIV-1 capsid cores

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