Role of common human TRIM5alpha variants in HIV-1 disease progression - PubMed (original) (raw)

Role of common human TRIM5alpha variants in HIV-1 disease progression

Valérie Goldschmidt et al. Retrovirology. 2006.

Abstract

Background: The retroviral restriction factor tripartite motif protein (TRIM)5alpha, is characterized by marked amino acid diversity among primates, including specific clusters of residues under positive selection. The identification of multiple non-synonymous changes in humans suggests that TRIM5alpha variants might be relevant to retroviral pathogenesis. Previous studies have shown that such variants are unlikely to modify susceptibility to HIV-1 infection, or the course of early infection. However, the longterm effect of carrying Trim5alpha variants on disease progression in individuals infected with HIV-1 has not previously been investigated.

Methods: In a cohort of 979 untreated individuals infected with HIV-1 with median follow up 3.2 years and 9,828 CD4 T cell measurements, we analysed common amino acid variations: H43Y, V112F, R136Q, G249D, and H419Y. The rate of CD4 T cell decline before treatment was used as the phenotype. In addition, we extended previous work on the in vitro susceptibility of purified donor CD4 T cells (n = 125) to HIV-1 infection, and on the susceptibility of HeLa cells that were stably transduced with the different TRIM5 variants. Haplotypes were analysed according to the most parsimonious evolutionary structure, where two main human TRIM5alpha groups can be defined according to the residue at amino acid 136. Humans present both Q136 and R136 at similar frequency, and additional TRIM5alpha amino acid variants are almost exclusively derived from R136-carrying haplotypes.

Results: We observed modest differences in disease progression for evolutionary branches carrying R136-derived haplotypes, and with the non-synonymous polymorphisms G249D and H419Y. In vitro analysis of susceptibility of donor CD4 T cells, and of the various transduced HeLa cell lines supported the absence of significant differential restriction of HIV-1 infection by the various huTRIM5alpha alleles.

Conclusion: Common human variants of TRIM5alpha have no effect or modest effect on HIV-1 disease progression. These variants occur at sites conserved throughout evolution, and are remote from clusters of positive selection in the primate lineage. The evolutionary value of the substitutions remains unclear.

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Figures

Figure 1

Figure 1

Position of common human TRIM5α amino acid variants in the context of primate sequence conservation and of the v1 and v2 patches of positive pressure. Y-axis: posterior probabilities of positively selected codons. X-axis: human TRIM5α amino acid numbering. The evolutionary analysis is adapted from reference [7].

Figure 2

Figure 2

Restriction of HIV-1 by common human TRIM5α variants. HeLa cells were stably transduced by oncoretroviral vectors expressing the Rhesus (Rh) TRIM5α, the common huTRIM5α and its variants, separately or in a hypothetical four-mutation protein. Panel A: Single-cycle infectivity assays used VSV-pseudotyped recombinant viruses (HIV.1-GFP) at various m.o.i. After 48 h, cells were analysed by fluorescence-activated cell sorter, and scored for number of GFP-positive cells. Panel B: Expression of HA-tagged TRIM5α proteins was determined by western blotting using an anti-HA antibody. Tubulin was detected with the anti-α tubulin antibody. Control: HeLa cells transduced with an empty oncoretroviral vector.

Figure 3

Figure 3

Association of human TRIM5α haplotypes with HIV-1 disease progression in vivo. Panel A, Inferred haplotypes carrying non-synonymous variants. Panel B, Analysis of haplotypes according to the most parsimonious evolutionary analysis, where two main huTRIM5α groups can be defined according to the residue at codon 136. Shown are square root CD4 gradient (reference slope for all patients is -2.01). Top set of slope estimates corresponds to one copy of haplotype(s) group, bottom set is for two copies of haplotype(s) group. Only the H7 haplotype presented a slope significantly different from that of all patients (uncorrected p value). However, p values did not reach the experiment-wide significance of 0.003 (Simes modified Bonferroni p value).

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