EXCEED THE SPACE PROVIDED. As a part of our on-going research focusing on therapeutic strategies against HIV transmission and disease progression, the long-term goal of this program is to develop novel therapeutic strategies against HIV replication in lymphoid tissues. While the tissues that harbor residual HIV outside the lymphatic system remains elusive, it is clear that a low but detectable fraction of HIV is found in visceral (e.g., mesenteric) lymph nodes, even in the presence of highly active anti-retroviral (combination drug) therapies (HAARTs). Our recent analysis of indinavir (an HIV protease inhibitor) levels in tissues (i.e., lymph nodes) and blood indicated that drug, particularly protease inhibitor, exposure in lymph nodes is far less than that of systemic (blood) exposure in human subjects under HAARTs. Increasing drug exposure to lymphoid tissues without increasing drug toxicity may further reduce the virus levels and intracellular virus concentrations in these tissues. Using an anti-HIV protease inhibitor, indinavir, as a model drug, we recently designed lipid-drug complexes of about 50-60 nm in diameter that permitted a significant enhancement in localization of indinavir in lymph nodes. The novel approach to form the lipid-drug complex permitted almost complete incorporation of drug into the complex, thereby greatly simplifying the drug formulation process. When administered subcutaneously to macaques (M. nemestrina), the lipid-associated drug complexes accumulated at high concentrations in lymph nodes; we observed drug concentrations in lymph nodes as much as 20-30-fold higher than in blood. Such levels of drug accumulation in lymph nodes could not be achieved with free drug. With enhanced delivery of drugs to lymph nodes of HIV-2287-infected macaques, at higher concentrations and for a longer duration, while keeping drug-associated toxicity at bay, we will determine whether increasing local drug concentration will further reduce the virus load in the lymphatic system by testing the following hypotheses: Hypothesis 1: Enhanced anti-HIV drug accumulation in lymph nodes throughout the lymphatic system can be achieved using a novel lipid-associated form. Hypothesis 2: Lipid-mediated enhanced drug accumulation strategy will further reduce the frequency of virus-infected cells or virus concentration in lymphoid tissues. As proof-of-principle, data collected using a highly sensitive virus quantitation and localization system for lymphoid tissues, from this study, will discern the differential effects of free and lipid-associated indinavir. In addition, these data will provide a solid foundation encompassing pharmacologic and therapeutic, as well as safety issues, essential for further evaluation of the novel drug-targeting strategies to enhance drug availability in lymph nodes and other tissues where virus typically persists. PERFORMANCE SITE ========================================Section End===========================================
Showing the most recent 10 out of 28 publications
