Copy Number Variation of CCL3-like Genes Affects Rate of Progression to Simian-AIDS in Rhesus Macaques (Macaca mulatta)

Abstract

Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at CCL3-like genes (CCL3L), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that CCL3L CNV explains approximately 18% of the variance in time to simian-AIDS (pCCL3L copy number associating with more rapid disease course. We also find that CCL3L copy number varies significantly (p−6) among rhesus subpopulations, with Indian-origin macaques having, on average, half as many CCL3L gene copies as Chinese-origin macaques. Lastly, we confirm that CCL3L shows variable copy number in humans and chimpanzees and report on CCL3L CNV within and among three additional primate species. On the basis of our findings we suggest that (1) the difference in population level copy number may explain previously reported observations of longer post-infection survivorship of Chinese-origin rhesus macaques, (2) stratification by CCL3L copy number in rhesus SIV vaccine trials will increase power and reduce noise due to non-vaccine-related differences in survival, and (3) CCL3L CNV is an ancestral component of the primate immune response and, therefore, copy number variation has not been driven by HIV or SIV per se. Development of vaccines for HIV/AIDS is a pressing global issue. The rhesus monkey remains the primary model for testing potential human vaccines; however, little is known about similarities and differences in host genes involved in HIV/AIDS response in humans and rhesus monkeys. Understanding these similarities and/or differences should allow more efficient testing of vaccines beneficial to humans. Here we describe the role that variation in the number of copies of CCL3-like genes (CCL3L) plays in SIV progression rates in rhesus monkeys. Copy number variation (CNV) of these genes has previously been shown to play a role in susceptibility and progression of HIV in humans. Our results suggest that individual monkeys with lower CCL3L copy number progress more rapidly. Accounting for CCL3L CNV in rhesus vaccine trials will improve researchers' abilities to interpret survival data.