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TRIM5 suppresses cross-species transmission of a primate immunodeficiency virus and selects for emergence of resistant variants in the new species.

Kirmaier A, Wu F, Newman RM, Hall LR, Morgan JS, O'Connor S, Marx PA, Meythaler M, Goldstein S, Buckler-White A, Kaur A, Hirsch VM, Johnson WE - PLoS Biol. (2010)

Bottom Line: Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and SIVstm in stump-tailed macaques.Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection.In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239.

View Article: PubMed Central - PubMed

Affiliation: New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts, United States of America.

ABSTRACT
Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and SIVstm in stump-tailed macaques. Cellular assays and phylogenetic comparisons indirectly support a role for TRIM5alpha, the product of the TRIM5 gene, in suppressing interspecies transmission and emergence of retroviruses in nature. Here, we investigate the in vivo role of TRIM5 directly, focusing on transmission of primate immunodeficiency viruses between outbred primate hosts. Specifically, we retrospectively analyzed experimental cross-species transmission of SIVsm in two cohorts of rhesus macaques and found a significant effect of TRIM5 genotype on viral replication levels. The effect was especially pronounced in a cohort of animals infected with SIVsmE543-3, where TRIM5 genotype correlated with approximately 100-fold to 1,000-fold differences in viral replication levels. Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection. In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239. Adaptations appeared in the viral capsid in animals with restrictive TRIM5 genotypes, and similar adaptations coincide with emergence of SIVmac in captive macaques in the 1970s. Thus, host TRIM5 can suppress viral replication in vivo, exerting selective pressure during the initial stages of cross-species transmission.

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Adaptations in the CA of SIVmac strains confer resistance to a subset of rhesus TRIM5 alleles.(A) Partial alignment of the NTD of CA from multiple primate lentiviruses highlights the unusual QQ89,90 sequence at the tip of the CypA-binding loop, which is unique to the SIVmac lineage. Also shown is an inferred change at position 97 at the base of the loop (in helix 5), identical to the R97S change that arose in the SIVsm experimental cohorts shown in Figures 2 and 3. (B) Location of LPA89–91 and R97 on the HIV-2 CA crystal structure, highlighted in red (structure is from reference [23]). (C) Infectivity of parental SIVmac239; bars are color-coded as described in the legend of Figure 2. (D) Infectivity of SIVmac239S97R, in which S97 has been reverted to the ancestral R97, reveals a gain of sensitivity to TRIM5TFP alleles (dark blue bars). (E) Infectivity of SIVmac239QQ/LPA (in which QQ89,90 has been reverted to the ancestral LPA89–91) reveals a gain of sensitivity to TRIM5TFP alleles (dark blue bars) and TRIM5CypA (orange bars). (F) Changing the ancestral IPA to QQ in SIVsmE041 (SIVsmE041IPA/QQ) results in a gain of resistance to TRIM5CypA.
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pbio-1000462-g006: Adaptations in the CA of SIVmac strains confer resistance to a subset of rhesus TRIM5 alleles.(A) Partial alignment of the NTD of CA from multiple primate lentiviruses highlights the unusual QQ89,90 sequence at the tip of the CypA-binding loop, which is unique to the SIVmac lineage. Also shown is an inferred change at position 97 at the base of the loop (in helix 5), identical to the R97S change that arose in the SIVsm experimental cohorts shown in Figures 2 and 3. (B) Location of LPA89–91 and R97 on the HIV-2 CA crystal structure, highlighted in red (structure is from reference [23]). (C) Infectivity of parental SIVmac239; bars are color-coded as described in the legend of Figure 2. (D) Infectivity of SIVmac239S97R, in which S97 has been reverted to the ancestral R97, reveals a gain of sensitivity to TRIM5TFP alleles (dark blue bars). (E) Infectivity of SIVmac239QQ/LPA (in which QQ89,90 has been reverted to the ancestral LPA89–91) reveals a gain of sensitivity to TRIM5TFP alleles (dark blue bars) and TRIM5CypA (orange bars). (F) Changing the ancestral IPA to QQ in SIVsmE041 (SIVsmE041IPA/QQ) results in a gain of resistance to TRIM5CypA.

