title: HIV-1 Tat B-cell epitope vaccination was ineffectual in preventing viral rebound after ART cessation: HIV rebound with current ART appears to be due to infection with new endogenous founder virus and not to resurgence of pre-existing Tat-dependent viremia.
abstract: CD4 T cell activation, essential for productive HIV infection, is provided initially in acute HIV infection by innate immune system secretion of activating cytokines. This cytokine response wanes with time and long-term activation of CD4 cells is maintained by HIV Tat protein secreted by HIV infected cells. Structured treatment interruption (STI) in well-controlled antiretroviral-treated (ART) subjects was explored a decade ago with a consensus finding that, in most subjects, HIV levels rebounded within four weeks to pre-ART levels. Based on these observations we initiated a randomized placebo-controlled study of a universal anti-Tat epitope vaccine, TUTI-16, to determine if immunological blockade of Tat would prevent HIV rebound after ART cessation. TUTI-16 immunization was safe, with predominantly mild local and systemic injection-related adverse reactions. TUTI-16 was also immunogenic, with high levels of anti-Tat antibodies compared with levels previously shown to reduce HIV replication in vivo. Of 21 subjects analyzed, 13 (62%) had HIV rebounds vs. 8 (38%) that remained aviremia, but this distribution was not vaccine-related (p = 0.61 log-rank (Mantel-Cox) test), nullifying our hypothesis that anti-Tat antibodies would block rebound of Tat-dependent set-point HIV viremia after ART cessation. Our present findings are consistent with recent molecular findings that rebounding virus following STI is homogeneous and unrelated to previous circulating HIV, suggesting that rebounding HIV represents new founder virus, akin to the original acute HIV infection. We propose, therefore, that STI may have potential as a practical and economical approach to testing the safety and efficacy of candidate prophylactic HIV vaccines.
authors.affiliation: Thymon LLC, Short Hills, NJ, USA. gidgold@gmail.com
authors.forename: Gideon
authors.initials: G
authors.lastname: Goldstein
authors.forename: Eve
authors.initials: E
authors.lastname: Damiano
authors.forename: Mardik
authors.initials: M
authors.lastname: Donikyan
authors.forename: Malika
authors.initials: M
authors.lastname: Pasha
authors.forename: Erik
authors.initials: E
authors.lastname: Beckwith
authors.forename: John
authors.initials: J
authors.lastname: Chicca
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology / Q000627:therapeutic use*; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018985:Epitopes, B-Lymphocyte / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D014766:Viremia / Q000188:drug therapy / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D018985:Epitopes, B-Lymphocyte; C421254:human immunodeficiency virus type 1 Tat vaccine
keywords: HIV-1; TUTI-16; Tat; acute HIV infection; antiretroviral; clinical trial; human vaccine; prophylactic; rebound; therapeutic