With the advent of novel anti-retroviral therapies, the prospect of potentially eliminating HIV from infected patients may become an achievable goal. However, such goal will require new tools with greater sensitivity than currently available to monitor the progress of such therapy, not only in blood but also in organs that do harbor such reservoirs and sites of residual viral replication in vivo. In addition, identifying early seeding of viral reservoirs during acute infection relative to the route of transmission and disease progression may open novel directions for chemotherapeutic or immune barriers to contain the new virus infection foyers and generalized dissemination of the infection with seeding of viral reservoirs. To harness such early viral dynamics and account for the natural individual variation that exists for such dynamics, there is a need to understand the dissemination patterns of HIV infection following mucosal transmission, the primary transmission mode of infection worldwide. However, the tools currently available to monitor such viral processes are either indirect or relatively invasive and clearly impractical for the human clinic. Even when one uses the nonhuman primate model of AIDS, understanding the viral dynamics in real time is challenging and prohibitively expensive if one chooses to perform serial sacrifices, not to mention fraught by a high degree of variability between individuals. In this project, we propose to optimize our established immuno-positron emission tomography (PET) with simultaneous X-ray computed tomography (CT), to determine real-time whole body maps of simian immunodeficiency virus replication sites in vivo to chart out the total body replication sites of SIV in vivo and determine viral dynamics and sites of residual viral replication during antiretroviral therapy. Thus we propose to determine the anatomic SIV viral dynamics following infection via the IV, rectal and vaginal route to determine the consecutive major sites of viral replication in vivo, which will be confirmed via targeted tissue collections. Next we will compare 2 combination ART therapies for reducing viral reservoirs and document residual foyers of replication in vivo as well as determine which such reservoirs might be fueling the viral resurgence after interruption of ART in vivo. We submit that these studies will provide critical information for the design of HIV eradication strategies in human HIV infection.
With the advent of novel anti-retroviral therapies, the prospect of potentially eliminating HIV from infected patients may become an achievable goal, yet, such goal will require new tools with greater sensitivity than the ones currently available to ascertain elimination of the virus in vivo The current virus detection methods to monitor HIV rely primarily on measures in blood, but fails to harness virus replication that may be ongoing in organs, even during antiretroviral therapy, or upon interruption of therapy, i.e. the functional virus reservoirs in vivo are not known. In this project, we propose to optimize our established imaging method using positron emission tomography (PET) with simultaneous X-ray computed tomography (CT), to determine real-time whole body maps of simian immunodeficiency virus replication sites in rhesus monkeys, during acute and post acute infection, during antiretroviral therapy and after cessation of such therapy to identify viral reservoirs and the sites from which virus replication reemerges after interruptio of treatment.
|Byrareddy, Siddappa N; Arthos, James; Cicala, Claudia et al. (2016) Sustained virologic control in SIV+ macaques after antiretroviral and Î±4Î²7 antibody therapy. Science 354:197-202|
|Santangelo, Philip J; Rogers, Kenneth A; Zurla, Chiara et al. (2015) Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy-treated macaques. Nat Methods 12:427-32|