HIV Defense: Scientific Detail

This project is aimed at preventing viral infection at the source, formulating trial vaccines to engage the body’s mucosal surfaces, the primary points of entry for the HIV contagion.

The process of HIV-1 viral replication is now fairly well understood. A central challenge facing researchers working on vaccines against retroviruses like HIV is how to derail the pathogen’s earliest invasive efforts. The HIV virus manages to integrate its genome into that of its host, initiating a chronic infection within days of primary exposure. This leaves only a narrow window of time to eliminate the virus completely. Further sabotaging efforts to combat HIV is the rapid, compulsive mutation of the virus which allows it to outpace the immune system’s efforts to generate an effective response.

In addition to mutation, HIV employs other tricks to evade immune detection, such as shielding critical protein components, camouflaging these in a thicket of surface glycans, while making use of sophisticated protein decoys to fool the body. Armed with this profile of the virus, Biodesign researchers are approaching the challenges of arresting the progression of HIV on the basis of four fundamental assumptions:

• The most effective place to interrupt HIV along the chain of transmission is at the beginning—the mucosal barrier, where initial interaction of virus particles and host cells/host cell defenses occurs.
• The study of rare cases of host immunity to HIV in highly exposed, persistently seronegative (HEPS) individuals provides an illuminating body of data for the study of effective immune response.
• Preexisting, neutralizing antibodies may provide complete, sterilizing immunity to HIV-1 infection.
• Novel, plant-based technologies offer impressive potential for a variety of anti-retroviral applications, including oral delivery of vaccine antigens.

The research team is applying protein engineering efforts to the design of vaccine candidates consisting of a mucosal targeting component fused to a peptide corresponding to a section of gp41—an HIV-1 envelope protein. The specific region of gp41 is not only the target of two broad-spectrum neutralizing monoclonal antibodies, 2F5 and 4E10, but was also shown to be critical for the mucosal transmission of the virus.
In pre-clinical trial experiments, systemic and mucosal antibodies raised against this novel immunogen were shown to inhibit the crossing of a tight epithelial cell layer by an HIV-1 primary isolate, and also displayed some ability to neutralize infection of CD4+ (helper-T) cells, a leading component in effective immunodefense. The immunogen, as well as “next generation” vaccine candidates, are expressed in a variety of systems including bacteria, insect cells and plants.

The majority of those infected with HIV reside in poor countries and cannot afford existing antiretroviral drugs. This research offers hope for an effective, stable, and low-cost means of preventing HIV exposure from developing into a lethal AIDS infection.