Therapeutic approaches to HIV infection based on virus structure and the host pathogen interaction.

The HIV-1 infection of central nervous system, with attendant neuropathy and dementia, poses a unique challenge for antiviral therapy. For practical considerations, it is important to define carefully the precise therapeutic objectives. (1) Is it necessary to inhibit spreading HIV-1 infection in the central nervous system? (2) What is the role of inflammatory responses in central nervous system disease during HIV-1 infection? (3) Is there a correlation between pathology and dementia? (4) Are virions or virus gene products toxic in the central nervous system? (5) Is there a role for immune suppression and opportunistic pathogens in AIDS dementia? The development of therapeutic agents for HIV-1 infection is guided by our knowledge of virus structure, the function of viral proteins, the interactions with host components, and detailed features of the virus life cycle. In each case, unique features of the virus can be identified and established as targets for unique antiviral compounds. Drugs acting as inhibitors of virus enzymatic functions are plagued by the rapid development in vivo of drug-resistant virus variants, although combination or alternating chemotherapeutic regimens may obviate some of these concerns. Novel approaches to inhibiting virus are flourishing. In vitro studies show the value of agents as diverse as molecular decoys for tat activity to efforts to mutagenize integrated proviruses by modified oligonucleotides that form triple helices with chromosomal genes. As each particular clinical situation is better defined, the design and application of these agents can be refined to inhibit HIV-1 replication and reduce the associated morbidity.