Lv4 Is a Capsid-Specific Antiviral Activity in Human Blood Cells That Restricts Viruses of the SIV(MAC)/SIV(SM)/HIV-2 Lineage Prior to Integration

HIV-2 and SIV(MAC) are AIDS-causing, zoonotic lentiviruses that jumped to humans and rhesus macaques, respectively, from SIV(SM)-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 SIV(SM)/SIV(MAC)/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 SIV(MAC), HIV-2, or SIV(SM) 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 SIV(MAC) 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. As(2)O(3), a drug that suppresses TRIM5-mediated restriction, increased human blood cell transduction by SIV(MAC) but not by HIV-1. Nonetheless, elimination of TRIM5 restriction activity did not rescue SIV(MAC) transduction. Also, in contrast to TRIM5-mediated restriction, the SIV(MAC) 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 SIV(MAC) 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/SIV(MAC)/SIV(SM) and that cross-species transmission of SIV(SM) to human T cells necessitated adaptation of HIV-2 to this putative restriction factor.