A regulatory polymorphism in HAVCR2 modulates susceptibility to HIV-1 infection

Manuela Sironi, Mara Biasin, Federica Gnudi, Rachele Cagliani, Irma Saulle, Diego Forni, Veronica Rainone, Daria Trabattoni, Micaela Garziano, Francesco Mazzotta, Luis Miguel Real, Antonio Rivero-Juarez, Antonio Caruz, Sergio Lo Caputo, Mario Clerici

Research output: Contribution to journalArticle

Abstract

The HAVCR2 gene encodes TIM-3, an immunoglobulin superfamily member expressed by exhausted CD8+ T cells during chronic viral infection. We investigated whether genetic variation at HAVCR2 modulates the susceptibility to HIV-1 acquisition; specifically we focused on a 39 UTR variant (rs4704846, A/G) that represents a natural selection target. We genotyped rs4704846 in three independent cohorts of HIV-1 exposed seronegative (HESN) individuals with different geographic origin (Italy and Spain) and distinct route of exposure to HIV-1 (sexual and injection drug use). Matched HIV-1 positive subjects and healthy controls were also analyzed. In all case-control cohorts the minor G allele at rs4704846 was more common in HIV-1 infected individuals than in HESN, with healthy controls showing intermediate frequency. Results from the three association analyses were combined through a random effect meta-analysis, which revealed no heterogeneity among samples (Cochrane's Q, p value = 0.89, I2 = 0) and yielded a p value of 6.861024. The minor G allele at rs4704846 was found to increase HAVCR2 expression after in vitro HIV-1 infection. Thus, a positively selected polymorphism in the 39 UTR, which modulates HAVCR2 expression, is associated with the susceptibility to HIV-1 infection. These data warrant further investigation into the role of TIM-3 in the prevention and treatment of HIV-1/AIDS.

Original languageEnglish
Article numbere106442
JournalPLoS One
Volume9
Issue number9
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Sironi, M., Biasin, M., Gnudi, F., Cagliani, R., Saulle, I., Forni, D., Rainone, V., Trabattoni, D., Garziano, M., Mazzotta, F., Real, L. M., Rivero-Juarez, A., Caruz, A., Caputo, S. L., & Clerici, M. (2014). A regulatory polymorphism in HAVCR2 modulates susceptibility to HIV-1 infection. PLoS One, 9(9), [e106442]. https://doi.org/10.1371/journal.pone.0106442