A Regulatory Polymorphism in HAVCR2 Modulates Susceptibility to HIV-1 Infection

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

来源：PLos One, 2014, 9(9): e106442.

DOI：10.1371/journal.pone.0106442

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 3%26apos; 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%26apos;s Q, p value = 0.89, I-2 = 0) and yielded a p value of 6.8 x 10(-4). 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 3%26apos; 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.

• 出版日期2014-9-2