Spatial technologies to evaluate the HIV-1 reservoir and its microenvironment in the lymph node

Abstract

The presence of the HIV-1 reservoir, a group of immune cells that contain intact, integrated, and replication-competent proviruses, is a major challenge to cure HIV-1. HIV-1 reservoir cells are largely unaffected by the cytopathic effects of viruses, antiviral immune responses, or antiretroviral therapy (ART). The HIV-1 reservoir is seeded early during HIV-1 infection and augmented during active viral replication. CD4+ T cells are the primary target for HIV-1 infection, and recent studies suggest that memory T follicular helper cells within the lymph node, more precisely in the B cell follicle, harbor integrated provirus, which contribute to viral rebound upon ART discontinuation. The B cell follicle, more specifically the germinal center, possesses a unique environment because of its distinct property of being partly immune privileged, potentially allowing HIV-1-infected cells within the lymph nodes to be protected from CD8+ T cells. This modified immune response in the germinal center of the follicle is potentially explained by the exclusion of CD8+ T cells and the presence of T regulatory cells at the junction of the follicle and extrafollicular region. The proviral makeup of HIV-1-infected cells is similar in lymph nodes and blood, suggesting trafficking between these compartments. Little is known about the cell-to-cell interactions, microenvironment of HIV-1-infected cells in the follicle, and trafficking between the lymph node follicle and other body compartments. Applying a spatiotemporal approach that integrates genomics, transcriptomics, and proteomics to investigate the HIV-1 reservoir and its neighboring cells in the lymph node has promising potential for informing HIV-1 cure efforts.

Keywords: HIV-1; HIV-1 reservoir; human immunodeficiency virus; lymph node; spatial technologies; tfh.

Fig 1

Potential mechanism of HIV-1 reservoir persistence and rebound in the lymph node. Schematic diagram of a lymph node illustrates HIV-1-infected Tfh cells and the cellular microenvironment inside the lymph node that supports establishing and maintaining the HIV-1 reservoir. Abbreviations: Tfh, T follicular helper cell; HEV, high endothelial venule; CTL, cytotoxic T lymphocyte; FDC, follicular dendritic cell. (A). Shown is a normal anatomy of the lymph node. (B) Infected CD4+ T cells and infected dendritic cells trafficking to the lymph nodes through afferent lymphatic or HEV. (C) Uninfected Tfh cells can get infected in the follicle via FDC or outside the follicle via dendritic cells. (D) Potentially, the infected CD4+ T cell can recirculate from the follicles to the body via efferent lymphatics or draining blood vessels. Created with BioRender.com.