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Multiple sites in the N-terminal half of simian immunodeficiency virus capsid protein contribute to evasion from rhesus monkey TRIM5?-mediated restriction.

ABSTRACT: BACKGROUND: We previously reported that cynomolgus monkey (CM) TRIM5? could restrict human immunodeficiency virus type 2 (HIV-2) strains carrying a proline at the 120th position of the capsid protein (CA), but it failed to restrict those with a glutamine or an alanine. In contrast, rhesus monkey (Rh) TRIM5? could restrict all HIV-2 strains tested but not simian immunodeficiency virus isolated from macaque (SIVmac), despite its genetic similarity to HIV-2. RESULTS: We attempted to identify the viral determinant of SIVmac evasion from Rh TRIM5?-mediated restriction using chimeric viruses formed between SIVmac239 and HIV-2 GH123 strains. Consistent with a previous study, chimeric viruses carrying the loop between ?-helices 4 and 5 (L4/5) (from the 82nd to 99th amino acid residues) of HIV-2 CA were efficiently restricted by Rh TRIM5?. However, the corresponding loop of SIVmac239 CA alone (from the 81st to 97th amino acid residues) was not sufficient to evade Rh TRIM5? restriction in the HIV-2 background. A single glutamine-to-proline substitution at the 118th amino acid of SIVmac239 CA, corresponding to the 120th amino acid of HIV-2 GH123, also increased susceptibility to Rh TRIM5?, indicating that glutamine at the 118th of SIVmac239 CA is necessary to evade Rh TRIM5?. In addition, the N-terminal portion (from the 5th to 12th amino acid residues) and the 107th and 109th amino acid residues in ?-helix 6 of SIVmac CA are necessary for complete evasion from Rh TRIM5?-mediated restriction. A three-dimensional model of hexameric GH123 CA showed that these multiple regions are located on the CA surface, suggesting their direct interaction with TRIM5?. CONCLUSION: We found that multiple regions of the SIVmac CA are necessary for complete evasion from Rh TRIM5? restriction.

SUBMITTER: Kono K

PROVIDER: S-EPMC2944288 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Multiple sites in the N-terminal half of simian immunodeficiency virus capsid protein contribute to evasion from rhesus monkey TRIM5α-mediated restriction.

Kono Ken K Song Haihan H Yokoyama Masaru M Sato Hironori H Shioda Tatsuo T Nakayama Emi E EE

Retrovirology 20100908

<h4>Background</h4>We previously reported that cynomolgus monkey (CM) TRIM5α could restrict human immunodeficiency virus type 2 (HIV-2) strains carrying a proline at the 120th position of the capsid protein (CA), but it failed to restrict those with a glutamine or an alanine. In contrast, rhesus monkey (Rh) TRIM5α could restrict all HIV-2 strains tested but not simian immunodeficiency virus isolated from macaque (SIVmac), despite its genetic similarity to HIV-2.<h4>Results</h4>We attempted to id ...[more]

