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.

Trial registration: ClinicalTrials.gov NCT01335191.

Keywords: HIV-1; TUTI-16; Tat; acute HIV infection; antiretroviral; clinical trial; human vaccine; prophylactic; rebound; therapeutic.

Figures

Figure 1. CONSORT subject disposition chart.

Figure 2. Baseline CD4 T cell counts (mean ± SEM) demonstrating successful randomization at study entry.

Figure 4. Kaplan-Meier rebound-free survival graph. Solid line denotes vaccine, interrupted line placebo. Rebound was defined as viral load greater than 3,000 HIV RNA copies/mL plasma.

Figure 5. Consolidated times from ART cessation to rebound or to non-rebound status at study termination for all analyzed subjects. Dotted horizontal line at 4 weeks indicates maximal time to rebound for 90% of subjects in earlier STI studies. Horizontal bars denote mean ± SEM.

Figure 3. Changes in anti-Tat antibody levels after TUTI-16 (blue) or placebo (red) injections. Arrows denote injection times. The blue lines and symbols represent individual vaccinated subjects. The red line and symbols show the non-responsiveness of the placebo group and two non-responding vaccine subjects are concealed behind this line. TUTI-16 induced antibody levels < 40 ng/mL were previously shown to lower plasma HIV levels in asymptomatic ART naïve HIV infected subjects.