ABSTRACT
Rhesus macaques immunized with the HIV-1 SF162DeltaV2 gp140 envelope using the DNA-prime plus protein-boost vaccination methodology, developed HIV envelope-specific T-cell lymphoproliferative responses and potent neutralizing antibodies. To evaluate the protective potential of these antibodies during acute infection, the animals were depleted of their CD8+ T lymphocytes using specific monoclonal antibodies and subsequently challenged intravenously with the pathogenic SHIV(SF162P4) isolate. As compared to non-vaccinated animals (one of which died from AIDS 16 weeks post-exposure) the vaccinated macaques had lower levels of peak viremia, rapidly cleared virus from the periphery and developed delayed seroconversion to SIV core antigens.
Subject(s)
AIDS Vaccines/pharmacology , Gene Products, env/immunology , HIV Antibodies/biosynthesis , HIV-1/immunology , Macaca mulatta/immunology , Vaccines, DNA/pharmacology , Animals , CD8-Positive T-Lymphocytes/immunology , Gene Products, env/genetics , HIV-1/genetics , HIV-1/isolation & purification , Lymphocyte Activation , Lymphocyte Depletion , Neutralization Tests , SAIDS Vaccines/pharmacology , Sequence Deletion , Simian Immunodeficiency Virus/immunology , T-Lymphocytes/immunology , env Gene Products, Human Immunodeficiency VirusABSTRACT
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, SF162DeltaV2, 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, SF162DeltaV2-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 SF162DeltaV2 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 SF162DeltaV2 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.
Subject(s)
AIDS Vaccines , Complementarity Determining Regions/genetics , Gene Deletion , Gene Products, env/immunology , HIV-1/immunology , AIDS Vaccines/genetics , AIDS Vaccines/immunology , Animals , Antibodies, Viral/blood , Antigens, Viral/immunology , Cross Reactions/immunology , Gene Products, env/chemistry , Gene Products, env/genetics , HIV Envelope Protein gp120/immunology , HIV Infections/immunology , HIV Infections/prevention & control , Humans , Immunization , Immunization, Secondary , Macaca mulatta , Neutralization Tests , Peptide Fragments/immunology , Rabbits , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/prevention & control , Vaccines, DNA/immunologyABSTRACT
DNA immunization of macaques with the SF162DeltaV2 envelope elicited lymphoproliferative responses and potent neutralizing antibodies. The animals were depleted of their CD8(+) T lymphocytes and then challenged intravenously with SHIV162P4. Compared to unvaccinated animals, the vaccinated macaques had lower peak viremia levels, rapidly cleared plasma virus, and showed delayed seroconversion.
