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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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Related in: MedlinePlus

TRIM5 genotype and replication of SIVsmE543-3 in rhesus macaques.Archived samples were obtained from 43 Indian origin rhesus macaques that had been infected intravenously (n = 35) or intrarectally (n = 9) with SIVsmE543-3 (TCID 50% from 1 to 1,000). None of the animals were treated or vaccinated prior to infection. Genomic DNA extracted from stored PBMC was used to determine TRIM5 genotype. Data are color-coded by genotype, as follows: red, TRIM5Q/Q; orange, TRIM5Q/CypA; blue, TRIM5TFP/Q; green, TRIM5TFP/TFP; and black, TRIM5TFP/CypA. (A) Viral replication (RNA copy equivalents per milliliter of plasma) through 12 wk post-infection; (B) Same data presented as geometric mean values for each genotype; (C) area under the curve; (D) acute infection (defined as peak viremia for each animal during the first 4 wk post-infection); (E) 8 wk post-infection. Viral replication levels were compared by non-parametric one-way ANOVA (Kruskal-Wallis test) with Dunn's post-test. Pairs of groups that differed significantly are indicated (p<0.01 or p<0.001).
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pbio-1000462-g004: TRIM5 genotype and replication of SIVsmE543-3 in rhesus macaques.Archived samples were obtained from 43 Indian origin rhesus macaques that had been infected intravenously (n = 35) or intrarectally (n = 9) with SIVsmE543-3 (TCID 50% from 1 to 1,000). None of the animals were treated or vaccinated prior to infection. Genomic DNA extracted from stored PBMC was used to determine TRIM5 genotype. Data are color-coded by genotype, as follows: red, TRIM5Q/Q; orange, TRIM5Q/CypA; blue, TRIM5TFP/Q; green, TRIM5TFP/TFP; and black, TRIM5TFP/CypA. (A) Viral replication (RNA copy equivalents per milliliter of plasma) through 12 wk post-infection; (B) Same data presented as geometric mean values for each genotype; (C) area under the curve; (D) acute infection (defined as peak viremia for each animal during the first 4 wk post-infection); (E) 8 wk post-infection. Viral replication levels were compared by non-parametric one-way ANOVA (Kruskal-Wallis test) with Dunn's post-test. Pairs of groups that differed significantly are indicated (p<0.01 or p<0.001).

Mentions: The second and larger cohort consisted of historical samples from 44 SIVsmE543-3-infected rhesus macaques. Genotype frequencies in this cohort were 30% TRIM5TFP/TFP, 23% TRIM5TFP/Q, 26% TRIM5TFP/CypA, 12% TRIM5Q/Q, 9% TRIM5Q/CypA, and 0% TRIM5CypA/CypA. Animals with two restrictive alleles (TRIM5TFP/TFP and TRIM5TFP/CypA) had dramatically diminished viral replication compared to TRIM5Q/Q homozygotes, with mean (geometric) differences of 830-fold and 1,728-fold, respectively, by 8 wk post-infection (Figure 4). Animals with one restrictive allele (TRIM5TFP/Q and TRIM5CypA/Q heterozygotes) displayed intermediate levels of viral replication. Taken in conjunction with the clear differences in restriction of SIVsmE543-3 by TRIM5TFP, TRIM5CypA, and TRIM5Q in vitro (Figure 2C), these results are consistent with allelic variation in TRIM5 having a significant impact on SIVsmE543 replication kinetics in rhesus macaques. We also obtained archived DNA from animal #E543, the source of the original SIVsmE543-3 clone [29], and determined that this animal had been a TRIM5Q/Q homozygote. The fact that E543 bore a non-restrictive genotype may well have facilitated isolation of the original SIVsmE543-3 clone.


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)

TRIM5 genotype and replication of SIVsmE543-3 in rhesus macaques.Archived samples were obtained from 43 Indian origin rhesus macaques that had been infected intravenously (n = 35) or intrarectally (n = 9) with SIVsmE543-3 (TCID 50% from 1 to 1,000). None of the animals were treated or vaccinated prior to infection. Genomic DNA extracted from stored PBMC was used to determine TRIM5 genotype. Data are color-coded by genotype, as follows: red, TRIM5Q/Q; orange, TRIM5Q/CypA; blue, TRIM5TFP/Q; green, TRIM5TFP/TFP; and black, TRIM5TFP/CypA. (A) Viral replication (RNA copy equivalents per milliliter of plasma) through 12 wk post-infection; (B) Same data presented as geometric mean values for each genotype; (C) area under the curve; (D) acute infection (defined as peak viremia for each animal during the first 4 wk post-infection); (E) 8 wk post-infection. Viral replication levels were compared by non-parametric one-way ANOVA (Kruskal-Wallis test) with Dunn's post-test. Pairs of groups that differed significantly are indicated (p<0.01 or p<0.001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2927514&req=5

pbio-1000462-g004: TRIM5 genotype and replication of SIVsmE543-3 in rhesus macaques.Archived samples were obtained from 43 Indian origin rhesus macaques that had been infected intravenously (n = 35) or intrarectally (n = 9) with SIVsmE543-3 (TCID 50% from 1 to 1,000). None of the animals were treated or vaccinated prior to infection. Genomic DNA extracted from stored PBMC was used to determine TRIM5 genotype. Data are color-coded by genotype, as follows: red, TRIM5Q/Q; orange, TRIM5Q/CypA; blue, TRIM5TFP/Q; green, TRIM5TFP/TFP; and black, TRIM5TFP/CypA. (A) Viral replication (RNA copy equivalents per milliliter of plasma) through 12 wk post-infection; (B) Same data presented as geometric mean values for each genotype; (C) area under the curve; (D) acute infection (defined as peak viremia for each animal during the first 4 wk post-infection); (E) 8 wk post-infection. Viral replication levels were compared by non-parametric one-way ANOVA (Kruskal-Wallis test) with Dunn's post-test. Pairs of groups that differed significantly are indicated (p<0.01 or p<0.001).
Mentions: The second and larger cohort consisted of historical samples from 44 SIVsmE543-3-infected rhesus macaques. Genotype frequencies in this cohort were 30% TRIM5TFP/TFP, 23% TRIM5TFP/Q, 26% TRIM5TFP/CypA, 12% TRIM5Q/Q, 9% TRIM5Q/CypA, and 0% TRIM5CypA/CypA. Animals with two restrictive alleles (TRIM5TFP/TFP and TRIM5TFP/CypA) had dramatically diminished viral replication compared to TRIM5Q/Q homozygotes, with mean (geometric) differences of 830-fold and 1,728-fold, respectively, by 8 wk post-infection (Figure 4). Animals with one restrictive allele (TRIM5TFP/Q and TRIM5CypA/Q heterozygotes) displayed intermediate levels of viral replication. Taken in conjunction with the clear differences in restriction of SIVsmE543-3 by TRIM5TFP, TRIM5CypA, and TRIM5Q in vitro (Figure 2C), these results are consistent with allelic variation in TRIM5 having a significant impact on SIVsmE543 replication kinetics in rhesus macaques. We also obtained archived DNA from animal #E543, the source of the original SIVsmE543-3 clone [29], and determined that this animal had been a TRIM5Q/Q homozygote. The fact that E543 bore a non-restrictive genotype may well have facilitated isolation of the original SIVsmE543-3 clone.

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