Although antiretroviral therapies have made considerable progress during the past decade, providing HIV infected patients with drug cocktails able to lower viral loads to undetectable levels, such therapy is unable to eliminate the virus from the host leading to a rapid reemergence of viremia to pre-treatment levels when such treatment is discontinued. Considerable efforts have been devoted to understand the seeding and long-term maintenance of HIV viral reservoirs, however, they are complex, and it is likely that residual replication is maintained in even well medicated hosts thanks to so called """"""""sanctuaries"""""""". Understanding the spatial dynamics for virus resurgence, continuous replication, as well as the initial dissemination during acute infection, could provide novel potential therapeutic and vaccine opportunities. However, the tools available to monitor such viral processes are either indirect or very invasive and clearly not practical in 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 use serial sacrifices, not to mention fraught by a great degree of variability between individuals. Conversely, measuring the effectiveness of individual antiretroviral drugs, preventive and therapeutic vaccines, immunotherapies and other therapies would benefit from a more precise monitoring of spatial viral replication in vivo, showing potential sites of poor drug penetration etc. Clearly, the development of a sensitive, specific and non invasive method for monitoring the dynamics and dissemination of HIV in humans or SIV in nonhuman primates would be of great benefit. Therefore, the goal of this project is to develop a fully validated immunoglobulin-based positron emission tomography (PET) contrast agent against SIV gp120, a viral surface glycoprotein, which will specifically target SIV infected cells and virus in SIV infected rhesus macaques. This agent will allow for whole body, non-invasive, quantitative interrogation of virally infected cells, tissue, and free virus as a function of time and space in living macaques. Through the aims of this project, an optimized dose and imaging protocol will be developed for the contrast agent, a thorough investigation of imaging accuracy and sensitivity using standard diagnostics will be performed, and last, an evaluation of the imaging agent's ability to image spatial variations in the infection during antiretroviral treatment will be performed.
Currently the tools available to monitor viral infections in living subjects are not capable of characterizing viral dynamics within the body in real time. In order to provide this information, we propose the development of a fully validated immunoglobulin-based positron emission tomography (PET) contrast agent against simian immunodeficiency virus (SIV) gp120, a viral surface glycoprotein present on SIV infected cells and virus in living SIV infected rhesus macaques, a model for HIV infected humans. When combined with computed tomography (CT), this technology for whole body imaging will lead to unprecedented views of virus replication, virus resurgence, virus response to antiretroviral treatment, as well as the initial dissemination during acute infection, which could provide novel potential therapeutic and vaccine monitoring opportunities.
|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|
|Byrareddy, Siddappa N; Kallam, Brianne; Arthos, James et al. (2014) Targeting ?4?7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection. Nat Med 20:1397-400|