title: Immunization with wild-type or CD4-binding-defective HIV-1 Env trimers reduces viremia equivalently following heterologous challenge with simian-human immunodeficiency virus.
abstract: We recently reported that rhesus macaques inoculated with CD4-binding-competent and CD4-binding-defective soluble YU2-derived HIV-1 envelope glycoprotein (Env) trimers in adjuvant generate comparable levels of Env-specific binding antibodies (Abs) and T cell responses. We also showed that Abs directed against the Env coreceptor binding site (CoRbs) were elicited only in animals immunized with CD4-binding-competent trimers and not in animals immunized with CD4-binding-defective trimers, indicating that a direct interaction between Env and CD4 occurs in vivo. To investigate both the overall consequences of in vivo Env-CD4 interactions and the elicitation of CoRbs-directed Abs for protection against heterologous simian-human immunodeficiency virus (SHIV) challenge, we exposed rhesus macaques immunized with CD4-binding-competent and CD4-binding-defective trimers to the CCR5-tropic SHIV-SF162P4 challenge virus. Compared to unvaccinated controls, all vaccinated animals displayed improved control of plasma viremia, independent of the presence or absence of CoRbs-directed Abs prior to challenge. Immunization resulted in plasma responses that neutralized the heterologous SHIV challenge stock in vitro, with similar neutralizing Ab titers elicited by the CD4-binding-competent and CD4-binding-defective trimers. The neutralizing responses against both the SHIV-SF162P4 stock and a recombinant virus pseudotyped with a cloned SHIV-SF162P4-derived Env were significantly boosted by the SHIV challenge. Collectively, these results suggest that the capacity of soluble Env trimers to interact with primate CD4 in vivo and to stimulate the production of moderate titers of CoRbs-directed Abs did not influence the magnitude of the neutralizing Ab recall response after viral challenge or the subsequent control of viremia in this heterologous SHIV challenge model.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sundling
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.forename: Iyadh
authors.initials: I
authors.lastname: Douagi
authors.forename: Mattias N
authors.initials: MN
authors.lastname: Forsell
authors.forename: Andreas
authors.initials: A
authors.lastname: Mörner
authors.forename: Karin
authors.initials: K
authors.lastname: Loré
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D005260:Female; D015686:Gene Products, env / Q000276:immunology*; D015483:HIV Antibodies / Q000097:blood; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008253:Macaca mulatta; D009500:Neutralization Tests; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014766:Viremia / Q000276:immunology / Q000517:prevention & control*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015686:Gene Products, env; D015483:HIV Antibodies