NCI investigators find CD4 t-cell protectors
NCI investigators find CD4 t-cell protectors
Researcher describes the findings
(Recently released research has shown that a novel human antibody is effective in preventing some strains of HIV from entering CD4 t-cells. The researchers, led by Dimiter S. Dimitrov, PhD, SCD, senior investigator with the National Cancer Institute in Frederick, MD, named the newly identified antibody X5 and found that it reacts strongly against a highly conserved region of the viral glycoprotein gp120.1 The findings were published in the Proceedings of the National Academy of Sciences in the May 14, 2002, issue. In this interview, Dimitrov discussed the discovery.)
AIDS Alert: How did your team’s discovery of X5 come about?
Dimitrov: In 1996, immediately after Eduard Berger described in his Science article2 the discovery of the HIV fusion co-factors, I hypothesized in a Nature Medicine article that the role of the fusion co-factors is to form complexes with the HIV envelope glycoprotein (ENV) and CD4, i.e., to serve as co-receptors. And I thought that interactions of receptors (CD4 and co-receptors) with the ENV can induce exposure of conserved ENV structure, which otherwise could be partially hidden as part of the HIV strategy to avoid immune responses.
Several years ago my group was able to produce relatively large amounts of complexes between gp120, CD4, and CCR5, and I contacted Dennis Burton, who was interested to screen these complexes against a human phage display library. Maxim Moullard from Burton’s laboratory selected X5 by using our antigen two years ago. Then, in my lab and in Burton’s lab, we characterized extensively the properties of this antibody Fab and found its potent and broad neutralizing activity against a total of about 30 primary isolates.
AIDS Alert: How does the X5 interrupt HIV progression?
Dimitrov: By inhibition of HIV entry into cells.
AIDS Alert: What type of research needs to be done before it is possible to develop a treatment using X5 or a similar mechanism?
Dimitrov: Tests in animal models, e.g. in monkeys.
AIDS Alert: How would any such future treatment differ from the therapies currently being used to treat HIV patients?
Dimitrov: X5 is an entry inhibitor, while the most widely used inhibitors affect other stages of the HIV life cycle — reverse transcriptase and maturation; recently there are several entry inhibitors, including other human monoclonal antibodies, which are at different stages of clinical testing but not yet for general use.
AIDS Alert: Is there a potential use of this knowledge in creating a vaccine?
Dimitrov: Yes, if we find an antigen able to elicit X5-like antibodies in humans, and we are currently performing such experiments.
References
1. Moulard M; Phogat SK; Shu Y, et al. Broadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes. Proceedings of the National Academy of Sciences 2002; 99(10):6,913-6,918.
2. Feng Y; Broder CC; Kennedy PE; Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 1996; 272 (5263):872-877.
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