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Studies Explore Viral Reactivation Strategies for Potential HIV Cure

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Compounds that increase random fluctuations or "noise" in HIV gene expression can help trigger reactivation of latent HIV in immune cells, one of the key barriers to a cure, researchers reported in the June 20 edition of Science. A related study identified another type of agent -- Ingenol B, derived from an Amazonian plant -- that reactivates latent HIV reservoirs, but another study found that one type of latency releaser may facilitate infection of CD4 cells.

Like other retroviruses, HIV is able to integrate its genetic material into host cell chromosomes and use the cell's machinery to reproduce. Early in the course of infection, HIV establishes reservoirs of latent viral genetic material in CD4 T-cells. This silent HIV DNA -- which is not visible to the immune system or susceptible to antiretroviral drugs -- can begin producing infectious virus when the cell is reactivated, making the virus difficult to eradicate.

One of the many approaches being explored as a cure for HIV involves a "shock and kill" strategy that reactivates this latent viral DNA, making the virus reveal itself so it can be targeted by antiretroviral therapy (ART). Several agents have been identified that reactivate latent HIV, including histone deacetylase inhibitors (HDACs), but researchers continue to look for stronger and more specific releasing agents with less toxicity.

Noise Enhancers

Roy Dar and Leor Weinberger from the Gladstone Institutes and colleagues screened a library of 1600 bioactive small molecules in a specialized cell line, identifying more than 80 compounds that modulate HIV gene-expression fluctuations -- or increase noise -- without changing the overall mean level of expression.

They found that noise-enhancing compounds, working synergistically with conventional transcription activators, reactivated HIV in latent cells significantly better than existing reactivation drug combinations, but with less "off-target" cell toxicity. The greater the noise, the greater the effect on reactivation, they reported. In contrast, noise-suppressing compounds helped stabilize viral latency.

"Understanding how to reactivate latent HIV is one of the major challenges we must overcome in order to find a cure for HIV," senior author Weinberger said in a Gladstone Institutes press release.

"If we can make the virus show itself, we can then use antiretrovirals to eliminate it," added lead author Dar. "This so-called 'shock and kill' approach holds great promise, but to date it has unfortunately shown only limited success."

"Strategies to reverse HIV latency will likely require multiple rounds of treatment, and these new results suggest that noise-enhancing compounds may allow each round of treatment to be more effective at getting HIV to reveal itself, according to the release.

"The implications for using noise also extend far beyond HIV reactivation, since random cellular activity contributes to a wide range of processes, from antibiotic persistence to cancer metastasis," Weinberger suggested. "Thus, this approach could represent a new tool for drug discovery across multiple fields."

Ingenol B

In a related study published in the July 17 edition of AIDS, Guochun Jiang from the University of California at Davis and colleagues evaluated whether Ingenol B (IngB), a derivative of Ingenol ester isolated from a Brazilian plant, could activate HIV from latent reservoirs.

The researchers tested IngB in a cell culture model of HIV latency and in purified primary CD4 cells from individuals with long-term viral suppression on ART.

They found that IngB was highly effective in reactivating HIV in the cell culture model, with relatively low cellular toxicity. IngB also reactivated latent HIV in CD4 cells from patients. IngB appeared to work both by activating the protein kinase C delta and nuclear factor kappa-B (NF-kB) pathway, and by directly inducing NF-kB protein expression.

"IngB is a new promising compound to activate latent HIV reservoirs," the study authors concluded. "Our data suggest that formulating novel derivatives from Ingenol esters may be an innovative approach to develop new lead compounds to reactivate latent HIV."

Vorinostat Ups Susceptibility

A third study provided a cautionary note, however, showing that the HDAC inhibitor vorinostat may increases the susceptibility of CD4 cells to HIV infection.

Vorinostat (also known SAHA or brand name Zolinza), which is used to treat lymphoma, has been tested as a reactivating agent in people with HIV. Small studies have shown that vorinostat does activate transcription of latent HIV, but so far it has not demonstrated a reduction in the size of the viral reservoir.

In a new study published in the July 9 advance edition of the Journal of Virology, Mark Luceraof Case Western Reserve University and colleagues demonstrated that vorinostat significantly increases the susceptibility of CD4 cells to HIV infection in a dose- and time-dependent manner that is independent of receptor and co-receptor (CCR5 or CXCR4) usage. They found that a class II HDAC inhibitor had a similar effect -- vorinostat is both a class I and II inhibitor -- and suggested that inhibitors that selectively target class I HDACs might reactivate latent HIV without increasing the susceptibility of uninfected cells.

"Vorinostat does not enhance viral fusion with cells, but rather enhances the kinetics and efficiency of post-entry viral events including reverse transcription, nuclear import, and integration and enhances viral production in a spreading infection assay," the authors wrote. "These findings reveal a previously unknown cytoplasmic effect of HDAC inhibitors promoting productive infection of CD4+ T cells that is distinct from their well-characterized effects on nuclear histone acetylation and LTR transcription."

"We demonstrate here that vorinostat increases the susceptibility of uninfected CD4+ T cells to infection with HIV, raising clinical concerns that vorinostat may reseed the viral reservoirs it is meant to purge, particularly during conditions of suboptimal drug exposure," they concluded. "Our results indicate that careful monitoring of patients and ART intensification are warranted during vorinostat treatment."

7/10/14

References

G Jiang, EA Mendes, P Kaiser, et al. Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cδ-NF-κB signaling. AIDS28(11):1555-1566. July 17, 2014.

RD Dar, NN Hosmane, MR Arkin, RF Siliciano, and LS Weinberger. Screening for noise in gene expression identifies drug synergies. Science344(6190):1392-1396. June 20, 2014.

M Lucera, CA Tilton, H Mao, et al. The histone deacetylase inhibitor vorinostat (SAHA) increases the susceptibility of uninfected CD4+ T cells to HIV by increasing the kinetics and efficiency of post-entry viral events. Journal of Virology. July 9, 2014 (Epub ahead of print).

Other Source

Gladstone Institutes. Researchers at the Gladstone Institutes Find Novel Approach to Reactivate Latent HIV. Press release. June 5, 2014.