Chemokine Receptors and HIV-1: An Attractive Pair?

Abstract

The implications of the discovery of the HIV-1 coreceptors are numerous and exciting. First, with these coreceptors in hand, studies on the mechanism of entry of HIV-1 will be greatly facilitated. For entry to occur, the virus must bind to the cell and then undergo a series of conformational changes postulated to be triggered by the receptor. As mentioned above, CD4 can induce some conformational changes in HIV-1 Env, but these are insufficient for entry. Possible roles for the coreceptors in promoting fusion include inducing further changes in Env either by direct interaction or indirectly by association with CD4, binding Env to orient the protein correctly with respect to the membrane to allow fusion, or possibly inducing chemokine signaling (involving Ca2+ influx), which may be required to depolarize or somehow destabilize the membrane so that fusion can occur.The ways in which chemokines interfere with fusion and infection can also be addressed. Do HIV-1 Env and chemokines directly compete for receptor, or is the coreceptor down-regulated in response to chemokine overexpression, making it unavailable for the virus? Is there genetic polymorphism in the CC-CKR receptors that could account for the relative insensitivity of some individuals to HIV-1 infection? If the polymorphic receptors function less efficiently for both HIV-1 entry and chemokine stimulation, one might expect observed viral resistance and increased levels of chemokines. Also, the chemokine receptors and/or chemokine levels might determine the viral burden and thus the rate of disease progression in infected individuals. The discovery of chemokine receptors as cofactors may also lead to development of new therapeutic strategies aimed at blocking the viral access to the receptor using small molecule inhibitors instead of chemokines.The role of the coreceptors in HIV-1 pathogenesis can also be analyzed. Inappropriate signaling, mediated by direct interaction of HIV-1 envelope and the coreceptor, could contribute to pathogenesis of the virus. In addition, a number of chemokine receptor homologs have been identified in DNA viruses, including human cytomegalovirus and Herpes saimiri (a close relative of the Kaposi sarcoma–associated herpes virus). It is interesting to speculate that interaction of HIV-1 with these receptors could be involved in pathogenesis by these viruses that are associated with HIV-1 infection.Finally, identification of factors (CD4 and fusin or CC-CKR5) sufficient for HIV-1 entry may allow development of a small animal model for HIV-1 infection in which viral replication could be studied and therapeutic interventions might be tested.