AIDSWEEKLY Plus, Monday, 28 April 1997
Daniel J. DeNoon, Senior Editor
A leading AIDS researcher says that the molecules that permit HIV to enter cells appear to be the keys to HIV disease.
These keys promise to unlock the doors to new drugs and vaccines and perhaps even to the long-sought animal model for AIDS.
"The numbers and identity of the coreceptor molecules on target cells, and the ability of HIV-1 strains to likely enter cells via the different coreceptors, seem to be the critical determinants of disease progression," wrote John P. Moore of the Aaron Diamond AIDS Research Center, New York.
Moore's article appeared in the journal Science ("Coreceptors: Implications for HIV Pathogenesis and Therapy," Science, 1997;246:51-2).
The impetus for his comments is the rapid series of developments stemming from the 1995 announcement by Robert C. Gallo and coworkers that the naturally occurring (beta)- chemokines RANTES, MIP-1(alpha), and MIP-1(beta) have anti-HIV activity (Cocchi et al., Science, 1995;270:1811-5) and the subsequent identification of the natural ligands for these cell-produced substances.
More recently, work in several laboratories has shown that cell entry by non-syncytia-forming (NSI), macrophage-tropic (M-tropic) HIV-1 strains requires the (beta)-chemokine CCR5 receptor while cell entry by syncytia-forming (SI), T-cell- tropic strains usually requires the (alpha)-chemokine CXCR4 receptor.
An estimated 90 percent of sexual HIV transmission is mediated by M-tropic strains. And the few people homozygous for a disabling deletion in their CCR5 genes cannot be infected with these viral strains.
Unsurprisingly, the race is underway to discover drugs capable of blocking the CCR5 receptor (see accompanying article). But Moore waved a yellow caution flag at the racers.
"The extensive plasticity of the HIV-1 binding sites on the coreceptors, combined with the virus's notorious mutability, might facilitate escape from coreceptor antagonists," he warned. "It is even feasible that blockade of CCR5 during established infection might drive HIV-1 evolution toward the use of CXCR4 (or other coreceptors) and, hence, the development of the more virulent T-tropic phenotype."
Moore pointed out that there is much more to coreceptors than is currently understood. For example, multiple factors affect CCR5 expression.
"For reasons that are not yet clear, the amount of CCR5 expression on the cell surface ... varies by 20-fold on CD4(+) T cells from individuals with two wild-type CCR5 alleles," he wrote. "The causes of this variation should be the subject of intensive studies, as they point to controllable factors that could increase resistance to disease."
One cause of CCR5 variation is the activation state of CD4(+) T cells. Because of this variation, Moore warned, HIV antibody studies using neutralization assays that measure virus entry into resting cells yield "badly skewed" results.
Moore suggested that the new information about CCR5 could lead to the creation of CD4(+) CCR5(+) transgenic animals for testing of HIV vaccines. But because non-human cells do not permit efficient HIV replication, these models would likely require unrealistic doses of infectious virus during challenge experiments.
But since CCR5 is also a coreceptor for simian immunodeficiency virus (SIV), studies with SIV could be made more relevant to HIV infection.
"It will be important to completely characterize the coreceptor usage of all the available SIV stocks, for it would be desirable to use as an HIV-1 vaccine model an SIV strain that enters cells via CCR5," Moore wrote.
Most SIV stocks more closely resemble T-tropic than M- tropic HIV strains, but Moore suggested that this could be due to the fact that SIV is commonly passaged in human cells and selected for virulence.
Beyond creation of more relevant animal models, CCR5 research holds forth the promise of a new approach to an HIV vaccine. This is because the requirement for CCR5 suggests that all HIV-1 genetic subtypes must enter cells in the same way. If so, then there must be a binding site that is much the same for all of these subtypes.
Moore suggested that this putative site is most likely shielded from antibody recognition by the variable loops in the HIV gp120 envelope glycoprotein. During cell fusion, it peeks out only briefly to mediate infection.
"A cross-reactive, antibody-based vaccine is possible - if only we could learn how to induce such antibodies," Moore wrote. "The CCR5 molecule itself is poorly immunogenic and so may not be a good candidate to use as a vaccine."
The corresponding author for this study is John P. Moore, Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016. Email: John_Moore@adarc.org.
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