HIV-2 evolved ZAP resistance despite increased CpG levels

Simian immunodeficiency viruses infecting sooty mangabeys (SIVsmm) have been transmitted to humans on multiple occasions, giving rise to human immunodeficiency virus type 2 (HIV-2) groups A to I. However, only groups A and B spread significantly in humans causing an epidemic in West Africa. The reasons for this are poorly understood. Here, we show that genetically diverse SIVsmm strains efficiently infect primary human T cells. However, they are highly sensitive to type I IFN, indicating that interferon stimulated genes (ISGs) pose a barrier to successful spread of SIVsmm in humans. One well-known ISG is the zinc finger antiviral protein (ZAP), which specifically targets CpG dinucleotides in viral RNAs. To evade ZAP restriction, many viruses including HIV-1 suppress their CpG content. Unexpectedly, we found that HIV-2 is less sensitive to restriction by ZAP than HIV-1 and SIVsmm despite significantly higher CpG content. Analyses of chimeric HIV-2/SIVsmm constructs revealed that the determinants of ZAP resistance map to the U3 region of the 3’ LTR that overlaps with the nef gene. Our results indicate that ZAP poses a barrier for efficient spread of SIVsmm in humans and that epidemic HIV-2 evolved an unique mechanism to evade it.