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.
Although HIV-1 can be effectively suppressed with antiretroviral therapy, it is not eradicated from the body. HIV-1 infected persons who cease therapy have resurgent viremia due to the presence of long-lived HIV-1 reservoirs. These reservoirs are maintained within tissues by mechanisms that are not entirely defined. Moreover, the locations of these persistent viral reservoirs have yet to be completely identified. Presently, my laboratory has discovered a novel class of TLR7 agonist(s) that act as highly potent virus latency reversal agents. This potent latency reversal activity can impact the size and constitution of the viral reservoir. We propose to evaluate these potent latency reversal agents in non-human primate models on antiretroviral therapy. A detailed understanding of these modalities will be critical to help develop combination cure approaches to eradicate HIV-1 in patients on antiretroviral therapy.
| Lim, So-Yon; Osuna, Christa E; Hraber, Peter T et al. (2018) TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. Sci Transl Med 10: |
| Kublin, Jessica L; Whitney, James B (2018) Zika virus research models. Virus Res 254:15-20 |
| Whitney, James B; Lim, So-Yon; Osuna, Christa E et al. (2018) Prevention of SIVmac251 reservoir seeding in rhesus monkeys by early antiretroviral therapy. Nat Commun 9:5429 |
| Best, Katharine; Guedj, Jeremie; Madelain, Vincent et al. (2017) Zika plasma viral dynamics in nonhuman primates provides insights into early infection and antiviral strategies. Proc Natl Acad Sci U S A 114:8847-8852 |
| Osuna, Christa E; Whitney, James B (2017) Nonhuman Primate Models of Zika Virus Infection, Immunity, and Therapeutic Development. J Infect Dis 216:S928-S934 |
