ABSTRACT
The AIDS epidemic continues to spread through the human population, now opening new fronts in Asia. The development of a safe and efficacious vaccine for either prophylaxis or treatment is the best hope for the control of this epidemic. Several vaccine strategies are under investigation, including recombinant poxviruses encoding viral proteins or epitopes, DNA vaccines, whole attenuated or inactivated viruses, and combinations of the above (see elsewhere in this book). However, developing an effective vaccine against HIV-1 has proven to be difficult, even with the benefit of the expertise derived from successful vaccines against viruses such as smallpox and polio. Although acute HIV-1 infection is
frequently associated with a vigorous immune response, which includes neutralizing antibodies and helper and cytotoxic T cells (1,2), this response invariably fails to eradicate the virus. Most of those infected will progress to AIDS and ultimately death. Similarly, most vaccines would elicit a transient immune response that fails to completely prevent infection or persistently suppress viral replication. The most effective vaccine tested in the rhesus macaque model is a live, attenuated SIV deleted in several nonessential genes including nef (3). However, the safety concerns for such a vaccine for people are formidable, and in fact there is evidence that such attenuated viruses have been able to induce AIDS in some experimental animals (4). Our rationale, therefore, is to further attenuate the virus such that it is conditionally infectious (i.e., upon pseudotyping with a heterologous viral envelope protein) for only one round. This is achieved by removing the envelope and accessory genes from an infectious HIV provirus and generating viral particles by pseudotyping with a heterologous viral envelope protein, e.g., the glycoprotein from vesicular stomatitis virus (VSV-G). By this means, we are essentially delivering HIV proteins (Gag, Env, Tat, and Rev) in an HIV-based gene delivery vector. The use of lentiviral vectors to express viral antigens as vaccines can be extended to other infectious agents as well.
