Download Media Release

Kicking latent HIV:
new strategies to reactivate reservoirs of latent infection
EMBARGO: July 30, 2015, 11am Pacific / 2pm Eastern
In cells with latent HIV infection, the virus is dormant, and such cells are therefore not
attacked by the immune system or by standard antiretroviral therapy. To eradicate the
virus from the human body and truly cure a patient, reservoirs of latently infected cells
need to be activated and eliminated—the so-called “kick-and-kill” approach. Two studies
published on July 30th in PLOS Pathogens report encouraging results on the use of a
combination of several drugs to efficiently reactivate HIV in cells with latent infection.
Please see the Authors’ Summaries below for details.
Please contact [email protected] if you would like more information.
Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate,
PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb
Activation
Summary from Satya Dandekar and colleagues, from the University of California at Davis,
USA:
Stable latent viral reservoirs in HIV infected individuals are rapidly reactivated following
the interruption of anti-retroviral therapy (ART). Despite an early initiation of ART, viral
reservoirs are established and persist as demonstrated in the case of the Mississippi baby
and from recent studies of the SIV model of AIDS. Therefore, new strategies are needed
for the eradication of the latent HIV reservoirs. We found that ingenol-3-angelate
(PEP005), a member of the new class of anti-cancer ingenol compounds, effectively
reactivated HIV from latency in primary CD4+ T cells from HIV infected individuals
receiving ART. Importantly, a combination of PEP005 and JQ1, a p-TEFb agonist,
reactivated HIV from latency at level on average 7.5-fold higher compared to PEP005
alone. The potency of synergistic effects of PEP005 and JQ1 provide novel opportunities for
advancing HIV eradication strategies in the future. In summary, ingenols represent a new
group of lead compounds for combating HIV latency.
Contact:
Satya Dandekar
e-mail: [email protected]
Please use this URL to provide readers access to the paper (Link goes live upon article
publication):
http://dx.plos.org/10.1371/journal.ppat.1005066
Press-Only Preview Of The Article:
https://www.plos.org/wp-content/uploads/2013/05/Pathogens_Dandekar_JUL_30.pdf
Funding: This study is supported by NIH grants DK61297 and AI43274 to SD and by a post-doctoral fellowship
from CAPES/Brazil (BEX 2951/12-6) to EAM. PK was supported by the Swiss National Science Foundation
(PBZHP3_147260). The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
Citation: Jiang G, Mendes EA, Kaiser P, Wong DP, Tang Y, Cai I, et al. (2015) Synergistic Reactivation of Latent
HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced pTEFb Activation. PLoS Pathog 11(7): e1005066. doi:10.1371/journal.ppat.1005066
An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In
Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and IngenolB+JQ1 to Potently Reactivate Viral Gene Expression
Summary from Carine Van Lint, from the Free University of Brussels, Belgium, and
colleagues:
Persistence of latently infected cells during cART is a major hurdle for HIV-1 eradication. A
widely proposed strategy to purge these reservoirs involves the reactivation of latent
proviruses. The low levels of active P-TEFb and the cytoplasmic sequestration of NF-κB in
resting infected cells largely contribute to maintenance of HIV-1 latency. Therefore,
utilization of chemical compounds that target both pathways may lead to more potent
effects on HIV-1 reactivation than the effect mediated by the individual drug treatments.
In this study, we showed that combined treatments of PKC agonists (prostratin,
bryostatin-1 and ing-B) with compounds releasing P-TEFb (JQ1, I-BET, I-BET151 and
HMBA) exhibited a synergistic increase in viral reactivation from latency. In-depth
comparison of combined treatments in various in vitro cellular models of HIV-1 latency as
well as in ex vivo primary cell cultures from cART-treated HIV+ aviremic patients identified
bryostatin-1+JQ1 and ing-B+JQ1 to potently reactivate latent HIV-1. The potent effects of
these two combinations were detected as early as 24 hours post-treatment. Importantly,
bryostatin-1 was used at concentrations below the drug plasma levels achieved by doses
used in children with refractory solid tumors. Our mechanistic data established a
correlation between potentiated P-TEFb activation and potentiated or synergistic
(depending on the HIV-1 latency cellular model used) induction of HIV-1 gene expression
observed after the combined versus individual drug treatments. In conclusion, our results
establish a proof-of-concept for PKC agonists combined with compounds releasing active PTEFb as a strategy proposed for a cure or a durable remission of HIV infection.
Contact:
Carine Van Lint
e-mail: [email protected]
Please use this URL to provide readers access to the paper (Link goes live upon article
publication):
http://dx.plos.org/10.1371/journal.ppat.1005063
Press-Only Preview Of The Article:
https://www.plos.org/wp-content/uploads/2013/05/Pathogens_VanLint_JUL_30.pdf
Citation: Darcis G, Kula A, Bouchat S, Fujinaga K, Corazza F, Ait-Ammar A, et al. (2015) An In-Depth
Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models
Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression. PLoS Pathog
11(7): e1005063. doi:10.1371/journal.ppat.1005063
Funding: We acknowledge grant support from the “Agence Nationale de Recherches sur le SIDA” (ANRS,
France), the Belgian Fund for Scientific Research (FRS-FNRS, Belgium), the “Fondation Roi Baudouin”, the NEAT
program, the Walloon Region (the Excellence Program “Cibles”) and the “Institut Universitaire de France (IUF)”
(to OR). AK is a fellow of "Les Amis des Instituts Pasteur à Bruxelles, asbl". SB is a fellow of the Belgian « Fonds
pour la Recherche dans l’Industrie et l’Agriculture (FRIA) ». GD and CVL are Aspirant fellow and Research
Director of the FRS-FNRS, respectively. The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
About PLOS Pathogens
PLOS Pathogens is a peer-reviewed, open-access science journal that advances the understanding of bacteria,
fungi, parasites, prions, and viruses, and how these pathogens interact with their host organisms. For more
information, visit http://www.plospathogens.org and follow @PLOSPathogens on Twitter.
About the Public Library of Science
PLOS is a nonprofit publisher and advocacy organization founded to accelerate progress in science and medicine
by leading a transformation in research communication.