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Researchers Make Progress In Learning How To Activate Latent HIV (CROI 2012)

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Published: Mar 28, 2012 11:00 am
Researchers Make Progress In Learning How To Activate Latent HIV (CROI 2012)

A review of several recent clinical advances indicates that researchers are making progress in finding methods to activate latent HIV. Results also confirm that activating dormant HIV to render it susceptible to antiretrovirals may represent a viable strategy to reduce latent infection.

“Some interventions that have already been tested have been relatively well tolerated,” said Dr. Sharon Lewin, director of the Infectious Disease Unit at Alfred Hospital in Melbourne, Australia, and author of the review.

Dr. Lewin noted that results so far are promising but still preliminary.

“Perhaps some very early signals that [Zolinza] and disulfiram might increase HIV production in vivo,” said Dr. Lewin.

“How that’s happening we still need to address, and we have no evidence that it’s made any difference to the number of latently infected cells,” she added.

The results were presented earlier this month at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Latent infection refers to HIV that is not actively replicating. In such cases, the virus inserts its own genetic material into a person’s DNA and remains dormant for an extended period of time.

Since most antiretroviral drugs target actively replicating HIV, they fail to eliminate latent forms of the virus. If antiretroviral therapy is stopped, latent HIV returns to an active form and reproduces quickly, resulting in a rebound of viral load (amount of virus in the blood).

As a result, many researchers believe that activating latent HIV is a necessary step for curing people of the infection. Strategies to target latent HIV often involve a combination of virus-activating treatment with standard antiretroviral therapy (see related AIDS Beacon news).

In her review at CROI, Dr. Lewin summarized results from several clinical trials that are using different approaches to activate latent HIV.

Histone Deactylase Inhibitors

Histone deacetylase (HDAC) inhibitors are a class of drugs that are currently in clinical trials to test their ability to activate latent HIV. According to Dr. Lewin, results so far have been suggestive but somewhat contradictory.

The U.S. Food and Drug Administration (FDA) approved one HDAC inhibitor, Zolinza (vorinostat), in 2006 for the treatment of a type of lymphoma. According to Dr. Lewin, Zolinza is currently being tested both by her own group in Melbourne, Australia, and by Dr. David Margolis’ group at the University of North Carolina (UNC) in Chapel Hill.

In the Melbourne-based study, nine HIV positive individuals (with HIV infection that was well controlled on antiretroviral therapy) received 400 mg of Zolinza daily for two weeks. Blood and samples of tissue from the participants’ rectums were collected before and after Zolinza treatment to measure the activity of HIV genetic material, a measure of activated latent HIV, in host CD4 (white blood) cells.

According to Dr. Lewin, results from the study showed that multi-dose treatment with Zolinza did not lead to a significant increase in the activation of latent HIV as expected, even when participants were followed up for 12 weeks. She reported that treatment-associated side effects such as lethargy, diarrhea, and nausea were seen in 90 percent of participants.

The study by researchers at UNC-Chapel Hill included six HIV-positive individuals whose HIV infection was well controlled with antiretroviral therapy. In this study, participants received a single 400 mg dose of Zolinza.

In contrast to the Melbourne-based trial, the results from this study suggested that Zolinza treatment resulted in a five-fold increase in the activity of HIV genetic material without serious side effects (see related AIDS Beacon news).

Other HDAC inhibitors such as panobinostat, gavinostat, and belinostat are also currently in clinical development. Preclinical results suggest that they effectively activate latent HIV in the laboratory; however, their ability to activate latent HIV in people has not yet been tested.

Other Strategies

Dr. Lewin also reported on clinical trial results for two other HIV-activating drugs: disulfiram and anti-PD1 antibodies.

Disulfiram (Antabuse) is an FDA-approved drug to help treat alcoholism. In 2011, researchers at Johns Hopkins University discovered that disulfiram can activate latent HIV. How disulfiram activates latent HIV is not well understood and remains under investigation.

Dr. Lewin discussed results from a recent disulfiram-based clinical trial by Dr. Steven Deeks’ group at the University of California at San Francisco and Dr. Adriana Andrade’s group at Johns Hopkins University. Fourteen HIV-positive individuals whose HIV was well controlled with antiretroviral therapy received 500 mg of disulfiram daily for two weeks.

Results from the trial indicated no significant differences in plasma viral load after disulfiram treatment, suggesting that the disulfiram did not significantly activate latent HIV (see related AIDS Beacon news). However, since a subset of participants showed a significant increase in viral load as early as two hours after disulfiram treatment, the researchers plan to study the drug’s efficacy at shorter time periods.

Another approach that is being investigated to activate latent HIV is the use of anti-PD1 antibodies.

Anti-PD1 antibodies bind to a molecule called ‘programmed cell death 1’ (PD1) on the surface of white blood cells. Upon chronic exposure to HIV, some white blood cells become ‘exhausted’, meaning that they lose function and cannot be activated anymore. Exhausted white blood cells produce high levels of molecules on their surface, including PD1, that prevent the cells from being activated further.

Previous studies have shown that in people with HIV, exhausted cells that produce high levels of PD1 harbor more latent HIV than active cells.

Dr. Nicolas Chomont’s group at the Vaccine and Gene Therapy Institute in Florida investigated whether antibodies that bind to PD1 on the surface of exhausted cells can mask it and help reactivate exhausted white blood cells. Reactivating the cells may help reduce latent HIV.

Results from the study indicate that treating white blood cells obtained from HIV-positive individuals with anti-PD1 antibodies in the laboratory led to increased activity of the integrated HIV genetic material, suggesting that latent HIV was being activated.

According to Dr. Lewin, Merck and Bristol Myers-Squibb both currently have anti-PD1 antibodies in clinical trials, for diseases such as melanoma. She also indicated that plans for a trial in people with HIV are underway.

Challenges And Future Directions

In evaluating the efficacy of latent HIV activators, Dr. Lewin underscored the need for a better understanding of what parameters to measure and at what time points.

“There’s still lots that we don’t know,” said Dr. Lewin. She noted that, of the drugs that are possible HIV activators, researchers still need to find the best dosages and figure out when to test for activated HIV. Scientists also are still working on how best to determine whether the drugs are effective and how to measure latent HIV.

Dr. Lewin also suggested that eradicating HIV will likely take a combination of multiple strategies. She noted that the simultaneous use of two approaches to activate latent HIV sometimes produces significantly better results than using the agents individually, and that activation of latent HIV will almost certainly need to be combined with other approaches, such as intensification of treatment with antiretrovirals.

For more information, please see the webcast on the CROI 2012 website.

Photo by Crafty_Dame on Flickr – some rights reserved.
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One Comment »

  • Kevin Griggs said:

    I’m curious to know what Dr. Lewin thinks about prostratin, another type of HIV-1 reservoir activator?