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21 Advances in Gene Therapy for HIV and Other Viral Infections

Eric M. Poeschla, Flossie Wong-Staal


Gene therapies and other treatment approaches to human immunodeficiency virus (HIV) disease are rapidly evolving in the context of several recent developments. Although the mechanisms that perturb T-cell homeostasis in HIV disease remain enigmatic, much has been gained from quantitative modelling of the dynamics of HIV replication in vivo (Embretson et al. 1993; Pantaleo et al. 1993; Piatak et al. 1993; Coffin 1995; Ho et al. 1995; Wei et al. 1995; Haase et al. 1996; Perelson et al. 1996, 1997; Cavert et al. 1997). These insights were enabled in part by a second discovery: HIV replication can be potently and durably suppressed in vivo in many patients by combining previously marginally effective reverse transcriptase inhibitors with HIV type 1 (HIV-1) protease inhibitors, which are peptidomimetic transition state analogs that were designed from knowledge of the crystal structure of this enzyme (Gulick et al. 1997; Hammer et al. 1997). In addition, the long-sought coreceptors to CD4 have been identified, a discovery that has yielded a coherent molecular explanation for how HIV infects varied cell types in vivo and imparted conceptual clarity to what was previously a murky phenomenology of viral phenotypes. This burst of discoveries about chemokines and chemokine receptors has also revealed the first convincing evidence for a link between a human genetic mutation and resistance to HIV infection. All of these findings have important implications for the potential of gene therapy for HIV disease.

HIV is a lentiretrovirus with specialized ability to infect nondividing and postmitotic cells permanently. It...

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