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

Platelet Function and Coronary Microvascular Dysfunction

The ability of platelets to activate and aggregate to form blood clots in response to endothelial injury is well established. They are therefore critical contributors to ischaemia in atherothrombosis [1]. However, their role in cardiovascular disease is not limited to end-stage thrombosis in large vessels [2]. Abundant experimental evidence has established that activated platelets are also important mediators of microvascular thrombosis and promote the inflammatory response during ischaemia-reperfusion (IR) injury [3–5]. While platelets do not physically interact with the healthy endothelium, they can bind to the wall of hypoxic microvessels and release a plethora of inflammatory mediators that further enhance the activation of the endothelial monolayer and the recruitment of circulating leukocytes (monocytes, neutrophils, T-cells) [2]. In addition, deposition of platelets to the dysfunctional endothelium can lead to vasoconstriction which accelerates microvascular occlusion, thereby impairing tissue perfusion [3]. In this chapter, we discuss the role of platelets in promoting microvascular dysfunction and inflammation during IR injury. Focus is placed on the cross-talk between platelets and other cell types (endothelial cells [ECs] and leukocytes) via platelet adhesion receptors and platelet-derived proinflammatory mediators. We also consider new paradoxical functionalities of platelets promoting cardiac recovery after myocardial infarction (MI)