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Clues For HIV Vaccine Design

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Two simple changes in its outer envelope protein could render the AIDS virus vulnerable to attack by the immune system, according to research from Kenya and the Fred Hutchinson Cancer Research Center.

The results could provide important clues for designing an effective AIDS vaccine, which is badly needed to decrease the number of new HIV infections, now estimated at about 2.5 million per year worldwide.

Although most people infected with HIV produce antibodies against the virus within several weeks following infection, these antibodies rarely prevent the infection from progressing to symptomatic AIDS.

While studying a group of women at risk of HIV in Mombasa, Julie Overbaugh and colleagues noticed that one woman carried an AIDS virus that was easily inactivated by antibodies. They initially described this case in 2007 in the Journal AIDS.

Analyzing this woman’s virus, they found that it contains mutations in four amino acids in the envelope protein, two of which, when introduced into unrelated strains of HIV in the laboratory, conferred sensitivity to inactivation by a number of antibodies produced in people infected with HIV.

The researchers propose that these mutations cause a change in the overall structure of the envelope protein that results in exposure to the immune system of regions that are normally hidden. If further research confirms this idea, vaccines containing envelope proteins that include these mutations might be able to stimulate an antibody response that would protect against infection with HIV.

PLoS Med 5(1): e9 doi:10.1371/journal.pmed.0050009

Blish CA, Nguyen MA, Overbaugh J (2008)

Enhancing Exposure of HIV-1 Neutralization Epitopes through Mutations in gp41.

BackgroundThe generation of broadly neutralizing antibodies is a priority in the design of vaccines against HIV-1. Unfortunately, most antibodies to HIV-1 are narrow in their specificity, and a basic understanding of how to develop antibodies with broad neutralizing activity is needed. Designing methods to target antibodies to conserved HIV-1 epitopes may allow for the generation of broadly neutralizing antibodies and aid the global fight against AIDS by providing new approaches to block HIV-1 infection. Using a naturally occurring HIV-1 Envelope (Env) variant as a template, we sought to identify features of Env that would enhance exposure of conserved HIV-1 epitopes.

Methods and Findings

Within a cohort study of high-risk women in Mombasa, Kenya, we previously identified a subtype A HIV-1 Env variant in one participant that was unusually sensitive to neutralization. Using site-directed mutagenesis, the unusual neutralization sensitivity of this variant was mapped to two amino acid mutations within conserved sites in the transmembrane subunit (gp41) of the HIV-1 Env protein. These two mutations, when introduced into a neutralization-resistant variant from the same participant, resulted in 3- to >360-fold enhanced neutralization by monoclonal antibodies specific for conserved regions of both gp41 and the Env surface subunit, gp120, >780-fold enhanced neutralization by soluble CD4, and >35-fold enhanced neutralization by the antibodies found within a pool of plasmas from unrelated individuals. Enhanced neutralization sensitivity was not explained by differences in Env infectivity, Env concentration, Env shedding, or apparent differences in fusion kinetics. Furthermore, introduction of these mutations into unrelated viral Env sequences, including those from both another subtype A variant and a subtype B variant, resulted in enhanced neutralization susceptibility to gp41- and gp120-specific antibodies, and to plasma antibodies. This enhanced neutralization sensitivity exceeded 1,000-fold in several cases.

Conclusions

Two amino acid mutations within gp41 were identified that expose multiple discontinuous neutralization epitopes on diverse HIV-1 Env proteins. These exposed epitopes were shielded on the unmodified viral Env proteins, and several of the exposed epitopes encompass desired target regions for protective antibodies. Env proteins containing these modifications could act as a scaffold for presentation of such conserved domains, and may aid in developing methods to target antibodies to such regions.

Written by huehueteotl

January 7, 2008 at 3:44 pm

Posted in HIV

Tagged with ,

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