A TRIM5α exon 2 polymorphism is associated with protection from HIV-1 infection in the Pumwani sex worker cohort

Price, Heather E.; Lacap, Philip; Tuff, Jeffrey; Wachihi, Charles; Kimani, Joshua; Ball, T. Blake; Luo, Ma; Plummer, Francis A.

doi:10.1097/qad.0b013e32833b5256

Cited by 45 publications

(43 citation statements)

References 24 publications

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“…15 Previous studies, including ours, showed the reduced antiviral activity of the H43Y substitution, but the associations with HIV-1 infection and disease progression were inconsistent among studies.…”

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confidence: 89%

A Naturally Occurring Single Amino Acid Substitution in Human TRIM5α Linker Region Affects Its Anti-HIV Type 1 Activity and Susceptibility to HIV Type 1 Infection

Nakayama

Nakajima

Kaur

et al. 2013

AIDS Research and Human Retroviruses

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TRIM5a is a factor contributing to intracellular defense mechanisms against retrovirus infection. Rhesus and cynomolgus monkey TRIM5as potently restrict HIV-1, whereas human TRIM5a shows weak effects against HIV-1. We investigated the association between a single nucleotide polymorphism in the TRIM5a linker 2 region (rs11038628), which substituted aspartic acid (D) for glycine (G) at position 249, with susceptibility to HIV-1 infection in Japanese and Indian subjects. rs11038628 is rare in Europeans but common in Asians and Africans. Functional analyses were performed by multiple-round replication and single-round assays, and indicated that the G249D substitution attenuated anti-HIV-1 activity of human TRIM5a. A slight attenuation of anti-HIV-2 activity was also observed in TRIM5a with 249D. The predicted secondary structure of the linker region suggested that the 249D substitution extended the a-helix in the neighboring coiled-coil domain, suggesting that human TRIM5a with 249D may lose the flexibility required for optimal recognition of retroviral capsid protein. We further analyzed the frequency of G249D in Japanese (93 HIV-1-infected subjects and 279 controls) and Indians (227 HIV-1-infected subjects and 280 controls). The frequency of 249D was significantly higher among HIV-1-infected Indian subjects than in ethnicity-matched control subjects [odds ratio (OR) = 1.52, p = 0.026]. A similar weak tendency was observed in Japanese subjects, but it was not statistically significant (OR = 1.19, p = 0.302). In conclusion, G249D, a common variant of human TRIM5a in Asians and Africans, is associated with increased susceptibility to HIV-1 infection.

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confidence: 89%

A Naturally Occurring Single Amino Acid Substitution in Human TRIM5α Linker Region Affects Its Anti-HIV Type 1 Activity and Susceptibility to HIV Type 1 Infection

Nakayama

Nakajima

Kaur

et al. 2013

AIDS Research and Human Retroviruses

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“…In addition, overall hTRIM5␣ activity can be influenced by its induction by IFN-␣ (44,86,87) and the relative expression of hTRIM5␣ and the inhibitory hTRIM5 splicing variants (gamma, delta, iota) (88). Furthermore, several hTRIM5␣ allelic variants have been identified with impaired activity, including those carrying the H43Y and G249D polymorphisms, although both the effect of these polymorphisms on TRIM5␣ activity and the impact of expression of these variants on disease progression remain controversial (44,83,(89)(90)(91)(92)(93)(94)(95)(96)(97). Interestingly, strain-specific differences in CA can also influence viral sensitivity to different TRIM5␣ allelic variants (44,83).…”

Section: Discussionmentioning

confidence: 99%

Pressure from TRIM5α Contributes to Control of HIV-1 Replication by Individuals Expressing Protective HLA-B Alleles

Granier

Battivelli

Lécuroux

et al. 2013

J Virol

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؉ patients who spontaneously controlled viral replication, but not viruses from viremic patients expressing these alleles, was significantly greater than that of viruses from patients not expressing these protective HLA-B alleles. Overall, a significant negative correlation between hTRIM5␣ sensitivity and viral load was observed. In HLA-B*57 ؉ patients, the T242N mutation in the HLA-B*57-restricted TW10 CD8 ؉ T lymphocyte (CTL) epitope was strongly associated with hTRIM5␣ sensitivity. In HLA-B*27 ؉ controllers, hTRIM5␣ sensitivity was associated with a significant reduction in emergence of key CTL mutations. In several patients, viral evolution to avoid hTRIM5␣ sensitivity was observed but could be associated with reduced viral replicative capacity. Thus, in individuals expressing protective HLA-B alleles, the combined pressures exerted by CTL, hTRIM5␣, and capsid structural constraints can prevent viral escape both by impeding the selection of necessary resistance/compensatory mutations and forcing the selection of escape mutations that increase hTRIM5␣ sensitivity or impair viral replicative capacity.

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“…[15][16][17] Nonetheless, cohort studies indicate that selected huTRIM5α alleles are associated with altered HIV-1 disease progression, [18][19][20][21] suggesting that huTRIM5α does play a role in ameliorating HIV-1 pathogenesis. Importantly, selected mutations within huTRIM5α that mirror rhTRIM5α dramatically augment restriction activity, with only a single substitution (R332P) required within the B30.2/SPRY domain to confer measureable restriction activity in single-round assays, 22 and as few as five substitutions within the B30.2/SPRY domain conferring potent restriction activity approaching that of rhTRIM5α.…”

Section: Introductionmentioning

confidence: 99%

Stabilized Human TRIM5α Protects Human T Cells From HIV-1 Infection

et al. 2014

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Rhesus (rh) but not human (hu) TRIM5α potently restricts human immunodeficiency virus (HIV)-1 infection. It is not clear why huTRIM5α fails to effectively block HIV infection, but it is thought to have a lower affinity for the viral core. Using primary human CD4 T cells, we investigated the ability of huTRIM5α, rhTRIM5α, and the huTRIM5αR323-332 B30.2/SPRY patch-mutant to form cytoplasmic bodies, postulated as key components of the HIV-1 restriction apparatus. Both rhTRIM5α and huTRIM5αR323-332 formed pronounced cytoplasmic bodies, whereas cytoplasmic bodies in T cells overexpressing huTRIM5α were present but more difficult to detect. As expression of all three TRIM5α orthologs was similar at the RNA level, we next investigated the role of protein stability in conferring TRIM5α-mediated HIV-1 restriction. Both steady-state and pulse-chase experiments revealed that the huTRIM5α protein was much less stable than rhTRIM5α, and this difference correlated with higher self-ubiquitination activity. Using a stabilized form of huTRIM5α in which the steady-state expression level was more similar to rhTRIM5α, we observed comparable HIV-1 restriction activity in multi-round HIV-1 challenge assays. Lastly, primary human CD4 T cells expressing a stabilized huTRIM5α were protected from HIV-1-mediated destruction in vivo, indicating that efforts to stabilize huTRIM5α should have significant long-term therapeutic value.

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A TRIM5α exon 2 polymorphism is associated with protection from HIV-1 infection in the Pumwani sex worker cohort

Cited by 45 publications

References 24 publications

A Naturally Occurring Single Amino Acid Substitution in Human TRIM5α Linker Region Affects Its Anti-HIV Type 1 Activity and Susceptibility to HIV Type 1 Infection

A Naturally Occurring Single Amino Acid Substitution in Human TRIM5α Linker Region Affects Its Anti-HIV Type 1 Activity and Susceptibility to HIV Type 1 Infection

Pressure from TRIM5α Contributes to Control of HIV-1 Replication by Individuals Expressing Protective HLA-B Alleles

Stabilized Human TRIM5α Protects Human T Cells From HIV-1 Infection

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