The parent grant, entitled ' Vaccine Efficacy of Modified HIV Envelopes' (RO1 A147708}, aims at identifying HIV envelope modifications that increase the exposure of conserved neutralization epitopes and at evaluating the immunogenicity of modified HIV envelopes in macaques. One of these modifications consists of partially deleting the V2 loop from the envelope derived from the SF162 virus. We reported that although both the unmodified SF162 and modified, termed AV2, envelope immunogens elicit strong antibody responses in macaques, only the modified immunogen elicits antibodies capable of neutralizing heterologous primary (PR) HIV-] isolates. Here, we propose to use the modified AV2 immunogen to generate and characterize MAbs with neutralizing activities against PR HIV isolates. The generation of such MAbs will be an important addition to the currently limited collection of broadly neutralizing MAbs available, in fact; only three such MAbs have been well-characterized to date. These MAbs were isolated from HIV-infected patients and MAbs with broad neutralizing activity against PR HtV isolates have yet to be generated by immunization with HIV envelope vaccines. The exposure and immunogenicity of conserved neutralization epitopes was not optimal on such vaccines. Based on our immunization studies we believe that such epitopes are effectively presented on the AV2 immunogen. We expect therefore this immunogen to elicit cross-reactive neutralizing MAbs. In contrast, we expect the unmodified SF162 immunogen to elicit neutralizing antibodies primarily against the homologous SF162 virus. We propose to define the epitopes recognized by the MAbs elicited by these two immunogens to better understand how V2 loop-deletion increases the immunogenicity of envelope regions containing conserved neutralization epitopes. This in turn may assist us at identifying new envelope modifications that will further improve the exposure of conserved epitopes. Finally, the MAbs generated during our proposed studies could eventually, once humanized, be used during prophylactic vaccination methodologies.
