Futuredirections

In the short period of time since the identification of the HIV-1 core-ceptors, tremendous insight has been gained into HIV-1 tropism, transmission, and pathogenesis. In terms of understanding the mechanisms that underlie viral tropism at the level of entry into the cell, the coreceptors have fulfilled a decade-long search for the host determinants that are responsible for triggering fusion between the viral envelope and cell membrane. In terms of host protection factors, the coreceptors explain some of the epide-miological data and anecdotal evidence that has surfaced over the last decade concerning exposed uninfected individuals. In terms of clinical relevance, the coreceptors have provided molecular insight into transmission, pathogenesis, and disease progression. Finally, in terms of therapeutic intervention, the coreceptors offer an important opportunity to combat a highly variable virus by targeting invariable host proteins that are critically important for virus entry. It is fortuitous that the HIV-1 coreceptors are members of the seven-transmembrane G-protein-coupled receptor family, since this is possibly the single most heavily funded and well studied class of proteins targeted by pharmaceutical companies. The hectic pace of work over the past 2 years has witnessed the identification of the coreceptors, investigation into the nature of their function, the identification of natural ligands that prevent HIV-1 entry, and the identification of small-molecule lead compounds that prevent HIV-1 entry. If the coming years are anything like the past, we should expect the chemokine receptors to become major clinical targets of HIV-1 therapeutics.

Acknowledgments. We thank Bill O'Brien and Allelix Pharmaceuticals for information about the use of ALX40-4C. This work was supported by NIH grants to R.W.D. and a Howard Hughes Medical Institute predoctoral fellowship to B.J.D.

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