HIV-2 evades restriction by ZAP through adaptations in the U3 LTR region despite increased CpG levels

Abstract

Simian immunodeficiency viruses infecting sooty mangabeys (SIVsmm) gave rise to nine groups of human immunodeficiency virus type 2 (HIV-2). Two of these (A and B) spread substantially with an estimated 1- 2 million individuals affected. The evolutionary adaptations that facilitated HIV-2s spread in humans are still poorly understood. Here, we report that diverse SIVsmm strains efficiently infect primary human T cells. However, they are more sensitive to interferon than HIV-2, indicating that interferon-stimulated genes (ISGs) pose a barrier to the successful spread of SIVsmm in humans. One of the best-known antiviral ISGs is the zinc finger antiviral protein (ZAP), which targets CpG dinucleotides in RNA. To evade ZAP-mediated restriction, many viruses, including HIV-1, suppress their CpG content. Unexpectedly, we found that HIV-2 is more resistant to ZAP restriction than HIV-1 and SIVsmm despite having 33% more CpGs. Identification of ZAP binding sites using RNA eCLIP and analyses of chimeric HIV-2/SIVsmm viruses, revealed that the determinants of ZAP resistance map to the U3 region of the long-terminal repeat and promote HIV-2 replication in primary human T cells. Our results indicate that ZAP poses a barrier to SIVsmm infection in humans and that HIV-2 evolved a CpG-independent mechanism to evade it.