Lv4 Is a Capsid-Specific Antiviral Activity in Human Blood Cells That Restricts Viruses of the SIVMAC/SIVSM/HIV-2 Lineage Prior to Integration

Hiv-2 and sivmac are aids-causing,zoonotic lentiviruses that jumped to humans and rhesus macaques,respectively,from sivsm-bearing sooty mangabey monkeys. cross-species transmission events such as these sometimes necessitate virus adaptation to species-specific,host restriction factors such as trim5. here,a new human restriction activity is described that blocks viruses of the sivsm/sivmac/hiv-2 lineage. human t,b,and myeloid cell lines,peripheral blood mononuclear cells and dendritic cells were 4 to >100-fold less transducible by vsv g-pseudotyped sivmac,hiv-2,or sivsm than by hiv-1. in contrast,transduction of six epithelial cell lines was equivalent to that by hiv-1. substitution of hiv-1 ca with the sivmac or hiv-2 ca was sufficient to reduce hiv-1 transduction to the level of the respective vectors. among such ca chimeras there was a general trend such that cas from epidemic hiv-2 group a and b isolates were the most infectious on human t cells,ca from a 1° sooty mangabey isolate was the least infectious,and non-epidemic hiv-2 group d,e,f,and g cas were in the middle. the ca-specific decrease in infectivity was observed with either hiv-1,hiv-2,ecotropic mlv,or alv env pseudotypes,indicating that it was independent of the virus entry pathway. as2o3,a drug that suppresses trim5-mediated restriction,increased human blood cell transduction by sivmac but not by hiv-1. nonetheless,elimination of trim5 restriction activity did not rescue sivmac transduction. also,in contrast to trim5-mediated restriction,the sivmac ca-specific block occurred after completion of reverse transcription and the formation of 2-ltr circles,but before establishment of the provirus. transduction efficiency in heterokaryons generated by fusing epithelial cells with t cells resembled that in the t cells,indicative of a dominant-acting sivmac restriction activity in the latter. these results suggest that the nucleus of human blood cells possesses a restriction factor specific for the ca of hiv-2/sivmac/sivsm and that cross-species transmission of sivsm to human t cells necessitated adaptation of hiv-2 to this putative restriction factor. © 2015 pizzato et al.