Human HIV Neutralizing Antibodies Identified

Emma Hitt, PhD

July 08, 2010

July 8, 2010 — Two antibodies, VRC01 and VRC02, identified in HIV-infected blood, attach to the CD4 binding site of HIV and appear to prevent the virus from attaching to and infecting T cells, according to new research.

Peter D. Kwong, PhD, with the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and colleagues reported the findings online today in Science.

"The discovery of these exceptionally broadly neutralizing antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use," said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, in a news release.

By determining the atomic structure of VRC01 when attached to HIV, the researchers were able to define how the antibody works and to locate the point of attachment to the virus. This knowledge may facilitate the design of a candidate vaccine that could stimulate the production of antibodies similar to VRC01 that might prevent HIV infection.

Constant Binding Site Makes for Global Vaccine Potential

One challenge in the "holy grail" of developing a vaccine against HIV has been that the virus continuously changes its surface proteins to evade recognition by the immune system. However, the point of attachment for VRC01 and VRC02 remains constant regardless of changes to the rest of the virus.

"What is different here is that we are attempting to replicate a natural human response," Dr. Kwong told Medscape Medical News. "Our findings show that the human immune system is capable of generating antibodies that are individually capable of neutralizing most strains of HIV-1. Moreover, these antibodies are not 'freaks of nature,' but ones that appear capable of being made by most humans," he added.

The researchers' analysis also found that VRC01 and VRC02 neutralized more HIV strains with greater overall strength than previously known antibodies to the virus. Together, the antibodies could stop more than 90 of the known global HIV strains from infecting human cells in the laboratory, the researchers estimate.

According to Dr. Kwong, one other group, the International AIDS Vaccine Initiative, has found near-pan-reactive antibodies that are also present in humans. "These antibodies (PG9/PG16), however, have an unusual feature — a very long CDR H3 region — and it is not clear how a response to such a region may be elicited," he said.

The researchers also found that VRC01 did not bind to human cells — a characteristic that might lead to its elimination from the body and lack of efficacy.

"We do not yet have a vaccine," Dr. Kwong emphasized. "Rather, we have made a significant advance in understanding how the human immune system can generate a response capable of neutralizing most strains of HIV-1."

According to Dr. Kwong, the primary barrier to eliciting more antibodies is a process called affinity maturation. "This is a process that is relatively well understood, so we are reasonably confident that we will be able to overcome this barrier, although this remains to be done."

New Findings Could Result in Both Preventive and Therapeutic Approaches

"This is potentially a significant step forward," noted Lindsey Robert Baden, MD, assistant professor of medicine at Brigham and Women's Hospital, in Boston, Massachusetts, when asked for comment. "If these findings are confirmed, then one can look at developing vaccines that can elicit this kind of response," he told Medscape Medical News.

According to Dr. Baden, the findings are not quite ready for prime time as a clinical strategy, but one could imagine that this could be an approach for vaccine development as a preventive strategy as well as a potential strategy for development of a monoclonal antibody for treatment of patients already infected with HIV.

Dr. Baden told Medscape Medical News that immunoglobulin G therapies requiring perhaps once-monthly infusion could be developed to replace antiretroviral therapies that have to be taken daily, although at this point this approach remains speculative.

Science. Published online July 8, 2010.