The Ability of an Oligomeric Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Antigen To Elicit Neutralizing Antibodies against Primary HIV-1 Isolates Is Improved following Partial Deletion of the Second Hypervariable Region

Abstract

Partial deletion of the second hypervariable region from the envelope of the primary-like SF162 virus increases the exposure of certain neutralization epitopes and renders the virus, SF162⌬V2, highly susceptible to neutralization by clade B and non-clade B human immunodeficiency virus (HIV-positive) sera (L. Stamatatos and C. Cheng-Mayer, J. Virol. 78:7840-7845, 1998). This observation led us to propose that the modified, SF162⌬V2-derived envelope may elicit higher titers of cross-reactive neutralizing antibodies than the unmodified SF162-derived envelope. To test this hypothesis, we immunized rabbits and rhesus macaques with the gp140 form of these two envelopes. In rabbits, both immunogens elicited similar titers of binding antibodies but the modified immunogen was more effective in eliciting neutralizing antibodies, not only against the SF162⌬V2 and SF162 viruses but also against several heterologous primary HIV type 1 (HIV-1) isolates. In rhesus macaques both immunogens elicited potent binding antibodies, but again the modified immunogen was more effective in eliciting the generation of neutralizing antibodies against the SF162⌬V2 and SF162 viruses. Antibodies capable of neutralizing several, but not all, heterologous primary HIV-1 isolates tested were elicited only in macaques immunized with the modified immunogen. The efficiency of neutralization of these heterologous isolates was lower than that recorded against the SF162 isolate. Our results strongly suggest that although soluble oligomeric envelope subunit vaccines may elicit neutralizing antibody responses against heterologous primary HIV-1 isolates, these responses will not be broad and potent unless specific modifications are introduced to increase the exposure of conserved neutralization epitopes.Analysis of the crystal structure of the gp120 human immunodeficiency virus (HIV) envelope subunit indicated that neutralization epitopes are primarily clustered in one face of this protein, which is naturally occluded within the oligomeric envelope form, i.e., that present on the surface of virions and infected cells (16,37). These structural observations are supported by numerous immunochemical and virological studies (1,24,25,27,28,31,35,38,40).Several reports have indicated that specific modifications (such as deglycosylations and loop deletions) introduced in the envelope glycoproteins of HIV and simian immunodeficiency virus (SIV) may increase the exposure of neutralization epitopes. Wyatt et al. demonstrated that on the background of the HXB2 virus, a laboratory-adapted CXCR4-using (X4-using) virus, deletions of the first, second, and third hypervariable regions (V1, V2, and V3 loops, respectively) of the gp120 envelope subunit increase the exposure of epitopes participating in HIV envelope-CD4 and -coreceptor binding (38,40). Subsequently, it was demonstrated that the simultaneous deletion of the V1 and V2 loops from the envelope of this virus increases it susceptibility to neutralization by anti-V3 loop and certain CD4-induced monoclonal antibodies...

Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state

“…The pattern of immunodominance of one response over another might therefore be altered. Modifications of Env immunogens through deletion of variable loops [81][82][83] or elimination of carbohydrate attachment sites [84,85], for example, have been made to improve immunogenicity of functionally relevant epitopes. Alternatively, introduction of glycosylation sites or other site-specific mutations have been performed in an attempt to redistribute immune responses away from unwanted dominant epitopes towards neutralizing sites of relevance [86,87].…”

Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding

“…(C) Subunit rotation along designated subunit axes (S 1 , S 2 , and S 3 , as previously described, protruding out of the plane of the page) further weakens gp120/gp41 interface, likely freeing up gp41 N-helix for association with the C-helix. ment of gp140 in a metastable state and the putative locations of its exposed epitopes contribute to the characterization of subsequent events occurring prior to membrane fusion, and utilization of gp140 as an immunogen in the unliganded and liganded forms with knowledge of epitope location and exposure could prove useful in elicitation of antibodies against both conserved epitopes, as opposed to the use of monomeric gp120 or of adenovirus-based cell-mediated immunity, thus providing a feasible direction for rational immunogen design (12,(42)(43)(44).…”

Efficient protein boosting after plasmid DNA or recombinant adenovirus immunization with HIV-1 vaccine constructs

“…Immunization with the dV2gp140 protein generates high titer antibody levels including homologous neutralizing antibodies [6,[38][39][40][41]. In addition, dV2gp140 elicits high antibody titers in monkeys primed with a DNA plasmids encoding the homologous env gene [42,43].…”

“…Thus, a major goal is to develop an HIV-1 vaccine strategy that will generate both cellular immunity and high titers of virus neutralizing antibodies. Serial immunization with HIV-1 envelope (Env) protein immunogens can result in high antibody levels, but little or no CD8 T-cell responses [4][5][6][7][8][9]. One approach to generating both cellular immunity and neutralizing antibodies is to initiate immunization with a gene based vector that is known to elicit CD4 and CD8 responses, and boost with a protein immunogen.…”