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Variation in the Antiretroviral Protein TRIM5a in Humans
Valérie Goldschmidt*1, M Ortiz1, M May2, R Martinez1, H Kaessmann3, G Bleiber1, and A Telenti1
1Inst of Microbiology, Lausanne, Switzerland; 2Dept of Social Med, Bristol, UK; and 3Ctr for Integrative Genomics, Lausanne, Switzerland
Background: The host protein TRIM5a is a key mediator of restriction to
foreign viruses. Although TRIM5 of Old World
monkeys shows high sequence similarity to human TRIM5, HIV encounters a
block after entry into these primate cells. We seek to identify differences in TRIM5
sequences in humans, to determine sequence conservation in monkeys, and to
assess their influence on HIV-1 progression in vitro and in vivo.
Methods: Single nucleotide polymorphism (SNP)
discovery used a panel of DNA from 128 healthy Swiss Caucasian blood donors.
DNA was investigated by single-strand conformation polymorphism and sequencing
using primers targeting exons, intron/exon
boundaries, and promoter. For evolutionary analysis, DNA of apes, Old and New World monkeys (n
= 15) was amplified with the same primers and subjected to sequence alignment
with the human reference. SNP were assessed in vitro by measuring HIV-1
replication in CD4+ T cells of healthy blood donors, and in vivo
by analyzing square root transformed CD4 T cell counts, modelled as a linear
function of time since estimated date of seroconversion, in participants of the
Swiss HIV Cohort Study (n = 851).
Results: Of 5970 bp analyzed
in human TRIM5, 21 polymorphisms were identified: 16 are in the non-coding region; and 5 are
coding, of which 4 change the amino acid: H43Y (ring domain), G249D, and H419Y (SPRY
domain) correspond to conserved residues among primates. On the other hand,
R136Q (coiled-coil domain) is present in all apes and monkeys except for
chimpanzee. No influence on HIV-1 replication in vitro was observed for
the SNP. The low frequency haplotype in vivo
(0.6%) comprising 746A (249D) and 1255T (419Y) associated with CD4+
cell improvement (gradient offset 0.94; SE 0.73) and with more favorable disease evolution.
Conclusions: Human TRIM5 shows a high sequence variability, with an unusually high number
of non-synonymous amino acid substitutions. They occur mainly at evolutionary
conserved sites and therefore deserve further analysis; in vivo data
would suggest a protective effect for 2 variant alleles‑trends that need
confirmation in a bigger dataset.
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