PMID: 20825647

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Project description:Tripartite motif-containing protein 5? (TRIM5?) is considered to be a potential target for cell-based gene modification therapy against human immunodeficiency virus type 1 (HIV-1) infection. In the present study, we used a relevant rhesus macaque model of infection with simian immunodeficiency virus from sooty mangabey (SIVsm) to evaluate the effect of TRIM5? restriction on clinical outcome. For macaques expressing a restrictive TRIM5 genotype, the disease outcomes of those infected with the wild-type TRIM-sensitive SIVsm strain and those infected with a virus with escape mutations in the capsid were compared. We found that TRIM5? restriction significantly delayed disease progression and improved the survival rate of SIV-infected macaques, supporting the feasibility of exploiting TRIM5? as a target for gene therapy against HIV-1. Furthermore, we also found that preservation of memory CD4 T cells was associated with protection by TRIM5? restriction, suggesting memory CD4 T cells or their progenitor cells as an ideal target for gene modification. Despite the significant effect of TRIM5? restriction on survival, SIV escape from TRIM5? restriction was also observed; therefore, this may not be an effective stand-alone strategy and may require combination with other targets.Recent studies suggest that it may be feasible not only to suppress viral replication with antiviral drugs but also potentially to eliminate or "cure" human immunodeficiency virus (HIV) infection. One approach being explored is the use of gene therapy to introduce genes that can restrict HIV replication, including a restrictive version of the host factor TRIM5?. TRIM5 was identified as a factor that restricts HIV replication in macaque cells. The rhesus gene is polymorphic, and some alleles are restrictive for primary SIVsm isolates, although escape mutations arise late in infection. Introduction of these escape mutations into the parental virus conferred resistance to TRIM5 on macaques. The present study evaluated these animals for long-term outcomes and found that TRIM5? restriction significantly delayed disease progression and improved the survival rate of SIV-infected macaques, suggesting that this could be a valid gene therapy approach that could be adapted for HIV.

Project description:Human cytomegalovirus (HCMV) possesses low pathogenic potential in an immunocompetent host. In the immunosuppressed host, however, a wide spectrum of infection outcomes, ranging from asymptomatic to life threatening, can follow either primary or nonprimary infection. The variability in the manifestations of HCMV infection in immunosuppressed individuals implies that there is a threshold of host antiviral immunity that can effectively limit disease potential. We used a nonhuman primate model of CMV infection to assess the relationship between CMV disease and the levels of developing anti-CMV immunity. Naive rhesus macaques were inoculated with rhesus cytomegalovirus (RhCMV) followed 2 or 11 weeks later by inoculation with pathogenic simian immunodeficiency virus SIVmac239. Two of four monkeys inoculated with SIV at 2 weeks after inoculation with RhCMV died within 11 weeks with simian AIDS (SAIDS), including activated RhCMV infection. Neither animal had detectable anti-SIV antibodies. The other two animals died 17 and 27 weeks after SIV inoculation with either SAIDS or early lymphoid depletion, although no histological evidence of activated RhCMV was observed. Both had weak anti-SIV antibody titers. RhCMV antibody responses for this group of monkeys were significantly below those of control animals inoculated with only RhCMV. In addition, all animals of this group had persistent RhCMV DNA in plasma and high copy numbers of RhCMV in tissues. In contrast, animals that were inoculated with SIV at 11 weeks after RhCMV infection rarely exhibited RhCMV DNA in plasma, had low copy numbers of RhCMV DNA in most tissues, and did not develop early onset of SAIDS or activated RhCMV. SIV antibody titers were mostly robust and sustained in these monkeys. SIV inoculation blunted further development of RhCMV humoral responses, unlike the normal pattern of development in control monkeys following RhCMV inoculation. Anti-RhCMV immunoglobulin G levels and avidity were slightly below control values, but levels maintained were higher than those observed following SIV infection at 2 weeks after RhCMV inoculation. These findings demonstrate that SIV produces long-lasting insults to the humoral immune system beginning very early after SIV infection. The results also indicate that anti-RhCMV immune development at 11 weeks after infection was sufficient to protect the host from acute RhCMV sequelae following SIV infection, in contrast to the lack of protection afforded by only 2 weeks of immune response to RhCMV. As previously observed, monkeys that were not able to mount a significant immune response to SIV were the most susceptible to SAIDS, including activated RhCMV infection. Rapid development of SAIDS in animals inoculated with SIV 2 weeks after RhCMV inoculation suggests that RhCMV can augment SIV pathogenesis, particularly during primary infection by both viruses.

Dataset Information

Multiple sites in the N-terminal half of simian immunodeficiency virus capsid protein contribute to evasion from rhesus monkey TRIM5?-mediated restriction.

Publications

Multiple sites in the N-terminal half of simian immunodeficiency virus capsid protein contribute to evasion from rhesus monkey TRIM5α-mediated restriction.

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