PubMed · 10581045
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1999. Replacing competition with cooperation.. https://doi.org/10.1038/70876
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Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be one component of an effective HIV-1 vaccine elicited response. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naïve B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-like antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses.
Development of a safe and effective vaccine for HIV is a major global priority. However, to date, efforts to design an HIV vaccine with methods used for development of other successful viral vaccines have not succeeded due to HIV diversity, HIV integration into the host genome, and ability of HIV to consistently evade anti-viral immune responses. Recent success in isolation of potent broadly neutralizing antibodies (bnAbs), in discovery of mechanisms of bnAb induction, and in discovery of atypical mechanisms of CD8T cell killing of HIV-infected cells, have opened new avenues for strategies for HIV vaccine design.
We have previously shown the induction of humoral and cytotoxic responses specific for human immunodeficiency virus (HIV) and hepatitis B virus (HBV) antigens, following genetic immunization of rhesus macaques with a plasmid encoding both the third variable domain of the HIV-1 external envelope glycoprotein and the pseudo-viral particle of hepatitis B surface antigen (HBsAg) as presenting molecules. The DNA-immunized primates and two control animals were then challenged with a chimeric simian/human immunodeficiency virus (SHIV). They were all infected. Significant frequencies of SHIV specific cytotoxic T lymphocyte precursors (CTLp) were detected early in peripheral blood. But, in all DNA-immunized macaques, HBV envelope specific CTLp were detected during the primary infection, and they were correlated with the peak of SHIV viremia. Furthermore, HBV or SHIV specific cytotoxicity corresponded in part to CD8(+) T cells presenting a memory phenotype. Several mechanisms could account for this cellular response. But our results suggest that an expansion of memory cytotoxic CD8(+) cells, not restricted to SHIV specific effectors, could occur in peripheral blood during SHIV primary infection.