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APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous A3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable A3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate A3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable A3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable A3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of A3H impose selective pressure on HIV-1.

APOBEC3 (A3) family proteins are DNA cytosine deaminases recognized for contributing to HIV-1 restriction and mutation. Prior studies have demonstrated that A3D, A3F, and A3G enzymes elicit a robust anti-HIV-1 effect in cell cultures and in humanized mouse models. Human A3H is polymorphic and can be categorized into three phenotypes: stable, intermediate, and unstable. However, the anti-viral effect of endogenous A3H in vivo has yet to be examined. Here we utilize a hematopoietic stem cell-transplanted humanized mouse model and demonstrate that stable A3H robustly affects HIV-1 fitness in vivo. In contrast, the selection pressure mediated by intermediate A3H is relaxed. Intriguingly, viral genomic RNA sequencing reveled that HIV-1 frequently adapts to better counteract stable A3H during replication in humanized mice. Molecular phylogenetic analyses and mathematical modeling suggest that stable A3H may be a critical factor in human-to-human viral transmission. Taken together, this study provides evidence that stable variants of A3H impose selective pressure on HIV-1., Author summary Human APOBEC3 family proteins are known as intrinsic defenses against HIV-1, whereas HIV-1 Vif counteracts APOBEC3-mediated anti-viral action. Using a hematopoietic stem cell-transplanted humanized mouse model, we demonstrated that endogenous APOBEC3D, APOBEC3F and APOBEC3G play pivotal roles in restricting HIV-1 replication in vivo. In addition to these three APOBEC3 family proteins, certain haplotypes of APOBEC3H have the ability to control HIV-1 replication in cell culture studies. However, the anti-viral effect of APOBEC3H polymorphism in vivo and in human population is yet to be addressed. Here we use a humanized mouse model to show that acquiring resistance to anti-viral APOBEC3H is necessary for HIV-1 replication. Together with phylogenetic analyses and mathematical modeling, we conclude that APOBEC3H is a critical determinant of HIV-1 replication within infected individuals and we propose that it may also be a factor in human-to-human HIV-1 transmission.

A large proportion of human malaria infections is asymptomatic, yet serves as a reservoir that sustains malaria transmission. To achieve malaria elimination, it is important to understand how asymptomatic infections affect malaria transmission among humans. Here we propose a simple mathematical model of malaria transmission with both symptomatic and asymptomatic infections, and investigate the effect of interventions targeting the reservoir population during an early phase of malaria spread under different transmission settings.