Species-specific differences in antagonism of APOBEC3 proteins by HIV-2 and SIVsmm Vif proteins

SIVsmm infecting sooty mangabeys has been transmitted to humans on at least nine independent occasions, giving rise to HIV-2 groups A to I. SIVsmm isolates replicate in human T cells and seem capable of overcoming major human restriction factors without adaptation. However, only groups A and B are responsible for the HIV-2 epidemic in Sub-Saharan Africa and it is largely unclear whether adaptive changes were associated with significant spread in humans. To address this, we examined the sensitivity of infectious molecular clones (IMCs) of five HIV-2 strains (4 group A and one AB recombinant) and representatives of five different SIVsmm lineages to inhibition by type I interferon (IFN) and various APOBEC3 proteins. We confirmed that SIVsmm strains replicate in primary human CD4+ T cells. However, SIVsmm replication was highly variable, typically lower relative to HIV-2 isolates and almost entirely prevented by type I IFN treatment. Viral propagation was generally dependent on intact vif genes, highlighting the need for efficient counteraction of APOBEC3 proteins. On average, SIVsmm strains were significantly more susceptible to inhibition by human APOBEC3D, F, G and H than HIV-2 IMCs. For example, human APOBEC3F reduced infectious virus yield of SIVsmm by [~]80% but achieved only [~]40% in the case of HIV-2. Functional and mutational analyses of human, sooty mangabey and rhesus macaque derived alleles revealed that an R128T polymorphism in APOBEC3F is important for species-specific counteraction by HIV-2 and SIVsmm Vif proteins. In addition, we found that changes of Y45H and T84S in SIVsmm Vif increase its ability to antagonize human APOBEC3F. Altogether, our results show that SIVsmm Vifs show some intrinsic activity against human ABOBEC3 proteins, but HIV-2 Vifs acquired adaptive changes to efficiently clear this barrier in the human host. AUTHOR SUMMARYSIVs infecting African monkey species do not infect humans, with one notable exception. SIVsmm from sooty mangabeys managed to cross the species barrier to humans on at least nine independent occasions. This is because SIVsmm strains seem capable of overcoming many innate defense mechanisms without adaptation and that their Vif proteins are active against human APOBEC3 proteins. Here, we show that replication of SIVsmm is highly variable in human CD4 T cells and more sensitive to interferon inhibition compared to HIV-2. While different lineages of SIVsmm were capable of counteracting human APOBEC3 proteins in a Vif-dependent manner, they were significantly more susceptible to inhibition by APOBEC3D/F/G/H compared to HIV-2. Mutational analyses revealed an R128T substitution in APOBEC3F and a T84S change in Vif are relevant for species-specific counteraction by HIV-2 and SIVsmm. Altogether, our results support that HIV-2 group A adapted to humans prior to or during epidemic spread.