CHEMOKINE RECEPTORS AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Paul D. Bieniasz and Bryan R. Cullen

Department of Genetics and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710

Received 12/15/97 Accepted 12/19/97

7. CORECEPTOR - GP120 INTERACTIONS: WHAT HAPPENS NEXT?

It is known that gp120 CD4 interaction induces conformational changes in envelope that expose previously concealed epitopes (99). These changes are not sufficient to induce membrane fusion, rather they are likely to facilitate coreceptor binding, Presumably coreceptor binding results in additional conformational modification, ultimately resulting in exposure of the gp41 N-terminal fusion peptide, although this remains to be proven. Are these events accompanied by conformational changes in the coreceptor, (potentially resulting in signal transduction) or does the coreceptor simply serve as a relatively rigid binding site with the bulk of the conformational change occurring on the viral side of the membrane fusion reaction?

The physiological function of 7TM receptors is to transduce signals via coupling to G-proteins. In several cases where post signalling events have been studied (using predominantly the beta 2 adrenergic receptor as a prototype) signalling is rapidly followed by receptor phosphorylation (mediated by specific G-protein coupled receptor kinases). Phosphorylation results in desensitization of the receptor and recognition by arrestins which are necessary for the subsequent internalisation and recycling of the phosphorylated receptor (100). We and others have investigated whether any of these processes are coupled to the function of CCR-5 as an HIV-1 coreceptor (101-103). Studies using mutant receptors which fail to couple to G-proteins and transduce chemokine signals reveal that signalling is fully dissociable from the role of CCR-5 as a coreceptor. Similar findings have been reported for CXCR-4 (65). In addition, over-expression of arrestin (which enhances chemokine induced internalization) or dominant negative arrestin mutants (which block chemokine induced internalization) had no effect on the ability of CCR-5 to function as an HIV coreceptor (103). Nevertheless, it remains possible that gp120 CCR5 interaction might result in signalling, even though this is not a necessary event for HIV-1 entry to occur.

Clearly much remains to be learned about the nature of viral envelope-coreceptor interactions. The functional sequences of the first wave of coreceptors are only partially characterized and no data have yet been published relating to those of the newly identified coreceptors. On the other side of the equation the identity of, and to what extent, non-V3 sequences influence recognition of the expanding array of coreceptors is yet to be determined. It is also unclear to what extent coreceptors other that CCR-5 and CXCR-4 are truly utilized in vivo, For example do viruses present in CCR-5 delta32 homozygotes utilize exclusively CXCR-4, or other coreceptors such as BOB/GPR15 and Bonzo/STRL33? Is the frequency of viruses using alternative receptors more frequent in individuals who express low levels of CCR-5? Virtually nothing is known about how the expression of coreceptor genes is regulated, and whether or not this might be a potential target for therapeutic intervention. Given the many unanswered questions, there can be no doubt the already substantial number of publications on the subject of primate lentivirus coreceptors will continue to grow for the forseable future.