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.

Hybrid Lymphatic Drug Delivery Vehicles as a New Avenue for Targeted Therapy: Lymphatic Trafficking, Applications, Challenges, and Future Horizons

“…In this regard, an elevated level of HIV is identified in the blood following infection that subsequently reduces owing to the immune response. Subsequently, virus concentration within the lymph node, particularly mononuclear cells, is intensified compared to systemic circulation (Scholz and Kashuba 2021 ). Lymphedema is detected in infected patients owing to multiple blockages and destruction of lymphatic vessels.…”

Eliminating HIV reservoirs for a cure: the issue is in the tissue

“…Even after ART, HIV-1 and SIV persist in these LT compartments for a variety of reasons (Fig. 1), including: (i) Tissue resident T follicular helper (T FH ) cells, which are a preferred cellular reservoir for HIV-1, and follicular dendritic cells (FDC; a noninfected cellular repository of infectious virions) are long-lived viral reservoirs that reside within B cell follicles (BCF) found in secondary LTs [3,4 ▪▪ ]; (ii) residual levels of immune activation and inflammatory mediators are heightened in many LTs (in particular the gut-associated lymphoid tissue [GALT]) during ART [5]; (iii) antiretroviral (ARV) drug penetration (particularly protease inhibitors) into tissue sites of viral persistence is very heterogeneous with limited combined exposure to all infected cells, potentially allowing for environments where low level, intermittent viral replication can occur [6,7 ▪ ]; and (iv) BCFs represent relative immune sanctuaries that are not highly accessible to HIV-1/SIV-specific cytotoxic CD8 + T cells (CTLs), thereby allowing viral reservoirs that reside in these microenvironments to escape CTL elimination [8]. Although of interest to the field, non-LT viral reservoirs fall outside the scope of this review, primarily because the mechanisms controlling reservoir establishment, persistence, and clearance have aspects that are unique to each tissue site.…”

HIV persistence in lymph nodes

“…Accumulating pharmacokinetic evidence of commonly used antiretrovirals has showed that the LN concentrations of some drugs were much lower compared to the concentrations achieved in blood [ [43][44][45], raising the possibility of viral production and low-level viral replication to contribute to HIV persistence in LNs [43,46,47]. To address the contribution of ongoing viral replication to HIV persistence in LNs, multiple studies assessed the attributes of genetic evolution in proviral DNA sequences isolated from LN CD4 T cells compared to ancestral viruses obtained from pretherapy plasma, the presence of which would reflect cycles of error-prone reverse transcription, production and replication [46,48,49].…”

“…Furthermore, a study based on mathematical modeling also proposed the possibility that ongoing replication might be - at least in part –fuelled by cell-to-cell spread of infections transmitting virion numbers much in excess of what is required to infect a cell in the absence of or at low drug concentrations within LNs [49]. Taken together, whether or not viral production and low-level replication occur needs to be further investigated [44].…”