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Trim5alpha protein restricts both HIV-1 and murine leukemia virus.

ABSTRACT: Replication of HIV-1 and N-tropic murine leukemia virus (N-MLV) is restricted in a number of different primate cells. In some cell lines, cross-saturation experiments suggest that the two viruses are interacting with the same restriction factor. Recently, Trim5alpha protein from rhesus monkey was found to restrict HIV-1. We have confirmed this result and have shown that Trim5alpha from two African green monkey cell lines, Vero and CV-1, also restricts HIV-1. In addition, we show that human, rhesus, and African green monkey Trim5alpha can restrict N-MLV. By using a panel of MLV capsid mutants, subtle differences in the anti-MLV activity were identified among the different primate Trim5alpha cDNAs. Trim1 isolated from humans and green monkeys was also found to restrict N-MLV. We hypothesize that the Trim family of proteins plays a widespread role in innate immunity to viral infection.

SUBMITTER: Yap MW

PROVIDER: S-EPMC490012 | biostudies-literature | 2004 Jul

REPOSITORIES: biostudies-literature

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Trim5alpha protein restricts both HIV-1 and murine leukemia virus.

Yap Melvyn W MW Nisole Sébastien S Lynch Clare C Stoye Jonathan P JP

Proceedings of the National Academy of Sciences of the United States of America 20040712 29

Replication of HIV-1 and N-tropic murine leukemia virus (N-MLV) is restricted in a number of different primate cells. In some cell lines, cross-saturation experiments suggest that the two viruses are interacting with the same restriction factor. Recently, Trim5alpha protein from rhesus monkey was found to restrict HIV-1. We have confirmed this result and have shown that Trim5alpha from two African green monkey cell lines, Vero and CV-1, also restricts HIV-1. In addition, we show that human, rhes ...[more]

PMID: 15249690

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Project description:BackgroundOne of the unique features of gammaretroviruses is that they contain an additional extended form of Gag, glyco-gag, which initiates in the leader sequence. MuLV glyco-gag, gPr80Gag, promotes retrovirus replication and disease progression. Although virtually all infectious MuLVs encode glyco-gag, XMRV (xenotropic murine leukemia virus-related virus) lacks the classical gPr80Gag sequence. We examined XMRV to determine if its leader sequence contains glyco-gag activity, whether the presence of conventional gPr80Gag affects replication of XMRV, and we describe the evolution of glyco-gag-deficient MuLVs in Mus.ResultsWe introduced several mutations disrupting two putative but noncanonical glyco-gag proteins in the leader sequence region in XMRV and found that those mutations did not affect virus release nor susceptibility to the antiviral activity of hA3G (human APOBEC3G). A chimeric XMRV encoding the Moloney MuLV (M-MuLV) leader sequence (MXMRV) demonstrated that M-MuLV glyco-gag facilitated MXMRV release and increased infectivity. Infectivity assays with several cell lines showed that glyco-gag increases XMRV infectivity in all cell lines tested, but the level of this increase varies in different cell lines. Because MuLV glyco-gag counteracts mouse APOBEC3, we investigated whether M-MuLV glyco-gag enhances XMRV infection by counteracting human APOBEC3. Comparison of hAPOBEC3 isoforms expressed in different cell lines indicated that hA3B was the most likely candidate for a restrictive hA3. However over-expression of hA3B showed no enhanced restriction of infection by XMRV compared to MXMRV. Endogenous MuLVs in the sequenced mouse genome were screened for canonical glyco-gag, which was identified in two clades of xenotropic MuLVs (X-MuLVs) and ecotropic MuLVs, but not in other X-MuLVs or in any polytropic MuLVs.ConclusionsM-MuLV glyco-gag facilitates XMRV replication, and the leader sequence region in XMRV does not encode proteins equivalent to M-MuLV glyco-gag. The fact that the ability of glyco-gag to enhance XMRV infection varies in different cell lines suggests a glyco-gag sensitive restrictive factor that further reduces XMRV infectivity. The M-MuLV glyco-gag enhancement for XMRV replication is through a hAPOBEC3 independent mechanism. The absence of glyco-gag in MuLVs carried by western European mice suggests that loss of this sequence is a relatively recent event with limited subspecies distribution.

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Trim5alpha protein restricts both HIV-1 and murine leukemia virus.

Publications

Trim5alpha protein restricts both HIV-1 and murine leukemia virus.

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