Abstract
A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.
Highlights
Elicitation of broadly cross-reactive neutralizing antibody (NAb) responses is a high priority for HIV-1 vaccines [1,2,3,4]
A central problem in HIV-1 vaccine design is that HIV-1 is extremely variable and employs a number of strategies to avoid being recognized by antibodies
We developed computational strategies for identifying correlations between mutational patterns in the HIV-1 envelope glycoproteins and neutralization phenotypes
Summary
Elicitation of broadly cross-reactive neutralizing antibody (NAb) responses is a high priority for HIV-1 vaccines [1,2,3,4]. Many candidate immunogens elicit strong NAb responses against highly neutralization-sensitive strains of HIV-1; these vaccine-elicited antibodies neutralize very few circulating strains [5,6,7] and have not afforded protection in past human efficacy trials [8,9,10]. Based on immunogenicity data from earlier phase I and II clinical trials of this and related vaccines [4,12], improved NAb responses may be one way to achieve greater protection. Such improvements are likely to require novel vaccine designs
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