Chemokinereceptorsaspathogenicdeterminants

Shortly after the identification of CXCR4 and CCR5 as coreceptors, a highly prevalent CCR5 polymorphism (allele frequency 10% in Whites) termed A32CCR5 was identified.3031 This polymorphism, a frameshift 32-bp deletion in the middle of CCR5 that precludes full-length translation and transport to the cell surface, helps explain the molecular basis of resistance demonstrated by some highly exposed individuals who nonetheless remain uninfected. Homozygotes for this mutation are nearly completely resistant to HIV-1 infection, with a handful of exceptions,32-34 and heterozygotes for this mutation demonstrate a 2- to 4-year delay in progression to AIDS.35-37 More than anything else, though, this discovery demonstrates that CCR5 is the primary coreceptor used by HIV-1 for transmission and that it plays a major role in determining the rate of disease progression once an individual is infected. Moreover, the lack of any apparent deficiency in individuals who are homozygous for this mutation makes CCR5 a nearly ideal candidate for pharmaceutical targeting directed to block HIV-1 at the level of entry. Additional mutations in CCR5 have also been reported, but these are much less prevalent and none are predicted to have any obvious protective consequences. One CCR5 polymorphism, however, that results in a severely truncated cytoplasmic tail is predicted to lack signaling properties.38 Although signaling of CCR5 is clearly not required for virus fusion and entry,39-42 signaling may play a role in postentry events such as integration into quiescent cells such as macrophages. Any possible protective effects of this mutation would therefore be of great interest in determining alternative mechanisms of inhibiting CCR5 coreceptor function.

The identification of the A32CCR5 polymorphism helped trigger a search for additional polymorphisms in either chemokines or chemokine receptors that might influence viral transmission and pathogenesis. A single-base pair mutation in CCRS that changes a valine to an isoleucine at position 64 in the CCR2 protein (V64I-CCR2) has been shown to correlate with a delay in disease progression.43 However, CCR2 is utilized by only a handful of HIV-1 strains for infection, and a complete explanation for its protective effects awaits resolution. Unlike A32CCR5, V64I-CCR2 reaches the cell surface, functions as both a coreceptor and as a signal-transducing chemokine receptor, and does not have any gross effects on cell function or other chemokine receptors that might explain its protective effects (unpublished data). Subtle effects, however, such as its ability to cross-regulate the surface expression of CCR5 and CXCR4, offer a viable explanation that might account for its effects on HIV-1 pathogenesis. Other alternatives, such as linkage to a mutation in the nearby CCR5 gene, or its contribution to the replication of a small percentage of highly pathogenic strains of HIV-1 in vivo, cannot yet be excluded, but appear less likely due to its subtle effects on progression, but not transmission. The V64I-CCR2 polymorphism may be most significant, however, in demonstrating that protective effects from mutations in other genes, and ultimately by alternative clinical interventions, may contribute to the suppression of HIV-1 pathogenesis through mechanisms other than direct coreceptor blockade.

Thus far, all HIV-1 strains identified use CCR5, CXCR4, or both as coreceptors. However, nearly a dozen additional chemokine receptors, orphan receptors, and viral chemokine-receptor homologs have been iden ti-fied as capable of mediating fusion with one or more HIV-1, HIV-2, or simian immunodeficiencyvirus (SIV) Envs in vitro (a current tabulation of corecep-tor usage is being kept in the Los Alamos National Laboratory's annual database of human retroviruses and AIDS). The significance of these alternative coreceptors for viral pathogenesis in vivo is uncertain, but it is possible that use of receptors other than CCR5 or CXCR4 may help explain some of the variable outcomes following HIV-1 infection. For example, it has been suggested that use of CCRS may be associated with neurotropism.44 Thus, as new coreceptors are identified, it will be important to determine if they can support virus infection in relevant target cells in vivo.

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