Conclusion

Rethinking the Immune Response to HIV gp160/gp120

Contrary to conventional assumptions, the appropriate immune response to the HIV membrane proteins gp160 and gp120 may be one of immunological tolerance rather than stimulation. Cloning this protein into a suitable plant and administering it orally to high-risk individuals could help induce tolerance. Oral tolerance to gp160/gp120 could significantly reduce many of the immune system disturbances commonly seen in HIV infections.

These disturbances fall into two primary categories:

1. Autoimmune Crossreactivity – as previously discussed.
2. Immune Complex-Mediated Damage – Anti-gp160/gp120 antibody immune complexes bind complement receptors on macrophages and dendritic cells. These complexes inappropriately crosslink CD4 molecules on healthy T and B cells, triggering apoptosis, particularly within lymph nodes.

Humoral Immune Responses and CD4 T Cell Depletion

The humoral immune response to the gp160/gp120 membrane proteins is believed to play a central role in the development of AIDS. This response remains problematic regardless of whether the virus is infectious. Although HIV proteins such as TAT, NEF, and VPR contribute to immunosuppression, the antibody-mediated response to gp160/gp120 may be the most rapid and damaging to CD4 T cell populations.

For example, in mice transgenic for the human CD4 molecule, immunization with purified gp120 led to a seven-fold reduction in CD4 T cells and a three-fold reduction in B cells within six days. These mice had no prior exposure to HIV. The CD4 depletion was directly mediated by anti-gp120 antibodies (Kang, Y., et al. Eur. J. Immunol. 28:2253, 1998).

This finding suggests that HIV vaccines targeting gp160 or gp120 could fail to prevent infection and may accelerate the depletion of normal CD4 T cells.

Evidence from Vaccine Trials and Rapid Disease Progression

A 1996 study published in Proceedings of the National Academy of Sciences detailed the case of a vaccine trial participant who received an experimental HIV vaccine regimen (McElrath, M. Juliana, et al. PNAS 93:3972, 1996). The subject underwent immunization over four years with a combination of live recombinant vaccinia virus expressing gp160 and recombinant gp160 protein.

Despite producing both neutralizing antibodies and strong T-cell responses in vitro, the subject became infected with HIV following unprotected sex ten weeks after the final booster. Within two years of infection, the CD4 T cell count declined to 250—indicative of extremely rapid disease progression.

This rapid decline may be attributed to the immune system’s prior sensitization to the gp160 protein through vaccination. The presence of a so-called “neutralizing” immune response to gp160/gp120 is considered contradictory, as such responses do not confer lasting protection and may, in fact, worsen disease outcomes.

Limitations of In Vitro Neutralization and Chimpanzee Studies

In vitro studies that claim to measure viral neutralization are not reliable indicators of vaccine efficacy. Inducing a vaccine-mediated humoral immune response to gp160/gp120 has been associated with harmful outcomes, including accelerated immune decline.

Additionally, studies in chimpanzees that appear to support the effectiveness of gp160/gp120 vaccines often suffer from design flaws. The viral challenge stocks used in these studies are typically cultured in human cell lines. The chimpanzees’ immune responses may be directed not at the viral envelope proteins but at the human histocompatibility antigens on the membranes of the viral particles.

Further Reading

For a detailed examination of the challenges facing current HIV vaccine strategies, refer to the essay titled Why Current HIV Vaccines Will Fail.