Effects of gp120 Inner Domain (ID2) Immunogen Doses on Elicitation of Anti-HIV-1 Functional Fc-Effector Response to C1/C2 (Cluster A) Epitopes in Mice

Sherburn, Rebekah; Tolbert, W.D.; Gottumukkala, Suneetha; Beaudoin-Bussières, Guillaume; Finzi, Andrés; Pazgier, M.

doi:10.3390/microorganisms8101490

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“…We recently developed an immunogen referred to as inner domain 2 (ID2), which stably expresses the conformational Cluster A epitope target within a minimal structural unit of gp120 [ 26 ]. Immunization studies in BALB/c mice with ID2 demonstrated that ID2 was highly immunogenic and that the Cluster A-specific responses were induced at levels that provided potent Fc-effector activities, including ADCC [ 27 , 28 , 29 , 30 ]. Here, we describe the engineering, functional analyses and immunogenicity of ID2-V1V2, an immunogen variant that incorporates both the Cluster A and V1V2 regions of HIV-1 Env to induce Fc-effector function responses to both epitope targets implicated in the protective effect of the RV144 vaccine trial.…”

Section: Introductionmentioning

confidence: 99%

Incorporating the Cluster A and V1V2 Targets into a Minimal Structural Unit of the HIV-1 Envelope to Elicit a Cross-Clade Response with Potent Fc-Effector Functions

et al. 2021

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The generation of a potent vaccine for the prevention and/or control of HIV-1 has been unsuccessful to date, despite decades of research. Existing evidence from both infected individuals and clinical trials support a role for non-neutralizing or weakly neutralizing antibodies with potent Fc-effector functions in the prevention and control of HIV-1 infection. Vaccination strategies that induce such antibodies have proven partially successful in preventing HIV-1 infection. This is largely thought to be due to the polyclonal response that is induced in a vaccine setting, as opposed to the infusion of a single therapeutic antibody, which is capable of diverse Fc-effector functions and targets multiple but highly conserved epitopes. Here, we build on the success of our inner domain antigen, ID2, which incorporates conformational CD4-inducible (CD4i) epitopes of constant region 1 and 2 (C1C2 or Cluster A), in the absence of neutralizing antibody epitopes, into a minimal structural unit of gp120. ID2 has been shown to induce Cluster A-specific antibodies in a BALB/c mouse model with Fc-effector functions against CD4i targets. In order to generate an immunogen that incorporates both epitope targets implicated in the protective Fc-effector functions of antibodies from the only partially successful human vaccine trial, RV144, we incorporated the V1V2 domain into our ID2 antigen generating ID2-V1V2, which we used to immunize in combination with ID2. Immunized BALB/c mice generated both Cluster A- and V1V2-specific antibodies, which synergized to significantly improve the Fc-mediated effector functions compared to mice immunized with ID2 alone. The sera were able to mediate both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). We therefore conclude that ID2-V1V2 + ID2 represents a promising vaccine immunogen candidate for the induction of antibodies with optimal Fc-mediated effector functions against HIV-1.

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