Fusion Mediated by the HIV-1 Envelope Protein - Fusion of Biological Membranes and Related Problems - page 471

independence appears to be associated with exposure of the conserved
coreceptor binding domain, acquisition of the ability to use CD4 might
make it possible to sequester this region until just before virus entry, pro-
tecting this site from neutralizing antibodies.
6. IMPLICATIONS FOR THERAPEUTIC INTERVENTION
AND CONCLUDING THOUGHTS
Identification of the HIV coreceptors coupled with detailed structural
information on CD4, gp120, and gp41 has suggested several new anti-viral
approaches. The remarkable resistance of individuals who lack CCR5 to
virus infection without obvious side effects due to loss of CCR5 function
suggests that CCR5 is an attractive antiviral target. Other seven trans-
membrane domain receptors are targets of highly effective and specific
drugs, making it likely that CCR5 antagonists can be developed. Increased
understanding of how gp120 and CCR5 interact should assist in the design
of small molecule inhibitors. Likewise, CXCR4 antagonists would also be
desirable given the prevalence of viruses that use this coreceptor. Indeed,
several CXCR4 inhibitors have already been described (Donzella et al.,
1998; Doranz et al., 1997; Murakami et al., 1997; Schols et al., 1997). Whether
coreceptor blockade will force HIV-1 to evolve to use other coreceptors is
not known, though as noted above receptors other than CCR5 or CXCR4
have not been shown to support infection of primary cells.
In addition to the coreceptors, Env itself can be targeted. The fusion
inhibitory peptide T20 shows that an inhibitor of membrane fusion can be
highly effective in vitro (Kilby et al., 1998). The high resolution structure of
gp41 and enhanced understanding of the mechanism by which T20 works
may suggest regions of gp41 that can be targets for rationale drug design
(Chan and Kim, 1998). The coreceptor binding site as well as the CD4
binding site on gp120 may also be targets for small molecule inhibitors.
Interestingly, advances in understanding Env-mediated membrane fusion
may also have implications for vaccine development. Recently, LaCasse
et al. showed that immunization of mice with “fusion competent” Env elicits
surprisingly potent and broadly cross reactive neutralizing antibodies
(LaCasse et al., 1999). In their study, cells expressing Env were mixed with
cells expressing CD4 and CCR5, and fusion was allowed to occur prior to
formaldehyde fixation. Immunization with these fixed cells, which presum-
ably contain triggered Env proteins in which both the coreceptor binding
site as well as gp41 determinants are exposed, resulted in this impressive
humoral response. This suggests that generation of triggered or partially
triggered Env proteins may elicit antibodies to highly conserved but poorly