Role of CCL3L1-CCR5 Genotypes in the Epidemic Spread of HIV-1 and Evaluation of Vaccine Efficacy

Abstract Background:Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressivechemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of thesegenetic factors on the epidemic spread of HIV, as well as on its prevention.Methods and Results:Ro, the basic reproductive number, is a fundamental concept in explaining the emergence andpersistence of epidemics. By modeling sexual transmission among HIV+/HIV2 partner pairs, we find that Ro estimates, andconcordantly, the temporal and spatial patterns of HIV outgrowth are highly dependent on the infecting partners’ CCL3L1-CCR5 genotype. Ro was least and highest when the infected partner possessed protective and detrimental CCL3L1-CCR5genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high CCL3L1 gene dose andprotective CCR5 genotypes, the spread of HIV might be minimal. Additionally, Pc, the critical vaccination proportion, anestimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was ,1 only whenthe infected partner had a protective CCL3L1-CCR5 genotype. Since in practice Pc cannot be .1, to prevent epidemicspread, population groups defined by specific CCL3L1-CCR5 genotypes might require repeated vaccination, or as our modelssuggest, a vaccine with an efficacy of .70%. Further, failure to account for CCL3L1-CCR5-based genetic risk might confoundestimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of CCL3L1-CCR5 genotype of only25 (5%) subjects between placebo and vaccine arms results in a relative error of ,12% from the true vaccine efficacy.Conclusions:CCL3L1-CCR5 genotypes may impact on the dynamics of the HIV epidemic and, consequently, the observedheterogeneous global distribution of HIV infection. As Ro is lowest when the infecting partner has beneficial CCL3L1-CCR5genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in haltingepidemic spread. Further, CCL3L1-CCR5 genotype may provide critical guidance for optimizing the design and evaluation ofHIV-1 vaccine trials and prevention programs.