Virus-Host Coevolution in Non-Pathogenic Infection of Reservoir Hosts.
April 2, 2003

Sooty mangabeys are old world monkeys whose geographic host range overlaps with the HIV-2 epidemic in humans in West Africa. Sooty mangabeys are naturally infected with simian immunodeficiency virus (SIV) which has the same genomic structure as HIV-2. We have found that sooty mangabeys tolerate high level viremia with viruses that cause immunodeficiency when transferred to macaques, which are asian monkeys that suffer simian AIDS after infection with SIV. We studied naturally infected sooty mangabeys at US-based primate centers using viral load assays based on quantitative-competitive reverse transcriptase PCR assay and real time PCR for SIVsm. This assay was validated by comparison with SIV bDNA (R2 = 0.96) and by comparison with limit-of-dilution analysis. Viral load was 100,000 to 100,000,000 SIV RNA copies/ml, a level comparable to those in pathogenic infections, such as HIV-1-infected humans and SIVmac-infected rhesus macaques. In addition, we collaborated with Drs. Amitidaur Kaur and Paul Johnson who evaluated anti-SIV cytotoxic T-lymphocyte responses in unstimulated PBMCs from mangabeys. After in vitro stimulation with SIV antigens for 7 to 10 days, low or moderate levels of anti-SIV cytotoxic T-lymphocyte activity were detected in some but not all mangabeys. Anti-SIV activity did not correlate with the level of SIV viremia. These observations suggest that the lack of SIV disease in sooty mangabeys is not due to greater host control of viral replication.

To understand mangabey adaptations that decrease host susceptibility to SIV disease, we have studied cell receptors known to be involved in SIV replication. Two CD4 protein variants in sooty mangabeys that differ at four residues, including one substitution in the CDR2 region known to be involved in HIV Env interactions, have been reported previously. Emil Palacios, in our laboratory, recently reported that sooty mangabeys are also polymorphic at the other major SIV/HIV receptor locus, CCR5. A variant 24-base pair deletion allele was identified that rendered the translated protein nonfunctional and unable to serve as a coreceptor for viral entry. To assess interactions between these loci and SIV infection, the entire sooty mangabey colony (258 animals) at the Yerkes Regional Primate Research Center has been genotyped at both CD4 and CCR5 loci. The genotypes were in Hardy-Weinberg equilibrium, suggesting no selection against the mutant alleles of CD4 and CCR5. At least one SIV-seropositive and apparently healthy mangabey was found in each genotypic group. Nevertheless, careful analysis of viral kinetics indicated slightly delayed SIV accumulation in cell cultures of PBMCs from sooty mangabeys that are homozygous for CD4-2 or heterozygous at the CCR5 locus. The unprecedented polymorphism of both CD4 and CCR5 in the natural host of SIV may yield clues to the selective pressures lentiviruses exert on primate hosts over evolutionary time vis-a-vis cellular receptors used for viral entry.

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