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

Abstract

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.

Characterization of two distinct early post-entry blocks to HIV-1 in common marmoset lymphocytes

“…Thus, the factor responsible for the marmoset B-LCL block probably exerts its action in the nucleus. The mechanism of action of this factor resembles the recently reported Lv4 activity that blocks viruses of the SIV mac /SIV sm /HIV-2 lineage in human blood cells42. In that work, Pizzato and colleagues also showed that the Lv4 activity targets the capsid of SIV mac , SIV sm , and HIV-2.…”

“…Arsenic trioxide treatment has been shown to suppress the antiviral activity of TRIM5α, Lv4, and a post-entry inhibitory factor present in dendritic cells (DC)404142. We found that treatment with arsenic specifically increased the infectivity of HIV-1 in the marmoset B-LCLs, whereas HIV-1 infectivity decreased in the human B-LCLs; the observed decrease in the human B-LCLs may have possibly resulted from non-specific toxic effects of the treatment.…”

“…This treatment has also been shown to suppress the antiviral activity of Lv4 and a post-entry inhibitory factor present in dendritic cells4142. We analyzed the effect of As 2 O 3 treatment on the infectivity of HIV-1 in the B-LCLs.…”

“…To date, a few dominant blocks to the early phase of lentivirus infection have been described in cells of different species: Lv1 (later identified as TRIM5α), Lv2, Lv3, Lv4, SAMHD1 and MX22345691222424344. The identity of the factors responsible for the Lv2, Lv3 and Lv4 activities are currently unknown.…”

Metabolic profiling during HIV-1 and HIV-2 infection of primary human monocyte-derived macrophages

“…Host Lv2 protein has HIV-2 specific envelope restriction function (McKnight et al, 2001). Recently Lv4 was reported to be another capsid specific host restriction factor inhibiting SIV mac and HIV-2 infection (Pizzato et al, 2015). Several studies have reported that host sterile alpha motif (SAM) and histidine/aspartic acid (HD) domain protein 1 (SAMHD1) acts as a myeloid specific host anti-HIV/SIV restriction factor (Hrecka et al, 2011; Laguette et al, 2011).…”