Mentions: Phylogenetic analyses are consistent with a minimum of two historical transmissions of SIVsm into macaques, one into stump-tailed macaques (SIVstm), and the other into rhesus macaques (SIVmac); both transmissions are thought to have occurred in captive macaques sometime prior to the 1970s [3]. If TRIM5-mediated restriction influences cross-species transmission of primate lentiviruses, we predict the existence of adaptive changes in SIV isolates corresponding to such events. Indeed, alignment of the NTD of several lentiviruses in the SIVsm/SIVmac/HIV-2 lineage revealed multiple potential adaptations in SIVmac (Figure 6). Most striking is an inferred R97S change, identical to the change that appeared in the SIVsmE041 and SIVsmE543 experimental cohorts described above (Figures 3 and 5B). Based on phylogeny of the SIVsm/SIVmac/HIV-2 lineage [3], the R97S change was probably selected twice, once coinciding with emergence of SIVmac in rhesus macaques and once coinciding with emergence of SIVstm in stump-tailed macaques. Consistent with this interpretation, the underlying nucleotide substitutions are different in the two viruses (AGA->AGC in SIVstm, and AGA->TCA in SIVmac). However, S97 is also found in a small percentage of HIV-2 and SIVsm isolates; thus, it is possible that one or both historical transmissions were initiated by an SIVsm with serine at position 97, rather than de novo mutation as seen in the experimental cohorts. In either case, these combined observations strongly suggest that S97 is selectively advantageous in macaques.


TRIM5 suppresses cross-species transmission of a primate immunodeficiency virus and selects for emergence of resistant variants in the new species.

Kirmaier A, Wu F, Newman RM, Hall LR, Morgan JS, O'Connor S, Marx PA, Meythaler M, Goldstein S, Buckler-White A, Kaur A, Hirsch VM, Johnson WE - PLoS Biol. (2010)

Adaptations in the CA of SIVmac strains confer resistance to a subset of rhesus TRIM5 alleles.(A) Partial alignment of the NTD of CA from multiple primate lentiviruses highlights the unusual QQ89,90 sequence at the tip of the CypA-binding loop, which is unique to the SIVmac lineage. Also shown is an inferred change at position 97 at the base of the loop (in helix 5), identical to the R97S change that arose in the SIVsm experimental cohorts shown in Figures 2 and 3. (B) Location of LPA89–91 and R97 on the HIV-2 CA crystal structure, highlighted in red (structure is from reference [23]). (C) Infectivity of parental SIVmac239; bars are color-coded as described in the legend of Figure 2. (D) Infectivity of SIVmac239S97R, in which S97 has been reverted to the ancestral R97, reveals a gain of sensitivity to TRIM5TFP alleles (dark blue bars). (E) Infectivity of SIVmac239QQ/LPA (in which QQ89,90 has been reverted to the ancestral LPA89–91) reveals a gain of sensitivity to TRIM5TFP alleles (dark blue bars) and TRIM5CypA (orange bars). (F) Changing the ancestral IPA to QQ in SIVsmE041 (SIVsmE041IPA/QQ) results in a gain of resistance to TRIM5CypA.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2927514&req=5

