8th Annual Retrovirus Conference
Report 2 from Jules Levin
Bernard Fields Memorial Lecture
Avoidance of Antibody Recognition by SIV- and HIV-Encoded Envelope Proteins
Harvard Med. School, New England Regional Primate Research Center, Southborough, MA
Desrosiers talked about his finding of a potential candidate for a vaccine for HIV. He talked about this at the DART Conference in Puerto Rico in December 2000 and Doug Richman talked about this on my radio show in December 2000 after DART. The human immune system response to invading pathogens is to eliicit a neutralizing antibody response. This has been lacking in HIV.
Desrosiers has been able to construct a virus in the test test, by eliminating certain sequences in the genetic make-up of the virus, which elicits neutralizing antibodies. Animal studies asre planned and of course if successful it will lead to human studies. On my radio show Richman talked about how if this idea can be developed its possible that this vaccine in combination with the Merck vaccine, which is in early human trials now, could provide a therapeutic vaccine for people with chronic HIV. Such an approach may work to stimulate the imune system to allow person on HAART to take a therapy interruption.
The vaccine approach would elicit an immune response which hopefully could control HIV without HAART. This was the goal of STIs but it has so far been unsuccessful in people with chronic HIV. Please bear in mind that the Desroseirs vaccine idea is just an idea and may not be successful. As well, the Merck vaccinis only in early human trials and still faces many challenges. So, although I think we should get hope from these developments it is premature to have too high expectations. As you know many ideas in HIV research don't succeed. And so far the we have not been able to elicit the requisite immune response by conducting an STI in people with chronic HIV infection.
It is now clear that HIV has evolved a variety of specific strategies for immune evasion that allow persistent, unrelenting viral replication. These strategies include:
i) emergence of genetic variants that are immune escape variants;
ii) destruction of CD4+ T-cell helper activity;
iii) accessibility of envelope proteins on virions to antibodies;
iv) nef-induced downregulation of MHC class I molecules;
v) latency and reactivation.
My laboratory has become interested over the last few years in how HIV envelope has configured itself to avoid antibody-mediated neutralization. We have studied four types of envelope modifications, using SIV or SHIV, for their effects on antibody mediated neutralization, ability to elicit antibodies capable of neutralizing viral infectivity, dependence on CD4 for viral infectivity, and ability to be controlled by the host immune response. We have been studying the effects of:
i) N-linked carbohydrate attachment mutations in the V1-V2 region of gp120;
ii) deletion of the entire V1-V2 region of gp120;
iii) N-linked carbohydrate attachment mutations in the ectodomain of gp41;
iv) point mutations in gp120 that confer high replicative capacity to tissue macrophages.
Our results indicate that a variety of mutational changes can impart neutralization sensitivity and that these changes result in more effective immunological control. These results are important at a fundamental level for better understanding of how immune evasion strategies contribute to pathogenesis. They may also be important at a practical level for improving envelope-based vaccine approaches.