TLR Immunotherapy to Eradicate Anatomic SIV Reservoirs

摘要

ABSTRACT The eradication of Human Immunodeficiency Virus (HIV-1) from infected individuals is the ultimate goal of antiretroviral therapy (ART). Major advances have been made towards this end with the advent of ART regimens. Despite the sustained suppression of plasma viremia below detectable limits in infected patients for 2 or more years on ART regimens, replication competent virus can still be recovered from a variety of subterfuges within the host, most notably long-lived quiescent memory CD4+ T lymphocytes. These and other unknown viral reservoirs represent the final impediment to the eradication of HIV infection. Although ART remains the gold standard of care, even intensified regimens do not impact the viral reservoir. Therefore, alternative therapeutic strategies must be explored. The use of “shock and kill” regimens might be a significant approach to perturb the HIV reservoir and enhance viral clearance or control. However, there are significant gaps in our understanding of these combinatorial modalities that cannot be easily ascertained by the study of human patients. Using our rhesus monkey (RM) model of SIV persistence (Whitney et al. Nature 2014), we propose to continue to evaluate a TLR7 agonist that we have discovered can potently reactivate SIV and HIV-1 from latency. This new class of viral latency reversing agent is orally deliverable, and in stark contrast to HDACi, markedly potentiates antiviral immune responses. We propose to determine the mechanisms by which TLR7 agonists can impact established anatomic reservoirs in the setting of potent ART. To investigate these hypotheses, we propose the following Specific Aims: 1. Determine the impact of early ART and LRAs (TLR7) upon the SIV reservoir in anatomic tissues. 2. Determine the impact of TLR7 treatment upon the constitution of the SIV reservoir in T cell and monocyte/macrophage lineages. 3. Determine the immunologic correlates of TLR7 induced immune control on the SIV reservoir after cessation of ART in Mamu A*01/A*02 monkeys.