pbio-1000462-g006: Adaptations in the CA of SIVmac strains confer resistance to a subset of rhesus TRIM5 alleles.(A) Partial alignment of the NTD of CA from multiple primate lentiviruses highlights the unusual QQ89,90 sequence at the tip of the CypA-binding loop, which is unique to the SIVmac lineage. Also shown is an inferred change at position 97 at the base of the loop (in helix 5), identical to the R97S change that arose in the SIVsm experimental cohorts shown in Figures 2 and 3. (B) Location of LPA89–91 and R97 on the HIV-2 CA crystal structure, highlighted in red (structure is from reference [23]). (C) Infectivity of parental SIVmac239; bars are color-coded as described in the legend of Figure 2. (D) Infectivity of SIVmac239S97R, in which S97 has been reverted to the ancestral R97, reveals a gain of sensitivity to TRIM5TFP alleles (dark blue bars). (E) Infectivity of SIVmac239QQ/LPA (in which QQ89,90 has been reverted to the ancestral LPA89–91) reveals a gain of sensitivity to TRIM5TFP alleles (dark blue bars) and TRIM5CypA (orange bars). (F) Changing the ancestral IPA to QQ in SIVsmE041 (SIVsmE041IPA/QQ) results in a gain of resistance to TRIM5CypA.
Mentions: Phylogenetic analyses are consistent with a minimum of two historical transmissions of SIVsm into macaques, one into stump-tailed macaques (SIVstm), and the other into rhesus macaques (SIVmac); both transmissions are thought to have occurred in captive macaques sometime prior to the 1970s [3]. If TRIM5-mediated restriction influences cross-species transmission of primate lentiviruses, we predict the existence of adaptive changes in SIV isolates corresponding to such events. Indeed, alignment of the NTD of several lentiviruses in the SIVsm/SIVmac/HIV-2 lineage revealed multiple potential adaptations in SIVmac (Figure 6). Most striking is an inferred R97S change, identical to the change that appeared in the SIVsmE041 and SIVsmE543 experimental cohorts described above (Figures 3 and 5B). Based on phylogeny of the SIVsm/SIVmac/HIV-2 lineage [3], the R97S change was probably selected twice, once coinciding with emergence of SIVmac in rhesus macaques and once coinciding with emergence of SIVstm in stump-tailed macaques. Consistent with this interpretation, the underlying nucleotide substitutions are different in the two viruses (AGA->AGC in SIVstm, and AGA->TCA in SIVmac). However, S97 is also found in a small percentage of HIV-2 and SIVsm isolates; thus, it is possible that one or both historical transmissions were initiated by an SIVsm with serine at position 97, rather than de novo mutation as seen in the experimental cohorts. In either case, these combined observations strongly suggest that S97 is selectively advantageous in macaques.

Bottom Line: Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and SIVstm in stump-tailed macaques.Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection.In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239.

View Article: PubMed Central - PubMed

Affiliation: New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts, United States of America.

ABSTRACT
Simian immunodeficiency viruses of sooty mangabeys (SIVsm) are the source of multiple, successful cross-species transmissions, having given rise to HIV-2 in humans, SIVmac in rhesus macaques, and SIVstm in stump-tailed macaques. Cellular assays and phylogenetic comparisons indirectly support a role for TRIM5alpha, the product of the TRIM5 gene, in suppressing interspecies transmission and emergence of retroviruses in nature. Here, we investigate the in vivo role of TRIM5 directly, focusing on transmission of primate immunodeficiency viruses between outbred primate hosts. Specifically, we retrospectively analyzed experimental cross-species transmission of SIVsm in two cohorts of rhesus macaques and found a significant effect of TRIM5 genotype on viral replication levels. The effect was especially pronounced in a cohort of animals infected with SIVsmE543-3, where TRIM5 genotype correlated with approximately 100-fold to 1,000-fold differences in viral replication levels. Surprisingly, transmission occurred even in individuals bearing restrictive TRIM5 genotypes, resulting in attenuation of replication rather than an outright block to infection. In cell-culture assays, the same TRIM5 alleles associated with viral suppression in vivo blocked infectivity of two SIVsm strains, but not the macaque-adapted strain SIVmac239. Adaptations appeared in the viral capsid in animals with restrictive TRIM5 genotypes, and similar adaptations coincide with emergence of SIVmac in captive macaques in the 1970s. Thus, host TRIM5 can suppress viral replication in vivo, exerting selective pressure during the initial stages of cross-species transmission.

Show MeSH
Related in: MedlinePlus