title: A replication-competent adenovirus-human immunodeficiency virus (Ad-HIV) tat and Ad-HIV env priming/Tat and envelope protein boosting regimen elicits enhanced protective efficacy against simian/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques.
abstract: We previously demonstrated that replication-competent adenovirus (Ad)-simian immunodeficiency virus (SIV) recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIV(mac251). Additionally, native Tat vaccines have conferred strong protection against simian/human immunodeficiency virus SHIV(89.6P) challenge of cynomolgus monkeys, while native, inactivated, or vectored Tat vaccines have failed to elicit similar protective efficacy in rhesus macaques. Here we asked if priming rhesus macaques with replicating Ad-human immunodeficiency virus (HIV) tat and boosting with the Tat protein would elicit protection against SHIV(89.6P). We also evaluated a Tat/Env regimen, adding an Ad-HIV env recombinant and envelope protein boost to test whether envelope antibodies would augment acute-phase protection. Further, expecting cellular immunity to enhance chronic viremia control, we tested a multigenic group: Ad-HIV tat, -HIV env, -SIV gag, and -SIV nef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in enzyme-linked immunospot responses (with the strongest response for Env, followed by Gag, followed by Nef, followed by Tat) and antibody titers (with the highest titer for Env, followed by Tat, followed by Nef, followed by Gag). Following intravenous SHIV(89.6P) challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports for rhesus macaques. However, the multigenic group blunted acute viremia by approximately 1 log (P = 0.017), and both the multigenic and Tat/Env groups reduced chronic viremia by 3 and 4 logs, respectively, compared to controls (multigenic, P = 0.0003; Tat/Env, P < 0.0001). The strikingly greater reduction in the Tat/Env group than in the multigenic group (P = 0.014) was correlated with Tat and Env binding antibodies. Since prechallenge anti-Env antibodies lacked SHIV(89.6P)-neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between the Tat and Env immunogens.
authors.affiliation: Vaccine Branch, National Cancer Institute/NIH, 41 Medlars Drive, Building 41, Bethesda, MD 20892-5065, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Demberg
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Florese
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Heath
authors.forename: Kay
authors.initials: K
authors.lastname: Larsen
authors.forename: Irene
authors.initials: I
authors.lastname: Kalisz
authors.forename: V S
authors.initials: VS
authors.lastname: Kalyanaraman
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Lee
authors.forename: Ranajit
authors.initials: R
authors.lastname: Pal
authors.forename: David
authors.initials: D
authors.lastname: Venzon
authors.forename: Richard
authors.initials: R
authors.lastname: Grant
authors.forename: L Jean
authors.initials: LJ
authors.lastname: Patterson
authors.forename: Birgit
authors.initials: B
authors.lastname: Korioth-Schmitz
authors.forename: Adam
authors.initials: A
authors.lastname: Buzby
authors.forename: Dilani
authors.initials: D
authors.lastname: Dombagoda
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Aurelio
authors.initials: A
authors.lastname: Cafaro
authors.forename: Barbara
authors.initials: B
authors.lastname: Ensoli
authors.forename: Marjorie
authors.initials: M
authors.lastname: Robert-Guroff
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology / Q000494:pharmacology; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015696:Gene Products, tat / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006678:HIV / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007156:Immunologic Memory / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008253:Macaca mulatta; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000914:Antibodies, Viral; D015686:Gene Products, env; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus