HIV infection persists despite prolonged suppression of plasma viremia to undetectable levels. Little pharmacologic data are available on viral reservoirs such as the lymph node (LN) and gut associated lymphoid tissue (GALT) where the virus preferentially replicates. Our most important findings in work we have conducted to date are: (1) intracellular concentrations (ICs) of the antiretrovirals (ARVs) evaluated were uniformly lower in LN when compared with concentrations in plasma and PBMCs, and (2) de novo virus production persisted in LT of these patients, who all have plasma viral load <50 copies/mL, strongly suggesting ICs in LT are not sufficient to suppress HIV production fully. These discoveries have identified fundamental gaps in our understanding of determinants of ARV concentrations in LT. This proposal builds upon these findings; we propose 3 specific aims. Aim 1: Define and compare lymphatic tissue pharmacokinetics (PK) and pharmacodynamics (PD) of antiretroviral drugs, with characteristics that may confer enhanced penetration and persistence in lymph nodes and gut-associated lymphoid tissue, in uninfected and chronically SIV-infected macaques. Aim 2: Characterize and understand the mechanisms underlying the extent of lymphatic distribution of antiretroviral drugs with in vitro and in vivo approaches. Aim 3: Confirm that an ARV regimen with enhanced LT penetration characteristics in macaques translates into improved LT PKPD in HIV-infected persons. The work we propose will lead to new in vitro and in vivo approaches on how to evaluate LT penetration of candidate ARVs. We will develop a pharmacologic-based strategy using combinations of existing and new agents to design ARV regimens that achieve enhanced LT drug delivery. We believe, and multiple lines of evidence support that optimized delivery of ARVs to LT will more fully contain viral production in LT reservoirs. Our long-term goal is to develop a scientific basis for the design of ARV regimens with enhanced LT penetration that more fully suppresses HIV production in LT, averts the long-term consequences of persistent virus production, and establishes the full viral suppression we believe is a prerequisite for a functional cure or for eradication. The data we have generated are compelling to pursue this research agenda, which has high human health relevance.