Comparative Immunogenicity of Subtype A Human Immunodeficiency Virus Type 1 Envelope Exhibiting Differential Exposure of Conserved Neutralization Epitopes

Abstract

Development of broadly cross-reactive neutralizing antibodies (NAbs) remains a major goal of HIV-1 vaccine development, but most candidate envelope immunogens have had limited ability to cross-neutralize heterologous strains. To evaluate the immunogenicity of subtype A variants of HIV-1, rabbits were immunized with pairs of closely related subtype A envelopes from the same individual. In each immunogen pair, one variant was readily neutralized by a variety of monoclonal antibodies and plasma antibodies, while the other was neutralization resistant, suggesting differences in the exposures of key epitopes. The breadth of the antibody response was evaluated against subtype A, B, C, and D variants of HIV-1. The specificity of the immunogen-derived neutralizing antibody response was also compared to that of the infected individuals from whom these variants were cloned. None of the immunogens produced broad neutralizing antibodies in immunized animals, and most of the neutralizing antibodies were directed to the variable loops, particularly the V3 loop. No detectable antibodies to either of the potentially exposed conserved epitopes, the membrane proximal external region, or the CD4 binding site were found with immunized rabbits. In contrast, relatively little of the neutralizing activity within the plasma samples of the infected individuals was directed to linear epitopes within the variable loops. These data indicate that immunogens designed to expose conserved regions did not enhance generation of broadly neutralizing antibodies in comparison with the immunogens that failed to expose those regions using this immunization approach.The ability to elicit broadly cross-reactive neutralizing antibodies (NAbs) is likely to be an important component of an effective vaccine to human immunodeficiency virus type 1 (HIV-1). Unfortunately, the HIV-1 envelope (Env)-based vaccines developed to date do not elicit such antibodies. Initial vaccines based on soluble, monomeric gp120 generated antibodies capable of only weakly neutralizing the homologous virus, with a very narrow breadth of cross-reactivity (13,30,53). Subsequent modifications to the Env immunogens, including variable loop deletions (15,20,31,34,35,61,(64)(65)(66), alterations in the glycosylation pattern (4,10,11,14,30,43,55,56), epitope repositioning (39, 46), the use of consensus Envs (22,36,37,47), and the use of soluble trimeric gp140 molecules as immunogens (1-3, 5, 14, 16, 20, 21, 24, 25) have led to only modest enhancements in NAb breadth or potency. These modified Env immunogens have failed to redirect NAbs from the variable loops to more conserved regions of Env (reviewed in reference 33).Differences in Env structure between HIV-1 subtypes may further hinder efforts to elicit broadly cross-reactive antibodies capable of protecting against transmitted strains worldwide. Most immunogens tested to date have been derived from subtype B Envs. However, there are clear antigenic differences between subtype B strains and the subtype A and C strains that account fo...

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

“…Only tier 1A viruses were neutralized at moderate to high levels, and similar to previous vaccine studies (12,17,19,35,36,48), almost no autologous neutralization was elicited (data not shown). This lack of autologous neutralization and limited heterologous neutralization compared to the moderate cross-clade neutralization breadth in the infected VC10014 and VC20013 subjects could be explained by several factors.…”

“…Prolonged antigenic exposure is a key clinical parameter associated with the natural development of bNAbs in elite neutralizers (24,(31)(32)(33), suggesting that the dynamic interactions occurring between viral quasispecies and host B cells result in continuously changing antibody specificities in vivo (24,25) and likely contribute to the generation of bNAbs (34). In fact, multiple pathways to neutralization breadth have been shown in different subjects (9,33,(35)(36)(37)(38), whereas in some subjects, antibodies with a single specificity or a few specificities can account for much of the neutralization activity (10,29,33,(39)(40)(41)(42). Thus, further understanding of the humoral response in infected individuals who naturally develop bNAbs could guide the selection of candidate Env immunogens and the design of vaccine strategies that elicit breadth (43).…”

Binding Interactions between Soluble HIV Envelope Glycoproteins and Quaternary-Structure-Specific Monoclonal Antibodies PG9 and PG16

“…Such broad anti-HIV neutralizingantibody responses have not yet been achieved by immunization (1,3,8,11,13,17,21,25,26,35,40,42,58,63,66). Initially, it was thought that such antiviral responses are extremely rare, even in the context of natural HIV-1 infection, and therefore, their elicitation by vaccination would be extremely difficult, if not impossible.…”

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

“…Thus, efforts to design vaccines that rapidly elicit an effective and broadly cross-reactive neutralizing Ab (nAb) response seem rational based primarily on the observation that doses of bNmAbs are the only formula to date that has been shown to prevent infection and to provide sterilizing immunity in NHP. Despite multiple efforts to develop an immunogen or immunogens that can elicit bNAbs following vaccination, success has been limited (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Some incremental advances have been made, including our recent immunogenicity studies (22) and those of others (23)(24)(25) that have shown an advantage of coimmunization with DNA and protein immunogens, including the potential of contracting the vaccine regimen to a small number of immunizations to reach peak NAb responses.…”