21 Advances in Gene Therapy for HIV and Other Viral Infections

Abstract

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...