Variability in a dominant block to SIV early reverse transcription in rhesus monkey cells predicts in vivo viral replication and time to death

Abstract

While it has long been appreciated that there is considerable variability in host containment of HIV/SIV replication, the determinants of that variability are not fully understood. Previous studies demonstrated that the degree of permissivity of a macaque's peripheral blood mononuclear cells (PBMC) for infection with simian immunodeficiency virus (SIV) in vitro predicted that animal's peak plasma virus RNA levels following SIV infection in vivo. The present study was conducted to define the mechanisms underlying the variable intrinsic susceptibility of rhesus monkey PBMC to SIVsmE660 infection. In a cohort of 15 unrelated Indian-origin rhesus monkeys, infectability of PBMC of individual animals with SIVsmE660, as defined by tissue culture infectious dose (TCID50), varied by more than 3 logs and was a stable phenotype over time. Susceptibility of a monkey's PBMC to wild type SIVsmE660 infection correlated with the susceptibility of that monkey's PBMC to infection with VSV-G pseudotyped SIVsm543-GFP. Moreover, the permissivity of an individual monkey's PBMC for infection with this construct correlated with the permissivity of a B-lymphoblastoid cell line (B-LCL) generated from PBMC of the same animal. We found that the degree of intrinsic resistance of monkey B-LCL correlated with the copy number of early reverse transcription (ERT) SIV DNA. The resistance of monkey B-LCL to SIVsmE660 replication could be abrogated by preincubation of cells with the SIV virus-like particles (VLPs) and SIV resistance phenotype could be transferred to a SIV susceptible B-LCL through cell fusion. Finally, we observed a positive correlation between susceptibility of monkey B-LCL to SIV infection with a VSV-G pseudotyped SIV-GFP construct in vitro and both the peak plasma virus RNA levels in vivo and time to death following wild type SIV infection. These findings suggest that a dominant early RT restricting factor that can be saturated by SIV capsid may contribute to the variable resistance to SIV infection in rhesus monkey B-LCL and that this differential intrinsic susceptibility contributes to the clinical outcome of an SIV infection.

The TRIM5 Gene Modulates Penile Mucosal Acquisition of Simian Immunodeficiency Virus in Rhesus Monkeys

“…Given that SIVsmE660 has become increasingly important in AIDS pathogenesis and vaccine challenge studies (14,20,28,32,36), we felt that it was important to understand the genetic contribution of this virus to mucosal acquisition and pathogenesis. We have previously shown that TRIM5 alleles in Indian-origin rhesus monkeys have a significant effect on the control of SIVmac239 and SIVmac251 replication in lymphocytes both in vitro and in vivo after intravenous infection (21,22,33). In addition, we have also shown that TRIM5 alleles affect SIVsmE543 replication in vitro (22).…”

“…In addition, our group and others have recently shown that allelic variation of TRIM5 modulates the in vitro infectivity and level of in vivo viral replication of SIV strains in susceptible host species (18,21,22,33). Viral inhibition by TRIM5␣ is mediated by an interaction between the B30.2/SPRY domain and virion Gag capsids that are released into the cytoplasm of the target cell after viral attachment and entry.…”

“…Two TRIM5 alleles are expressed codominantly in Indian-origin rhesus monkeys. If one or both of those alleles are from the group of alleles 6 to 11, we have previously demonstrated that SIV replicates at a higher level after infection (both peak and set-point viral loads) than if both are from the group of alleles 1 to 5 (21,22,33). Accordingly, common variants of TRIM5 in Indian-origin rhesus monkeys can be grouped into three genotypes: homozygous restrictive, heterozygous permissive, and homozygous permissive (21,22).…”

Pressure from TRIM5α Contributes to Control of HIV-1 Replication by Individuals Expressing Protective HLA-B Alleles

“…However, we recently showed that viruses car-rying CA sequences from two different clinical isolates were 4-to 7-fold more sensitive to hTRIM5␣ than the laboratory-adapted NL4-3 strain, and this sensitivity was explained by the presence of mutations known to promote escape from CTL responses directed against CA epitopes presented by HLA-B*27 and/or HLA-B*57 (38,44). In this regard, it is noteworthy that studies in simian models have shown that differences in TRIM5␣ activity of this magnitude against infecting viruses can influence both viral replication and disease progression (49)(50)(51)(52). Taken together, these findings are consistent with the possibility that hTRIM5␣ activity could reduce viral replication in patients expressing protective HLA alleles.…”

“…Although greater viral sensitivity to TRIM5␣ may be required to have a strong impact on crossspecies transmission (76), studies in some simian models have shown that only modest changes in sensitivity to TRIM5␣ can influence both transmission and disease progression (49)(50)(51)(52). For example, simian immunodeficiency virus SIV mac251 has been highly adapted for replication in Rhesus monkeys, and replication of this virus is inhibited by only 3-to 4-fold in cells expressing the most active allelic variants of Macaca mulatta TRIM5␣ and inhibited only 2-fold in cells expressing the less active allelic variants (51).…”