A positively selected APOBEC3H haplotype is associated with natural resistance to HIV-1 infection

Rachele Cagliani, Stefania Riva, Matteo Fumagalli, Mara Biasin, Sergio Lo Caputo, Francesco Mazzotta, Luca Piacentini, Uberto Pozzoli, Nereo Bresolin, Mario Clerici, Manuela Sironi

Research output: Contribution to journalArticlepeer-review

Abstract

APOBEC3 genes encode cytidine deaminases endowed with the ability to inhibit retroviruses and retrotransposons. These genes have been targets of natural selection throughout primate evolutionary history. We analyzed their selection pattern in human populations observing that APOBEC3F and 3G are neutrally evolving. Conversely, nucleotide diversity was extremely high for APOBEC3H, and most tests rejected the hypothesis of selective neutrality in Eurasian populations. Haplotype analysis and the derived intraallelic nucleotide diversity test indicated that positive selection has driven the increase in frequency of one haplotype (Hap I) outside Africa. Consistently, population genetic differentiation between African and non-African populations was higher than expected under neutrality. A case-control association analysis indicated that Hap I is associated with protection from sexually transmitted HIV-1 infection. Hap I carries a protein-destabilizing variant and a residue conferring resistance to Vif-mediated degradation. Data herein suggest that lower protein stability might have been traded-off with a higher ability to circumvent Vif-mediated hijacking. Alternatively, transcription regulatory variants might represent the selection target. Our data represent an example of how the selective pressures exerted by extinct or unknown viral agents can be exploited to provide valuable information on the allelic determinants of susceptibility to modern infections.

Original languageEnglish
Pages (from-to)3311-3322
Number of pages12
JournalEvolution
Volume65
Issue number11
DOIs
Publication statusPublished - Nov 2011

Keywords

  • APOBEC3H
  • Cytidine deaminase genes
  • Haplotype
  • HIV-1 infection
  • Positive selection

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Ecology, Evolution, Behavior and Systematics
  • Genetics

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