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Background  Polymorphisms in CCR5, the major coreceptor for HIV, and CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine, are determinants of HIV-AIDS susceptibility. Here, we mathematically modeled the potential impact of these genetic 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 and persistence of epidemics. By modeling sexual transmission among HIV+/HIV− partner pairs, we find that  Ro  estimates, and concordantly, 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-CCR5  genotypes, respectively. The modeling data indicate that in populations such as Pygmies with a high  CCL3L1  gene dose and protective  CCR5  genotypes, the spread of HIV might be minimal. Additionally,  Pc , the critical vaccination proportion, an estimate of the fraction of the population that must be vaccinated successfully to eradicate an epidemic was <1 only when the infected partner had a protective  CCL3L1-CCR5  genotype. Since in practice  Pc  cannot be >1, to prevent epidemic spread, population groups defined by specific  CCL3L1-CCR5  genotypes might require repeated vaccination, or as our models suggest, a vaccine with an efficacy of >70%. Further, failure to account for  CCL3L1-CCR5 -based genetic risk might confound estimates of vaccine efficacy. For example, in a modeled trial of 500 subjects, misallocation of  CCL3L1-CCR5  genotype of only 25 (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 observed heterogeneous global distribution of HIV infection. As  Ro  is lowest when the infecting partner has beneficial  CCL3L1-CCR5  genotypes, we infer that therapeutic vaccines directed towards reducing the infectivity of the host may play a role in halting epidemic spread. Further,  CCL3L1-CCR5  genotype may provide critical guidance for optimizing the design and evaluation of HIV-1 vaccine trials and prevention programs.

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