The multifaceted nature of HIV tissue reservoirs

Abstract

Purpose of review: To underline the complexity and the heterogeneity of the HIV reservoir.

Recent findings: While lymphoid tissues (spleen, lymph nodes, gut-associated lymphoid tissue) harbor specific subsets of specialized CD4 + T cells enriched in HIV-infected cells, non-CD4 + T cell reservoirs such as tissue-resident macrophages and dendritic cells have also been implicated to contribute to viral persistence. Moreover, studies have applied highly sensitive tools to detect transcriptional activity within HIV-infected cells during prolonged ART and revealed a broader spectrum of transcriptional activity for proviruses than previously thought. Finally, while a combination of factors might be involved in the regulation of HIV persistence within different tissues and remains to be fully elucidated, recent results from autopsy samples of HIV-infected ART suppressed individuals indicate extensive clonality of HIV reservoirs in multiple tissues and suggest that the recirculation of HIV-infected cells and their local expansions in tissues may also contribute to the complexity of the HIV reservoirs in humans.

Summary: HIV persistence in blood and multiple tissues despite long-standing and potent therapy is one of the major barriers to a cure. Given that the HIV reservoir is established early and is highly complex based on its composition, viral diversity, tissue distribution, transcriptional activity, replication competence, migration dynamics and proliferative potential across the human body and possible compartmentalization in specific tissues, combinatorial therapeutic approaches are needed that may synergize to target multiple viral reservoirs to achieve a cure for HIV infection.

Box 1

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FIGURE 1

Schematic representation of potential HIV tissue reservoirs in the body: The figure represents the complexity of the HIV reservoir in terms of its cellular composition, broad anatomical distribution and transcriptional status during ART. Major HIV reservoirs depicted include: blood, lymphoid tissues, i.e. spleen, lymph nodes, gut-associated lymphoid tissues (GALT), bone marrow, lungs, genitourinary systems and central nervous system (CNS). Proposed cellular reservoirs within blood and tissues are depicted. Cell types are color-coded; HIV-infected cells are depicted harboring integrated HIV DNA; transcriptionally active HIV-infected cells are shown with dashed red lines. ‘cTfh’ refers to circulating T follicular helper cells; ‘GI’ refers to gastrointestinal tract. ‘M’ refers to male genitourinary system and ‘F’ refers to female genital tract.