title: 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 (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.
authors.affiliation: Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Degenhardt
authors.forename: Paola
authors.initials: P
authors.lastname: de Candia
authors.forename: Adrien
authors.initials: A
authors.lastname: Chabot
authors.forename: Stuart
authors.initials: S
authors.lastname: Schwartz
authors.forename: Les
authors.initials: L
authors.lastname: Henderson
authors.forename: Binhua
authors.initials: B
authors.lastname: Ling
authors.forename: Meredith
authors.initials: M
authors.lastname: Hunter
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Jiang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Palermo
authors.forename: Michael
authors.initials: M
authors.lastname: Katze
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.forename: Mario
authors.initials: M
authors.lastname: Ventura
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rogers
authors.forename: Preston
authors.initials: P
authors.lastname: Marx
authors.forename: Yoav
authors.initials: Y
authors.lastname: Gilad
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
mesh_terms: D000818:Animals; D002138:Calibration; D054405:Chemokine CCL3 / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry; D018450:Disease Progression; D018628:Gene Dosage; D005828:Genetics, Population; D007107:Immune System; D016013:Likelihood Functions; D008253:Macaca mulatta; D018895:Microsatellite Repeats; D015233:Models, Statistical; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D054405:Chemokine CCL3; D017931:DNA Primers