The Lymph Node Reservoir: Physiology, HIV Infection, and Antiretroviral Therapy

Abstract

Despite advances in treatment, finding a cure for HIV remains a top priority. Chronic HIV infection is associated with increased risk of comorbidities, such as diabetes and cardiovascular disease. Additionally, people living with HIV must remain adherent to daily antiretroviral therapy, because lapses in medication adherence can lead to viral rebound and disease progression. Viral recrudescence occurs from cellular reservoirs in lymphoid tissues. In particular, lymph nodes are central to the pathology of HIV due to their unique architecture and compartmentalization of immune cells. Understanding how antiretrovirals (ARVs) penetrate lymph nodes may explain why these tissues are maintained as HIV reservoirs, and how they contribute to viral rebound upon treatment interruption. In this report, we review (i) the physiology of the lymph nodes and their function as part of the immune and lymphatic systems, (ii) the pathogenesis and outcomes of HIV infection in lymph nodes, and (iii) ARV concentrations and distribution in lymph nodes, and the relationship between ARVs and HIV in this important reservoir.

Figure 1:

A) An overview of the structure and flow (arrows) in a lymph node. The capsule (1) is the outmost later of endothelial cells. Lymphatic fluid flows into the node through the afferent (2) lymphatics, around the node through the subcapsular sinus (3), then between each lymph node lobule (dashed region, expanded in B) through the transverse sinuses (4). From the subcapsular sinus fluid can diffuse into the cortex (5), and from the transverse sinuses into the paracortex (6). Finally, lymphatic fluid collects in the medulla (7), and makes its way out of the node through the efferent lymphatics (8) in the hilus (9). B) An overview of the structure and cellular organization of a lymph node lobule. The cortex (1) is the outermost region containing follicles (2), which are made up primarily of B cells and FDCs. The next region is the paracortex (3), containing primarily T cells and DCs, as well as the HEVs (4). Lastly, the medulla (5) is an area of lymph flow and cell trafficking, and its appearance is characterized by a maze-like appearance of medullary cords (dark green) sinuses (light green). Throughout the lymph node the FRC network (gray lines) gives the tissue shape and structure.

Figure 2:

An overview of expected A) HIV and B) ARV distribution in the lymph node. A) The red color gradient represents variability in HIV distribution throughout the lymph node, with more virus located in dark regions and less virus in lighter regions. Higher HIV concentrations are expected the the B cells follicles, where virions are trapped on FDCs, and in the T cell zone in infected CD4+ T cells. B) The green color gradient represents changes in drug distribution throughout the lymph node, with higher drug concentrations in dark regions and lower drug concentrations in lighter regions. Increased ARV penetration is expected around the subcapsular and transverse sinuses, and surrounding HEVs.