Friday, February 12, 2016

Latent Reservoirs: The Achilles Heel of AIDS Research?

cd4_hiv_infected.jpg - Photo © National Institute of Allergies and Infectious Diseases (NIAID)
HIV-1 infected CD4+ T-cell.  Photo © National Institute of Allergies and Infectious Diseases (NIAID)
Written or medically reviewed by a board-certified physician. See'sMedical Review Policy.
Updated August 24, 2015.
Latent reservoirs are the cells of the body where HIV is able to hide (or "persist") even in the face of optimalantiretroviral therapy (ART). These cellular reservoirs are located throughout the body, including the brain, lymphoid tissue, bone marrow and genital tract.
Viral latency is defined as the ability of a virus like HIV to lie dormant within a cell. In this so-called "proviral" state, HIV is able to integrate its viral genome (genetic code) into that of the host cell DNA.
In doing so, the viral genome is effectively carried along from generation to generation as the host cell replicates, largely shielded from immune detection.
In exploring potential strategies for HIV eradication ("the cure"), researchers have been focusing on achieving one or both of the following goals:
  • **Purging HIV from their latent reservoirs, thereby exposing them to any number of potential neutralizing agents (a strategy popularly known as "kick-kill").
  • **Preventing the establishment of these reservoirs in the first place.
Can Latent Reservoirs Be Prevented With Early ART?
One of the more recent theories suggests that early ART intervention, ideally soon after infection occurs during or before the so-called "acute conversation stage," may prevent the establishment of these hidden viral reservoirs.
The theory was largely supported by the Mississippi baby case, in which a newborn provided ART within hours of birth was believed to have been "cleared" of virus. In that same year, a number of patients in a French cohort study, provided ART during acute conversation, later stopped treatment and appeared to be able to control the virus without treatment.
While the results seemed promising, the Mississippi baby was reported to have experienced viral rebound within a year, suggesting not only that the establishment of latent reservoirs occur very quickly, but that it takes very little proviral HIV—certainly beyond the scope of current detection tools—to do so.
While this doesn't necessarily negate the call for early ART, some are suggesting that other factors, primarily genetic, may better explain the so-called "long-term non-progressors" identified in the French cohort.
How Close Are We to Achieving "Kick-Kill"
Since as far back as the early 2000s, scientists have been exploring the use of certain agents to "flush out" HIV from their latent reservoirs. Much of the focus has been placed on a class of drugs called histone deacetylase (HDAC) inhibitors, many of which have proven in in vitro studies to reactivate HIV within latent cells.
By July 2014, a Danish team from Aarhus University Hospital reported that the HDAC inhibitor, romidespin (Istodax), was able to flush HIV out of six patients, all of whom had been on ART for an average of three years—the first type of result achieved in humans.
While the pilot trial lent further credence to the "kick-kill" approach, a number of subsequent studies have raise doubts as to whether the effect is ample enough to effect complete clearance of these reservoirs. The Danish researchers themselves reported that, while HIV reactivation occurred, the size of the reservoirs was not actually reduced.
John Hopkins researchers similarly suggested that the size of the reservoirs may, in fact, be 60 times larger than imagined—making the eradication strategy all the more difficult to achieve.
Some of the latest research also demonstrates that HDAC inhibitors may negatively impact the "kill" portion of the "kick-kill" strategy.
In August 2014, scientists from the Ragon Institute of Massachusetts General Hospital investigated whether the use of three different HDAC inhibitors (romidepsin, panobinostat, SAHA) had any impact on defensive white blood cells called cytotoxic T-lymphocytes (or "killer T-cells"), considered central to the two-pronged eradication strategy.
In cell cultures test, the three HDAC drugs were seen to not only impair the ability of these T-cells to kill HIV-infected target cells, but that they rapidly suppressed the production ofinterferon gamma, necessary for the activation, growth and differentiation of defensive T-cells.
While the findings are limited by the cell culture setting, they do highlight the barriers still ahead, some formidable, if a "kick-kill" strategy is to be at all achievable.
The HIV/AIDS Channel of is pleased to have been named one the "Best HIV/STD Health Blogs" of 2015 by the editors of San Francisco-based Healthline.
National Institute of Allergy and Infectious Diseases (NIAID). "'Mississippi Baby' now has detectable HIV, researchers find." ScienceDaily.  July 10, 2014.
Regoes, R.; McLaren, P.; Battegay, M.; et al. "Disentangling Human Tolerance and Resistance Against HIV."PLoS|Biology. September 16, 2014; 12(9): e1001951.
Søgaard, O.; Graverson, M.; Leth, S.; et al. "The HDAC inhibitor romidepsin is safe and effectively reverses HIV-1 latency in vivo as measured by standard clinical assays. " 20th International AIDS Conference; July 22, 2014; Melbourne, Australia; abstract TUAA0106LB.
Ho, Y.; Shan, L.; Hosmane, N.; et al. "Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure." The Cell. October 23, 2013. 155(3):540-551.
Jones, R.; O'Connor, R.; Mueller, S.; et al. "Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes." PLoS Pathogens. August 14, 2014; 10 (8): e1004287 DOI: 10.1371/journal.ppat.1004287.

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