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Eliminating the latent HIV reservoir by reactivation strategies: advancing to clinical trials.

ABSTRACT: Combination antiretroviral therapy (cART) has transformed HIV from a deadly to a chronic disease, but HIV patients are still burdened with excess morbidity and mortality, long-term toxicities from cART, stigmatization, and insufficient access to cART worldwide. Thus, a cure for HIV would have enormous impact on society as well as the individual. As the complexity and mechanisms of HIV persistence during therapy are being unraveled, new therapeutic targets for HIV eradication are discovered. Substances that activate HIV production in the latently infected cells have recently received much attention. By turning on expression of latent HIV proviruses, reactivation strategies could contribute to the eradication HIV infection. Compounds that are currently being or soon to be tested in clinical trials are emphasized. The results from these trials will provide important clues as to whether or not reactivating strategies could become significant components of a cure for HIV.

SUBMITTER: Rasmussen TA

PROVIDER: S-EPMC3903897 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Eliminating the latent HIV reservoir by reactivation strategies: advancing to clinical trials.

Rasmussen Thomas A TA Tolstrup Martin M Winckelmann Anni A Østergaard Lars L Søgaard Ole S OS

Human vaccines & immunotherapeutics 20130401 4

Combination antiretroviral therapy (cART) has transformed HIV from a deadly to a chronic disease, but HIV patients are still burdened with excess morbidity and mortality, long-term toxicities from cART, stigmatization, and insufficient access to cART worldwide. Thus, a cure for HIV would have enormous impact on society as well as the individual. As the complexity and mechanisms of HIV persistence during therapy are being unraveled, new therapeutic targets for HIV eradication are discovered. Subs ...[more]

PMID: 23563519

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Project description:Upon HIV-1 infection, a reservoir of latently infected resting T cells prevents the eradication of the virus from patients. To achieve complete depletion, the existing virus-suppressing antiretroviral therapy must be combined with drugs that reactivate the dormant viruses. We previously described a novel chemical scaffold compound, MMQO (8-methoxy-6-methylquinolin-4-ol), that is able to reactivate viral transcription in several models of HIV latency, including J-Lat cells, through an unknown mechanism. MMQO potentiates the activity of known latency-reversing agents (LRAs) or "shock" drugs, such as protein kinase C (PKC) agonists or histone deacetylase (HDAC) inhibitors. Here, we demonstrate that MMQO activates HIV-1 independently of the Tat transactivator. Gene expression microarrays in Jurkat cells indicated that MMQO treatment results in robust immunosuppression, diminishes expression of c-Myc, and causes the dysregulation of acetylation-sensitive genes. These hallmarks indicated that MMQO mimics acetylated lysines of core histones and might function as a bromodomain and extraterminal domain protein family inhibitor (BETi). MMQO functionally mimics the effects of JQ1, a well-known BETi. We confirmed that MMQO interacts with the BET family protein BRD4. Utilizing MMQO and JQ1, we demonstrate how the inhibition of BRD4 targets a subset of latently integrated barcoded proviruses distinct from those targeted by HDAC inhibitors or PKC pathway agonists. Thus, the quinoline-based compound MMQO represents a new class of BET bromodomain inhibitors that, due to its minimalistic structure, holds promise for further optimization for increased affinity and specificity for distinct bromodomain family members and could potentially be of use against a variety of diseases, including HIV infection.IMPORTANCE The suggested "shock and kill" therapy aims to eradicate the latent functional proportion of HIV-1 proviruses in a patient. However, to this day, clinical studies investigating the "shocking" element of this strategy have proven it to be considerably more difficult than anticipated. While the proportion of intracellular viral RNA production and general plasma viral load have been shown to increase upon a shock regimen, the global viral reservoir remains unaffected, highlighting both the inefficiency of the treatments used and the gap in our understanding of viral reactivation in vivo Utilizing a new BRD4 inhibitor and barcoded HIV-1 minigenomes, we demonstrate that PKC pathway activators and HDAC and bromodomain inhibitors all target different subsets of proviral integration. Considering the fundamental differences of these compounds and the synergies displayed between them, we propose that the field should concentrate on investigating the development of combinatory shock cocktail therapies for improved reservoir reactivation.

Dataset Information

Eliminating the latent HIV reservoir by reactivation strategies: advancing to clinical trials.

Publications

Eliminating the latent HIV reservoir by reactivation strategies: advancing to clinical trials.

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