GP120 VACCINES

The most eagerly awaited new development in the HIV community is the HIV vaccine. Because of the rapid spread of disease worldwide and, in many countries, limited resources to effectively treat the infection, a vaccine to prevent HIV infection is highly desirable.

Ideally, a vaccine would provide the following four important functions: elicit neutralizing antibodies, stimulate a T cell immune response, stimulate mucosal immunity, and stimulate the innate immune system.⁸⁹ In order to effectively achieve all four of these immune functions, a live- attenuated virus vaccine would be necessary. In the macaque model, a live-attenuated SIV vaccine caused persisting infection and even AIDS in some animals.^90,91 Therefore, the live-virus vaccine has been banned in humans. Instead, a safer killed-virus vaccine was developed using gp120 as the target. This took the form of a vaccine-stimulated neutralizing antibody but did not create a cytotoxic CD8⁺ T cell response. This approach was successful at producing neutralizing antibodies to laboratory-adapted strains but was ineffective at producing good antibodies against clinical isolates of viruses. Because the HIV envelope is a trimer of gp120, coated with carbohydrate, large portions of the surface are hidden from antibodies by the sugars and important functional parts of the glycoprotein are folded in and not exposed for antibody production. Although the important parts of gp120 that bind to CD4 and chemokine co-receptors are conserved, they are folded deeply into the gp120 pocket, and the outside areas are the hypervariable portions that frequently mutate and make consistent antibody production difficult.⁹² Many of the important functional portions of the gp120, such as the chemokine receptor binding site, are exposed for only a fraction of a second after the gp120 binds CD4 and changes conformation before binding to the co-receptor. The gp120 envelope is, therefore, an elusive protein to target for neutralizing antibodies.⁸⁹ Several vaccines were designed to a killed-viral version of gp120 and are under study in the United States and Thailand. Great clinical success, however, is not predicted.⁹³ This work has suggested that a vaccine that elicits a cytotoxic CD8⁺ T cell response is instead preferable, using parts of the virus that are processed in the endoplasmic reticulum and are presented by MHC I.