Abstract
The most relevant endpoint in therapeutic HIV vaccination is the assessment of time to viral rebound or duration of sustained control of low-level viremia upon cART treatment cessation. Structured treatment interruptions (STI) are however not without risk to the patient and reliable predictors of viral rebound/control after therapeutic HIV-1 vaccination are urgently needed to ensure patient safety and guide therapeutic vaccine development. Here, we integrated immunological and virological parameters together with viral rebound dynamics after STI in a phase I therapeutic vaccine trial of a polyvalent MVA-B vaccine candidate to define predictors of viral control. Clinical parameters, proviral DNA, host HLA genetics and measures of humoral and cellular immunity were evaluated. A sieve effect analysis was conducted comparing pre-treatment viral sequences to breakthrough viruses after STI. Our results show that a reduced proviral HIV-1 DNA at study entry was independently associated with two virological parameters, delayed HIV-1 RNA rebound (p = 0.029) and lower peak viremia after treatment cessation (p = 0.019). Reduced peak viremia was also positively correlated with a decreased number of HLA class I allele associated polymorphisms in Gag sequences in the rebounding virus population (p = 0.012). Our findings suggest that proviral DNA levels and the number of HLA-associated Gag polymorphisms may have an impact on the clinical outcome of STI. Incorporation of these parameters in future therapeutic vaccine trials may guide refined immunogen design and help conduct safer STI approaches.
Highlights
Effective treatments for human immunodeficiency virus (HIV) infection exist and combination antiretroviral therapy has resulted in a dramatic decrease in morbidity and mortality
The recently reported immunological and virological outcome MVA-B based therapeutic vaccination in the trial RISVAC03 demonstrated increased Gag-specific T cell responses in vaccinees compared to placebo controls [14]
We show that, in contrast to the modest elevation in magnitude of immune responses seen upon vaccination and reported previously[14] [16], there was a major increase in breadth and total magnitude of HIV-1 specific T cell responses after treatment interruption
Summary
Effective treatments for human immunodeficiency virus (HIV) infection exist and combination antiretroviral therapy (cART) has resulted in a dramatic decrease in morbidity and mortality. Since HIV forms latent viral reservoirs from which the virus reactivates and replicates when treatment is interrupted, cART is a non-curative life-long treatment. Therapeutic vaccination in infected individuals aims to boost adaptive immunity against HIV and help to maintain viral replication at undetectable or low-levels in the absence of cART. While results from cross-sectional cohorts of natural HIV infection point to various immune markers that are associated with viral load, no robust immune parameters have been identified that could serve as reliable predictors of viral control in patients receiving therapeutic vaccines and interrupting antiretroviral treatment [5][6][7][8]
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