Finding could point a way to medications that prevent HIV that has entered the body from establishing infection.
The lead story (basic science category) on the NIDA (National Institute of Drug Abuse) Notes website for March 2016 features a collaborative study by 16 investigators including Dr. Bradley Aouizerat, professor of oral and maxillofacial surgery and deputy director of the Bluestone Center for Clinical Research. The study, “Novel Genetic Locus Implicated for HIV-1 Acquisition with Putative Regulatory Links to HIV Replication and Infectivity: A Genome-Wide Association Study,” published March 18, 2015, in PLOS One, identified a gene variant that appears to partially shield people whose behaviors entail high risk for exposure to human immunodeficiency virus (HIV) from being infected. According to NIDA Notes, the finding could point a way to medications that prevent HIV that has entered the body from establishing infection.
Lead author Dr. Eric O. Johnson at RTI International and colleagues found that participants in the two large study cohorts who possessed the G allele of a single-nucleotide polymorphism in the FRMPD1 gene (rs4878712) had modestly lower odds of acquiring HIV infection than those with alternative alleles, after accounting for behavioral and environmental risk factors.
All participants in each cohort – the Urban Health Study (UHS: 3,136 males and females), and the Women’s Interagency HIV Study (WIHS: 2,533 females) – were considered to be at high risk for HIV infection related to their sexual , sexually transmitted disease, or drug-use histories. Using genome-wide association analysis, the researchers first established the gene-infection association with data from the UHS cohort and then replicated their finding in the WIHS cohort.
Dr. Aouizerat, who leads the WIHS cohort, commented, “The identification of host genes that influence HIV infection and progression has had some early successes; e.g., CCR5 (Chemokine [C-C Motif] Receptor 5 and the subsequent development of a CCR5 receptor antagonist that inhibits HIV entry into cells. However, subsequent progress has been slow due in part to the lack of appropriate control groups, which, thanks to Dr. Johnson’s efforts, we have now addressed. Our hope is that others will replicate this preliminary finding and that this approach will lead to the discovery of additional risk alleles for HIV acquisition.”
The researchers suggest that the pathway linking the FRMPD1 gene variant to reduced risk for HIV infection involves altered expression of two genes, FBOX10 and BCL2. They found that the G allele of rs4878712 was associated with lower expression of the gene FBOX10, and that lower FBOX10- expression was associated with higher BCL2 expression. Greater expression of the BCL2 gene leads to higher levels of Bcl-2 protein, which other studies have shown to lower HIV replication during acute infection, and thereby reduce the likelihood of transition to persistent infection.
Although previous studies have estimated that half of a person’s risk for acquiring HIV infection depends on his or her genes, rs4878712 is only the second gene variant that researchers have associated with risk for infection. The finding is most significant for the insight it may provide into biological mechanisms that can facilitate or impede persistent HIV infection and could become targets for medications.