Abstract
Human immunodeficiency virus (HIV-1) indefinitely persists, despite effective antiretroviral therapy (ART), within a small pool of latently infected cells. These cells often display markers of immunologic memory and harbor both replication-competent and -incompetent proviruses at approximately a 1:100 ratio. Although complete HIV eradication is a highly desirable goal, this likely represents a bridge too far for our current and foreseeable technologies. A more tractable goal involves engineering a sustained viral remission in the absence of ART––a “functional cure.” In this setting, HIV remains detectable during remission, but the size of the reservoir is small and the residual virus is effectively controlled by an engineered immune response or other intervention. Biological precedence for such an approach is found in the post-treatment controllers (PTCs), a rare group of HIV-infected individuals who, following ART withdrawal, do not experience viral rebound. PTCs are characterized by a small reservoir, greatly reduced inflammation, and the presence of a poorly understood immune response that limits viral rebound. Our goal is to devise a safe and effective means for replicating durable post-treatment control on a global scale. This requires devising methods to reduce the size of the reservoir and to control replication of this residual virus. In the following sections, we will review many of the approaches and tools that likely will be important for implementing such a “reduce and control” strategy and for achieving a PTC-like sustained HIV remission in the absence of ART.
Highlights
The history of human immunodeficiency virus (HIV-1)/acquired immunodeficiency syndrome (AIDS) is a story of initial fear and panic followed by rapid, frankly stunning, scientific and medical progress [1]
In rhesus macaques infected with simian immunodeficiency virus (SIV) and in HIV-infected individuals, both on antiretroviral therapy (ART), the administration of the TLR7 agonists GS-986 and GS-9620 led to significant increases in plasma SIV
Since initial attempts to attack the reservoir using “shock and kill” began nearly ten years ago [71], this approach has proved disappointing for a number of reasons: (1) the initial latency-reversing agents (LRAs) tested either lacked potency or exhibited unacceptably high levels of toxicity both in vitro and in vivo [115,116]; (2) after a single dose, the tested LRAs only reactivate a small fraction of cells within the latent reservoir [70,117], indicating that serial administration of the agent will be required, placing toxicity issues front and center; (3) HIV can establish viral reservoirs in the central nervous system (CNS) [118], where certain
Summary
The history of human immunodeficiency virus (HIV-1)/acquired immunodeficiency syndrome (AIDS) is a story of initial fear and panic followed by rapid, frankly stunning, scientific and medical progress [1]. Its etiologic linkage to the acquired immunodeficiency syndrome (AIDS) [3,4,5], this virus has been extensively dissected, its pathogenic mechanisms defined, and the host’s defensive immune responses well characterized. This deep understanding of the virus accelerated development of antiretroviral therapy (ART) principally targeting the major enzymes of the virus. With access to and compliance with these drugs, viremia in essentially every HIV-infected individual can be suppressed to undetectable levels These therapeutic advances will be recorded as a true milestone in the history of modern medicine. Africa bring a close to its long struggle against HIV/AIDS
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