The development of therapeutic interventions that can target viral reservoirs in HIV-1 infected individuals is a major goal of HIV-1 research. Recent evidence that infusion of HIV-1 specific broadly neutralizing antibodies (bnAbs) in chronically SHIV-infected macaques resulted in transient suppression of viremia and reduction of proviral DNA in both peripheral blood and tissues, have led to renewed interest in the development of therapeutic strategies that can improve the control of virus rebound after anti-retroviral treatment (ART) interruption and diminish the viral reservoir size. Extending the bnAbs circulation half- lives and improving their ability to mediate killing of infected cells though engineering of the Fc region is a viable strategy to enhance bnAbs impact on the virus reservoir. However, even if engineered antibodies can be a significant improvement over wild type molecules, they will likely need to be used in combination with other immune-based interventions, such as therapeutic vaccines, to overcome the limitations of monotherapies and exert a significant impact on the viral reservoir. The proposed studies will determine whether the combination of a therapeutic vaccine based on an integrase defective lentiviral vector (IDLV) and a cocktail of Fc-engineered bnAbs (e-bnAbs) could be a strategy to induce durable virologic control and reservoir size reduction. Our prior work has demonstrated that IDLV can drive prolonged transgene expression and durable immune responses following intramuscular injection. In preliminary data, we show that a single immunization with an IDLV-Gag therapeutic vaccine was effective at enhancing anti- Gag CD8+ T cell responses in chronically SHIV infected macaques and resulted in durable suppression of virus replication in absence of ART. We propose to further improve the IDLV platform by assessing the impact that modulation of transgene expression levels, in both dendritic cells and muscle cells, have on the resulting immune responses (Aim 1). We will perform pharmacokinetics studies in transgenic mice expressing the human Fc receptor (FcRn) to determine the half-lives and effector functions of combinations of bnAbs that have been engineered (e-bnAbs) to improve their half-lives and effector functions (Aim 2). We will assess the impact that the combination of the cocktail of e-bnAbs and the improved IDLV therapeutic vaccine have on viral load and reservoir size in efficacy studies in SHIV- infected macaques (Aim 3). Collectively, results from this work will provide valuable information for the design of therapeutic strategies against the HIV-1 reservoir.
STATEMENT Therapeutic approaches combining the use of engineered antibodies to therapeutic vaccination represents a promising strategy to achieve durable control of HIV-1 replication and reduce the viral reservoir, which poses the greatest challenge to achieving an HIV-1 cure. Previously tested therapeutic vaccines, including DNA, proteins and different viral vectors demonstrated limited efficacy. Therefore, it is important to evaluate other vector platforms, including Integrase Defective Lentiviral Vectors (IDLV) that showed promising preliminary results, and their suitability for therapeutic interventions against HIV- 1.
