Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design (original) (raw)
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The Journal of infectious diseases, 2017
Quiescent proviral genomes that persist during human immunodeficiency virus type 1 (HIV-1) infection despite effective antiretroviral therapy (ART) can fuel rebound viremia after ART interruption and is a central obstacle to the cure of HIV infection. The induction of quiescent provirus is the goal of a new class of potential therapeutics, latency reversing agents (LRAs). The discovery, development, and testing of HIV LRAs is a key part of current efforts to develop latency reversal and viral clearance strategies to eradicate established HIV infection. The development of LRAs is burdened by many uncertainties that make drug discovery difficult. The biology of HIV latency is complex and incompletely understood. Potential targets for LRAs are host factors, and the potential toxicities of host-directed therapies in individuals that are otherwise clinically stable may be unacceptable. Assays to measure latency reversal and assess the effectiveness of potential therapeutics are complex a...
The Current Status of Latency Reversing Agents for HIV-1 Remission
Annual Review of Virology
Combinatory antiretroviral therapy (cART) reduces human immunodeficiency virus type 1 (HIV-1) replication but is not curative because cART interruption almost invariably leads to a rapid rebound of viremia due to the persistence of stable HIV-1-infected cellular reservoirs. These reservoirs are mainly composed of CD4+ T cells harboring replication-competent latent proviruses. A broadly explored approach to reduce the HIV-1 reservoir size, the shock and kill strategy, consists of reactivating HIV-1 gene expression from the latently infected cellular reservoirs (the shock), followed by killing of the virus-producing infected cells (the kill). Based on improved understanding of the multiple molecular mechanisms controlling HIV-1 latency, distinct classes of latency reversing agents (LRAs) have been studied for their efficiency to reactivate viral gene expression in in vitro and ex vivo cell models. Here, we provide an up-to-date review of these different mechanistic classes of LRAs and...
Latency reversal and viral clearance to cure HIV-1
Science (New York, N.Y.), 2016
Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication--a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society.
HIV latency: present knowledge and future directions
Future Virology, 2006
Current therapies do not eradicate HIV from infected patients. Indeed, HIV hides in a latent form insensitive to these therapies. Thus, one priority is to purge these latent reservoirs. But what mechanisms are responsible for latency and what are the reservoirs of latently infected cells? The present knowledge in terms of HIV latency is still incomplete and current therapeutic strategies fail to eradicate completely latently infected cells. What could the future bring?
Human immunodeficiency virus (HIV) latency: the major hurdle in HIV eradication
Molecular medicine (Cambridge, Mass.), 2012
Failure of highly active antiretroviral therapy to eradicate the human immunodeficiency virus (HIV), even in patients who suppress the virus to undetectable levels for many years, underscores the problems associated with fighting this infection. The existence of persistent infection in certain cellular and anatomical reservoirs appears to be the major hurdle in HIV eradication. The development of therapeutic interventions that eliminate or limit the latent viral pools or prevent the reemergence of the viruses from producing cells will therefore be required to enhance the effectiveness of current antiretroviral strategies. To achieve this goal, there is a pressing need to understand HIV latency at the molecular level to design novel and improved therapies to either eradicate HIV or find a functional cure in which patients could maintain a manageable viral pool without AIDS in the absence of antiretroviral therapy. The integrated proviral genome remains transcriptionally silent for a ...
Elimination of HIV-1-Infected Primary T Cell Reservoirs in an In Vitro Model of Latency
PLOS ONE, 2015
Establishment of long-lived cellular reservoirs of HIV-1 represents a major therapeutic challenge to virus eradication. In this study, we utilized a human primary cell model of HIV-1 latency to evaluate the requirements for efficient virus reactivation from, and the selective elimination of, latently infected human T cells. Ectopic expression of BCL2 supported the replication and spread of R5-tropic HIV-1 in activated CD4 + T cells. After IL-2 withdrawal, the HIV-1-infected T cells survived as resting cells for several months. Unexpectedly, these resting T cells continue to produce detectable levels of infectious virus, albeit at a lower frequency than cells maintained in IL-2. In the presence of HIV-1 inhibitors, reactivation of the resting T cells with γc-cytokines and allogeneic dendritic cells completely extinguished HIV-1 infectivity. We also evaluated the ability of the bacterial LukED cytotoxin to target and kill CCR5-expressing cells. After γc-cytokine stimulation, LukED treatment eliminated both HIV-1-infected resting cells and the non-infected CCR5 + cells. Importantly, complete clearance of in vitro HIV-1 reservoirs by LukED required a lower threshold of cytokine signals relative to HIV-1 inhibitors. Thus, the primary T cell-based HIV-1 latency model could facilitate the development of novel agents and therapeutic strategies that could effectively eradicate HIV-1.
Current views on HIV-1 latency, persistence, and cure
Folia Microbiologica, 2016
HIV-1 infection cannot be cured as it persists in latently infected cells that are targeted neither by the immune system nor by available therapeutic approaches. Consequently, a lifelong therapy suppressing only the actively replicating virus is necessary. The latent reservoir has been defined and characterized in various experimental models and in human patients, allowing research and development of approaches targeting individual steps critical for HIV-1 latency establishment, maintenance, and reactivation. However, additional mechanisms and processes driving the remaining low-level HIV-1 replication in the presence of the suppressive therapy still remain to be identified and targeted. Current approaches toward HIV-1 cure involve namely attempts to reactivate and purge HIV latently infected cells (so-called Bshock and kill^strategy), as well as approaches involving gene therapy and/or gene editing and stem cell transplantation aiming at generation of cells resistant to HIV-1. This review summarizes current views and concepts underlying different approaches aiming at functional or sterilizing cure of HIV-1 infection.
Modeling the timing of antilatency drug administration during HIV treatment
Journal of virology, 2014
Latently infected cells are considered a major barrier to the cure of HIV infection, since they are long-lived under antiretroviral therapy (ART) and cause viral replication to restart soon after stopping ART. In the last decade, different types of antilatency drugs have been explored with the aim of reactivating and purging this latent reservoir and the hope of achieving a cure. Because of toxicity and safety considerations, antilatency drugs can only be given for a short time to patients on long-term ART, with little effect. We recently investigated the turnover of latently infected cells during active infection and have found that it was strongly correlated with viral load. This implies that although latently infected cells had long life spans in a setting of a low viral load (such as during ART), they turned over quickly under a high viral load. Possible reasons for this could be that an increased viral load causes increased activation or death of CD4(+) T cells, including those...
HIV Latency: Should We Shock or Lock?
Trends in Immunology, 2017
Combinatory antiretroviral therapy (cART) increases the survival and quality of life of HIV-1-infected patients. However, interruption of therapy almost invariably leads to the re-emergence of detectable viral replication because HIV-1 persists in viral latent reservoirs. Improved understanding of the molecular mechanisms involved in HIV-1 latency has paved the way for innovative strategies that attempt to purge latent virus. In this article we discuss the results of the broadly explored 'shock and kill' strategy, and also highlight the major hurdles facing this approach. Finally, we present recent innovative works suggesting that locking out latent proviruses could be a potential alternative therapeutic strategy. HIV-1 [ 6 _ T D $ D I F F ] As a Chronic Infection The advent of improved cART allows clinicians to successfully manage HIV-infected patients and to decrease side effects. However, cART is not curative, and a new set of HIV-associated complications have emerged, resulting in a chronic disease that for many will span several decades of life.