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

2. INTRODUCTION

Since the first cases of acquired immunodeficiency syndrome (AIDS) were reported in 1981, over 20 million people world-wide have become infected with human immunodeficiency virus type 1 (HIV-1), the etiologic agent for AIDS (1). Because of the large world-wide impact of AIDS and because of the speed with which the AIDS pandemic has spread, there has been an intense global effort into understanding the biology of HIV-1 and the host response to HIV-1 infection. This effort has resulted in rapid progress toward understanding HIV-1 pathogenesis, including an improved understanding of viral dynamics and the viral life cycle. These advances have lead to the development of several new drugs that are effective against HIV-1. Because of the rapid mutation rate of HIV-1, viral resistance to these new drugs is a major problem. Therefore combinations of drugs have been used to treat patients with HIV-1 infection with the goal of completely suppressing viral replication so that drug resistance mutations cannot occur. Although new drug combinations can suppress plasma RNA concentrations to low or undetectable levels in a large proportion of patients (2, 3), not all patients respond well to therapy and drug resistance is still a problem. In patients that do respond, the duration of the response is unknown, and the side effects related to long term use of antiretroviral combinations is also unknown. In addition, these new combination drug therapies are very expensive, thus limiting their use in less developed countries. Because of these problems, there is a need for continued research on the pathogenesis and treatment of HIV-1 infection.

In addition to developing new drugs that are effective against HIV-1, considerable research effort has been directed toward blocking HIV-1 using gene therapy approaches. Advances in our understanding of the viral life cycle has lead to the identification of numerous potential viral targets for gene therapy. Gene therapy approaches directed at several of these viral targets have been successful at inhibiting HIV-1 replication in cultured human cells. These promising results in cell culture experiments have lead to optimism about the future prospect of using gene therapy to treat HIV-1 infection. Several obstacles need to be overcome, however, including development of appropriate gene delivery systems and evaluating the safety of gene therapy approaches in humans. Clinical trials involving gene therapy directed at HIV-1 have begun but are still in their infancy. This manuscript begins with a brief review of the viral life cycle with an emphasis on the function of viral gene products and then summarizes the gene therapy approaches that have targeted these viral genes or gene products to inhibit HIV-1 replication.