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Evolution of the HIV-1 Envelope Glycoprotein Genes and Neutralizing Antibody Response in an Individual with Broadly Cross Neutralizing Antibodies

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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The induction of broadly cross neutralizing BCN antibodies is likely to be a critical component of an effective immune response to an HIV-1 vaccine. Thus far, induction of such a response remains elusive. However, the identification of HIV-1 infected individuals who develop a BCN antibody response provides hope that an HIV-1vaccine is possible. The characterizations of HIV -1 envelope genes from such individuals are of interest as they may contain epitopes responsible for the generation of the observed BCN response. For this project, we hypothesized that the study of HIV-1 envelope glycoprotein gene variation and evolution of the neutralizing antibody response from a patient HNS2 donor whose plasma contains BCN antibodies will reveal evidence of the mechanisms of induction and maintenance of a BCN response. DNA extracted from primary or co-cultured PBMC representing 21 years of sample availability from the patient was used as the source for envelope gene cloning throughout this study. Results indicated that the patient was infected early in his course with at least two strains of HIV-1 , one of which differentiated into distinct neutralization sensitive L1a and neutralization resistant L1b lineages. L1a and variants derived from a second lineage L2 remained neutralization sensitive for several years. Analysis of positive selection rates among the lineages did not indicate positive selection for L1a and L2, consistent with possible low levels of replication of these strains. The eventual displacement of neutralization sensitive Lla and L2 variants with neutralization resistant variants was accompanied by the loss of BCN antibodies and loss of circulating CD4 T cells. Findings in this patient that might be related to the BCN response include infection with more than one strain of HIV-1 and the apparent persistence of low levels of neutralization sensitive variants presenting cross-reactive neutralization epitopes.

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