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

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 (p<0.001) with lower CCL3L copy number associating with more rapid disease course. We also find that CCL3L copy number varies significantly (p<10−6) 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

Influence of Fcγ RIIA and MBL polymorphisms on severe acute respiratory syndrome

Polymorphisms of human Fc γ-receptor IIA (FcγRIIA) and mannose-binding lectin (MBL) genes have been associated with susceptibility to or severity of some infectious diseases. In order to investigate whether these genetic factors might influence susceptibility to infection with the severe acute respiratory syndrome-associated coronavirus (SARS-Cov) as well as the course and severity of the infection, we evaluated polymorphisms of FcγRIIA and MBL genes in DNA samples from a group of approximately 180 people from Hong Kong who were infected with SARS-Cov. These included 132 patients who had moderate course of SARS infection (home subgroup), 26 patients with a severe course requiring treatment in an intensive care ward (ICU subgroup) and a subgroup of 22 patients who died from SARS (deceased subgroup). A total of 200 normal blood donors from the same region were used as controls. A significant association was found between the FcγRIIA-R/R131 genotype and a severe course of SARS, with higher frequency of homozygosity for FcγRIIA-R/R131 in the ICU subgroup of SARS patients when compared with controls (P = 0.03; odds ratio: 3.2; 95% confidence interval: 1.1-9.1). In comparison with controls, a significant difference in linear trend distribution of FcγRIIA genotypes was seen among the severe SARS patients (ICU and deceased subgroups) without co-morbidity, and the incidence of FcγRIIA-H/H131 was lower in these patients as well. There were no significant differences in MBL genotypes and allele frequencies among SARS patients and controls. The study reveals that in addition to age and co-morbidity, FcγRIIA polymorphism of individuals may also influence outcome after infection with the SARS-Cov. © 2005 Blackwell Publishing Ltd.link_to_subscribed_fulltex