Background. It has been predicted that CD4 C868T, a novel CD4 single-nucleotide polymorphism (SNP) that has been found to be highly prevalent among Africans, changes the tertiary structure of CD4, which may alter susceptibility to human immunodeficiency virus (HIV) infection. Methods. Participants were from a Kenyan cohort and included 87 uninfected and 277 HIV-1-infected individuals. DNA sequencing was used to determine CD4 genotype. A2.01 cells expressing similar levels of either wild-type CD4 or CD4-Trp240 as well as peripheral blood mononuclear cells from uninfected donors were infected with HIV-1IIIB or a Kenyan primary HIV-1 isolate. HIV-1 p24 enzyme-linked immunosorbent assay was used to determine the outcome of infection. Results. CD4 C868T was found to be significantly more prevalent among HIV-1-infected participants than among HIV-1-uninfected participants (P = .002), and C868T was associated with an increased incidence of HIV-1 infection as well (P = .005, log-rank test; P = .009, Wilcoxon test), with an odds ratio of 2.49 (P = .009). Both in vitro and ex vivo models demonstrated a significant association between CD4 C868T and susceptibility to HIV-1 infection (P > .001 and P = .003, respectively). Conclusion. Overall, the present study found a strong correlation between CD4 C868T and increased susceptibility to HIV-1 infection. Given the high prevalence of both HIV infection and CD4 C868T in African populations, the effect of this SNP on the epidemic in Africa could be dramatic.
Bibliographical noteFunding Information:
Financial support: Paul H. T. Thorlakson Foundation (funding for a pilot study of CD4 genetics); Elizabeth Glaser Pediatric AIDS Foundation (funding for a pilot study of CD4 genetics); Canadian Association for AIDS Research (funding for a preliminary study of CD4 function); Manitoba Health Research Council (studentship to J.O.O. and Manitoba Research Chair Career Award to K.R.F.); Canadian Institutes for Health Research (grant MOP-81377 to study CD4 genetics and function and New Investigator Career Award to K.R.F.); Natural Science and Engineering Research Council of Canada (scholarship to F.C.M.V.); Manitoba Medical Service Foundation (Basic Sciences Career Development Research Award to X.Y.). F.A.P. is a Canada Research Chair in Resistance and Susceptibility to Infections. a J.O.O. and F.C.M.V. contributed equally to this work.