CCR5 and HIV: the less, the better

Two reports in this issue of Blood underscore the central importance of the regulation of chemokine receptor CCR5 expression to the pathogenic infection of SIV and associated destruction of gut mucosa in nonnatural hosts. CCR5 is the obligate coreceptor for infection by SIV and most transmitted forms of HIV; humans who lack CCR5 expression (CCR5Δ32) are highly resistant to HIV infection. Now it appears that a selection for low expression of CCR5 in natural hosts of SIV has evolved as one mechanism to escape the pathogenic consequences of infection.

Pandrea and colleagues surveyed a range of primate species whose susceptibility to SIV pathogenesis varies. Those with low levels of CCR5⁺ cells in both mucosal and peripheral tissues, such as the sooty mangabeys, escape the pathogenic consequences of massive infection and destruction of CD4 T cells commonly observed in nonnatural hosts such as humans and macaques. This effect was most apparent in the gut, where low CCR5 expression was associated with better protection and preservation of gut CD4 T cells; in nonnatural hosts (including humans), there is a near total and irreparable destruction of CD4 memory T-cell compartment following infection.

All CD4 memory cells can express low levels of CCR5; those that are CCR5⁺ by immunofluorescence express at least 10-fold more. While all memory cells can sustain infection, those that are CCR5⁺ are more efficiently infected; and, perhaps by virtue of the fact that CCR5⁺ memory cells are more differentiated and activated, may produce much more virus than their CCR5⁻ counterparts. Immediately following infection, the very high viremia and/or acute inflammation overpowers the differences in CCR5 expression among memory T cells, and all CD4 memory cells are efficiently destroyed. However, during chronic infection, when viremia is much reduced, infection may be largely biased towards cells expressing high levels of CCR5.

Pandrea and colleagues' study suggests that natural infection with SIV has selected for animals that either lack or exhibit much lower levels of CCR5, leading to nonpathogenic infection. In contrast, species that are not natural hosts such as humans and macaques have higher levels of CCR5⁺ CD4 cells, and infection by SIV/HIV is accompanied by severe pathogenesis. Similarly, it might be predicted that neonates, whose naive immune systems have very few memory T cells, should be relatively resistant to infection. Nevertheless, Wang and colleagues demonstrate that massive destruction of intestinal CD4 T cells and associated immunopathogenesis does occur in neonatal macaques; the gut mucosa already harbor large numbers of highly susceptible CCR5⁺ CD4 memory T-cell subsets. This further underscores how different the blood and gut mucosa are, and why the study of the gut-associated lymphoid tissue is so important to understanding SIV/HIV immunopathogenesis.

There is no longer any doubt about whether the gut is a primary site for harboring virus; it serves as a potent reservoir for the persistence of SIV/HIV infection. Perhaps more important, the massive activation and destruction of CD4 cells in the gut during pathogenic infection leads to a cascade of events, including extensive damage to the mucosal epithelium. This breakdown in mucosal integrity and immunity in turn allows commensal bacterial products such as endotoxins to cross the mucosal barrier.¹  The elevated blood levels of endotoxin are highly correlated with activation of the innate and adaptive immune systems and thus with disease progression. Through natural selection, some species of primates exhibit lower levels of CCR5⁺ cells in the gut, thereby escaping the massive immunopathogenesis and associated sequelae, allowing the host to maintain long-term nonprogression even in the face of relatively high plasma viremia.

These studies highlight the central role of the regulation of CCR5 expression to HIV pathogenesis. Is there a serious immunologic consequence to having fewer CCR5⁺ cells? Probably not; humans who have no CCR5, as well as natural hosts such as the sooty mangabeys, appear to be largely healthy in addition to being resistant to the devastating effects of SIV/HIV infection. Should HIV infection persist uncontrolled in humans, we might find our own subspecies undergoing a selection for low CCR5 expression.