A 6-Amino-Acid Insertion/Deletion Polymorphism in TIM1 Confers Protections Against HIV1

TIM-1 (T-cell immunoglobulin and mucin domain 1), a cell surface glycoprotein, facilitates the entry of enveloped virus, such as HIV, into host cells. Because the length of the mucin domain of TIM-1 is a critical factor in modulating viral entry, we assessed whether the TIM-1 18-bp insertion/deletion polymorphism modulates susceptibility to HIV-1 infection in three independent cohorts of HIV-exposed seronegative (HESN) individuals. The Tim-1 18-bp insertion/deletion polymorphism was genotyped in three case/control cohorts of HIV sexually-exposed HESN and their HIV-1-infected partners with different geographic origin (Italy, Peru and Colombia); data from an additional cohort were retrieved from a previous study conducted in Thailand. CD4+ T lymphocytes purified from 34 healthy controls (HC) grouped according to their TIM-1 genotype were infected in vitro with HIV-1Ba-L and viral replication was assessed after 5 days by measuring viral p24 levels produced by the infected cells. In all comparisons, homozygosity for the short TIM-1 allele was more common in HESN than in HIV-1 infected subjects. A meta-analysis of the four association analyses, revealing no heterogeneity among samples, yielded a p value of 0.005. These results were sustained by a drastic and significant reduction of viral replication in CD4+ T lymphocytes isolated from HC that were homozygous for the short TIM-1 allele compared to subjects carrying at least one long allele (t-test, p= 0.042). The TIM-1 deletion allele protects from infection with a recessive effect. In vitro infection assays on CD4+ T lymphocytes support this conclusion and underscore a complex interaction between enveloped viruses and TIM molecules that need further investigation.