Revealing HIV Hiding Places: Identification and Characterization of Cellular and Tissue ReservoirsSubmit Manuscript on this topic
Human immunodeficiency virus (HIV) establishes a persistent infection, resulting in acquired immunodeficiency syndrome (AIDS) if left untreated. Around 37 million people in the world live with HIV with a global HIV prevalence of 0.8% among adults. Combination antiretroviral therapy (ART) has saved millions of lives, as it suppresses HIV-1 replication, blocks transmission, and improves immune responses, preventing the development of AIDS. However, ART has to be taken lifelong, is prone to side-effects, and is unable to eradicate the virus. On top of that, 40% of HIV-infected people in the world still do not have access to ART. Therefore, HIV cure research has flourished in recent years, inspired by an apparent cure in a single individual.
By establishing latent infection, HIV forms long-lived reservoirs in infected individuals that persist despite decades of suppressive ART and are considered the main obstacle to an HIV cure. Studies of viral reservoirs are thus central to HIV cure research. A viral reservoir in an infected individual is usually defined as a particular cell type that supports long-term persistence of replication-competent proviruses (viral genomes that are integrated into host chromosomes and capable of reigniting viral spread when ART is stopped), although defective proviruses can also have an impact on immune activation and contribute to HIV pathogenesis. The frequency of HIV reservoir cells in long-term ART-treated individuals is estimated as 1/100.000 - 1/1.000.000 of peripheral blood CD4+ lymphocytes, although it might be somewhat higher in tissues and varies significantly between individuals. However, stopping ART almost inevitably leads to fast viral rebound, indicating that eradicating or at least significantly depleting the reservoirs will be necessary to achieve an HIV cure or long-term ART-free remission.
A major focus in HIV cure research has recently been on the reactivation of HIV reservoirs with the hope of their subsequent elimination by viral cytopathic effects and/or host immunity (the “shock-and-kill” approach). However, this approach has so far demonstrated limited success in clinical trials, mainly attributed to insufficient basic understanding of the reservoir biology, which prevents the development of efficient therapeutic strategies for eradication of the reservoirs. Therefore, we need to accumulate much more knowledge about the reservoirs, before we can design a meaningful therapeutic intervention. Likewise, despite the challenges presented by the extreme paucity of the reservoir cells, accurate measurement of the viral reservoirs is necessary for monitoring the effectiveness of interventions aimed at HIV remission or cure. Unfortunately, while significant progress has been made in our understanding of HIV biology and pathogenesis, cellular composition and tissue/organ localization of the viral reservoirs, as well as the mechanism(s) of reservoir maintenance (cellular proliferation, residual virus replication), remain largely ill-defined. Resting memory CD4+ T cells in peripheral blood and lymphoid tissues is the most studied HIV reservoir, but numerous studies have indicated the heterogeneity of CD4 T cells and the existence of reservoirs in other cell and tissue types. Furthermore, it has even been challenging to precisely measure the reservoirs, as all existing methods either over- or underestimate its size.
In this Research Topic, we seek Reviews, Mini-Reviews, and Original Research articles that discuss the latest developments in identification, characterization, and measurement of cellular and tissue HIV reservoirs. We will be especially welcoming articles that discuss parallels (and differences) between blood and tissue reservoirs. We also welcome articles reporting on the mechanisms of HIV persistence in blood and tissues, as well as reports on novel markers of HIV reservoirs.