Martin Cranage, Marjorie Robert-Guroff, Soe Than, Yvette Edghill-Smith, Kamalpreet Arora, Phillip D. Markham, Ruth A. Woodward, Dimiter S. Dimitrov, Michel Leno, Bo Peng, Sanjay Phogat, Lulu Lim, and Rebecca Voltan
Elucidation of host factors that modulate susceptibility to infection with human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) and influence disease outcome will not only broaden our understanding of virus-cell interactions but will also have important practical implications. Knowledge of natural host defense mechanisms may lead to their exploitation for therapeutic or prophylactic purposes. Identification of host susceptibility factors may influence treatment decisions and further define risk factors for HIV acquisition. Clarification of host susceptibility and resistance factors in nonhuman primates should limit the variability in experimental groups and lead to improved design of preclinical studies. A few immunologic and genetic host factors have been identified which influence HIV or SIV infection and viral replication (11). The former includes acquired immunity resulting from viral infection, as well as innate immunity involving many inducible cytokines and chemokines. Genetic factors, such as HLA haplotypes, can influence the host's immune response. Two haplotypes have been associated with rapid disease progression after HIV infection (10), whereas another has been linked to long-term nonprogression (39). A similar protective effect of the rhesus macaque Mamu A*01 genotype has been recently demonstrated (43). The most dramatic genetic influence on HIV transmission and disease progression involves a 32-bp deletion (Δ32) in the CCR5 gene, the major coreceptor for macrophage-tropic, non-syncytium-inducing HIV isolates. This deletion results in a truncated, nonfunctional gene product and is associated with protection against HIV infection in individuals homozygous for the CCR5 Δ32 allele (20, 30, 49) and with delayed disease progression and decreased CCR5 expression on T cells among heterozygous individuals (13, 45, 59). Additional CCR5 polymorphisms exist but have not been shown to modulate HIV infection (37). Polymorphisms in the CCR5 promoter have been associated with accelerated disease progression (34, 36), but the mechanisms for this are unclear. A minor coreceptor mutation, CCR2-64I, with strong linkage disequilibrium with a CCR5 promoter region mutation (25), was initially associated with delayed disease progression (53), although subsequent studies have yielded conflicting results (33, 37, 38). Alterations in chemokine or cytokine genes or their promoters can also affect the course of HIV disease. Delayed disease progression has been attributed to a polymorphism in the RANTES promoter (29) and to an SDF-1 gene mutation, although the latter finding is controversial (19, 41, 57, 58). Polymorphisms in the interleukin-10 (IL-10) promoter have been linked to AIDS progression (52). Identification of host factors which contribute to susceptible or resistant phenotypes is difficult in humans. Our observation, summarized below, of unusually strong resistance to SIV infection in a rhesus macaque, presented a unique opportunity for investigating novel host resistance mechanisms. In general, intravaginal infection of rhesus macaques can result in either transient or persistent viremia (40), as well as in occult systemic infection in some cases (35). In earlier preclinical vaccine studies in which rhesus macaques were challenged with infectious, pathogenic SIVmac251, we observed such variable outcomes in both controls and immunized monkeys with regard to infection and disease progression (7, 8). One naive control macaque, 359, resisted two intravaginal exposures with escalating dosages of SIVmac251. Here we report that, after an additional intrarectal challenge with SIVmac32H, macaque 359 became only transiently viremic and cleared virus from the peripheral blood. In vitro studies confirmed that the animal's peripheral blood mononuclear cells (PBMCs) were highly resistant to SIV infection, even though adequate levels of CCR5 were expressed on the surface of the cells. In order to elucidate the basis for the unusually strong resistance of macaque 359 to in vivo and in vitro SIV infection, early events in the viral infection and replication process were examined. We examined several coreceptor genes for mutational changes. Genetic polymorphisms were detected in the CCR5 gene; however, none of the changes led to amino acid substitutions. Investigation of reverse transcription events revealed significant inhibition in the accumulation of early DNA replication intermediates. However, macaque 359 cells were able to fuse with cells expressing a SIVmac251 envelope or a CCR5-tropic HIV envelope as readily as cells from macaques highly susceptible to SIV infection. Taken together, our results indicate that the resistance of macaque 359 to SIV infection is due to postentry inhibition of viral replication and implicate a host cell mechanism in this process.