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

Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, United States of America.
PLoS Genetics (Impact Factor: 7.53). 01/2009; 5(1):e1000346. DOI: 10.1371/journal.pgen.1000346
Source: PubMed


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.

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Available from: Meredith Hunter, Oct 12, 2015
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    • "Higher numbers of genes and/or higher expression of AMPs could be detrimental to the host, supported by the evidence that a higher number of AMP gene copies is not necessarily related with an enhanced immune protection. Copy number variations have been associated to human diseases [54], and when acting on immune genes they could possibly contribute to immune differences between individuals [55,56]. Therefore, future work must be oriented towards the comprehension of this correlation that may contribute to successful immune response in oyster. "
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    ABSTRACT: Summer mortalities of Crassostreagigas are a major concern in oyster aquaculture. They are the result of a complex interaction between the host, pathogens and environmental factors. Oyster genetics have been identified as an essential determinant of oyster susceptibility to summer mortalities. As the capability of oysters to circumvent diseases depends in part on their immune defenses, we aimed to analyze the gene expression and sequence polymorphism of 42 immune related genes in two oyster lines selected for their "High" (H) and "Low" (L) survival to summer mortalities. Results showed that the variability of gene expression and the sequence polymorphism acting on particular genes could enable the discrimination between H and L oyster lines. Besides, a higher sequence polymorphism was observed on the L line affecting 11 of the 42 analyzed genes. By analyzing gene expression, sequence polymorphism and gene copy number of two antimicrobial peptide families (Cg-Defs and Cg-Prp), and an antimicrobial protein (Cg-BPI) on individual oysters, we showed that gene expression and/or sequence polymorphism could also discriminate H and L oyster lines. Finally, we observed a positive correlation between the gene expression and the gene copy number of antimicrobials and that sequence polymorphism could be encoded in the genome. Overall, this study gives new insights in the relationship between oyster immunity and divergent phenotypes, and discusses the potential implication of antimicrobial diversity in oyster survival to summer mortalities.
    PLoS ONE 09/2013; 8(9):e75900. DOI:10.1371/journal.pone.0075900 · 3.23 Impact Factor
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    • "Quantification of the copy numbers of CCL3L, a CCR5 ligand that blocks viral entry, identified that Indian RM usually harbor much lower copy number of CCL3L compared to Chinese RM, suggesting that slower progression of SIV infection in Chinese RM may be a result of a block in entry by increased CCL3L in these animals [82]. In terms of adaptive immune response, it was shown that Chinese RM demonstrated stronger and longer lasting antiviral antibody response as well as SIV-specific CD8 CTL response [81] than Indian RM after SIV infection [20]. "
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    ABSTRACT: Simian immunodeficiency virus (SIV) infection of Indian-origin rhesus macaques (RM) has been widely used as a well-established nonhuman primate (NHP) model for HIV/AIDS research. However, there have been a growing number of studies using Chinese RM to evaluate immunopathogenesis of SIV infection. In this paper, we have for the first time reviewed and discussed the major publications related to SIV or SHIV infection of Chinese RM in the past decades. We have compared the differences in the pathogenesis of SIV infection between Chinese RM and Indian RM with regard to viral infection, immunological response, and host genetic background. Given AIDS is a disease that affects humans of diverse origins, it is of importance to study animals with different geographical background. Therefore, to examine and compare results obtained from RM models of Indian and Chinese origins should lead to further validation and improvement of these animal models for HIV/AIDS research.
    Retrovirology 08/2013; 10(1):89. DOI:10.1186/1742-4690-10-89 · 4.19 Impact Factor
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    • "In 2005, Gonzalez et al. reported an inverse correlation between copy number of CCL3L1, which encodes a ligand for CCR5, and susceptibility to HIV-1 infection (Gonzalez et al. 2005). Interestingly, a similar link between CCL3L1 copy number and disease progression in SIVmac-infected macaques has also been described (Degenhardt et al. 2009). The correlations have intuitive appeal, as ligands of CCR5 have been shown experimentally to inhibit HIV-1 replication (Cocchi et al. 1995; Menten et al. 1999, 2002; Nibbs et al. 1999; Xin et al. 1999). "
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    ABSTRACT: Recent years have seen a significant increase in understanding of the host genetic and genomic determinants of susceptibility to HIV-1 infection and disease progression, driven in large part by candidate gene studies, genome-wide association studies, genome-wide transcriptome analyses, and large-scale in vitro genome screens. These studies have identified common variants in some host loci that clearly influence disease progression, characterized the scale and dynamics of gene and protein expression changes in response to infection, and provided the first comprehensive catalogs of genes and pathways involved in viral replication. Experimental models of AIDS and studies in natural hosts of primate lentiviruses have complemented and in some cases extended these findings. As the relevant technology continues to progress, the expectation is that such studies will increase in depth (e.g., to include host whole exome and whole genome sequencing) and in breadth (in particular, by integrating multiple data types).
    Cold Spring Harbor Perspectives in Medicine 04/2012; 2(4):a007203. DOI:10.1101/cshperspect.a007203 · 9.47 Impact Factor
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