HUMAN IMMUNODEFICIENCY VIRUS TYPE I AS A TARGET FOR GENE THERAPY

Magnús Gottfredsson and Paul R. Bohjanen

Division of Infectious Diseases and International Health, Department of Medicine, Duke University Medical Center, Durham, NC 27710

Received 11/17/97 Accepted 11/24/97

6. PERSPECTIVE

Research on the pathogenesis of HIV-1 infection and the HIV-1 life cycle has lead to the identification of numerous potential viral targets for gene therapy. As summarized here, gene therapy approaches directed at several of these viral targets have been successful in inhibiting HIV-1 replication in cultured human cells, although clinical trials to study the safety and efficacy of gene therapy for HIV-1 infection are only beginning. Although this review has focused on viral targets, gene therapy directed at cellular targets also has potential. For example, people who have homozygous deletions in the HIV-1 coreceptor CCR-5 gene display resistance to HIV-1 infection (191). These people have normal immune systems and no obvious abnormal phenotype, suggesting that the CCR-5 gene is non-essential. Therefore gene therapy approaches designed to knock out expression of CCR-5 expression in CD4+ cells from HIV-1 infected individuals could potentially be useful in treating HIV-1 infection. Gene therapy approaches designed to enhance the immune response to HIV-1 infection also have potential (192, 193).

Because of recent advances in our understanding of the pathogenesis and treatment of HIV-1 infection, this is an exciting time to care for patients infected with HIV-1. Although there is no cure for AIDS, we now have drugs that are effective against HIV-1, and we can offer patients hope. Combinations of new drugs have been shown to reduce the occurrence of clinical events (development of opportunistic infections and death) in patients infected with HIV-1 (194). Despite these advances, there is clearly a need to develop better therapies. Although triple drug regimens consisting of reverse transcriptase inhibitors and protease inhibitors suppress plasma virus levels to low or undetectable levels in a large percentage of patients, not all patients respond to the same extent (3), and in those patients that respond, the duration of the response is not known. Vigorous research efforts should continue on the development of more effective drugs against HIV-1 as well as on the development of gene therapy approaches. In addition to potentially providing new therapies for HIV-1 infection, continued research on gene therapy for HIV-1 will likely provide new insights into the pathogenesis of HIV-1 infection. Advances in our understanding of gene therapy for HIV-1 infection may be helpful in developing gene therapy approaches to other human diseases.