This article is the second in a four-part series that will investigate current research toward finding a cure for HIV, including advances, promising treatment strategies, and barriers to reaching a cure. Part 1 discusses general types of HIV cures. Part 2 discusses specific strategies for targeting latent HIV. Part 3 discusses gene therapy and therapeutic vaccines. Part 4 discusses barriers to obtaining a cure.

As researchers work toward developing a cure for HIV, most agree that the major obstacle to a cure is latent HIV, HIV that lies dormant during treatment until treatment is stopped. As a result, eradicating latent HIV is a top priority for scientists, and several drugs are currently being tested for their ability to reduce or eliminate this hidden reserve of virus.

“The major barrier to eradication is undoubtedly the presence of long-lived latently infected resting memory cells,” said Dr. Steven Deeks, a professor of medicine at the University of San Francisco. Dr. Deeks participated yesterday in a LiveChat on HIV cures on the Science Magazine website.

Latent HIV is HIV that is not actively replicating. Instead, it lies dormant, often in immune system cells with long lifespans, such as memory cells (cells that “remember” bacteria and viruses from past infections so they can be effectively fought again). Since antiretroviral drugs usually work by blocking replication, they do not work on latent HIV.

As a result, antiretrovirals can never fully remove HIV from the body. Latent HIV will activate if therapy is stopped, renewing the HIV infection.

Targeting this HIV involves activating it so that infected immune cells start producing HIV again. The HIV then kills the infected cells. At the same time, antiretroviral drugs prevent new cells from being infected. The result is that infected cells are killed off, leaving only uninfected cells behind (see related AIDS Beacon news).

In a recent review, Dr. Sharon Lewin, director of the Infectious Diseases Unit at Alfred Hospital in Australia, and Professor Christine Rouzioux from the Université Paris Descartes in France discussed the strategies that are currently considered most promising for targeting latent HIV reservoirs.

Strategies for targeting latent HIV, of necessity, typically combine new treatments with standard antiretroviral therapy.

“This strategy is only viable if active viral replication is completely inhibited on cART [combination antiretroviral therapy],” wrote Dr. Lewin and Prof. Rouzioux in the review.

Latent HIV Activators

Most current methods for targeting latent HIV involve testing drugs to see whether they activate the virus. Dr. Lewin and Prof. Rouzioux’s review discussed several types of drugs under consideration, one of which is histone deacetylase (HDAC) inhibitors. HDAC inhibitors are currently used as mood stabilizers and anti-epileptic drugs; more recently, researchers have begun investigating them as anti-cancer treatments.

Zolinza (vorinostat), an HDAC inhibitor, is a drug currently approved to treat a type of lymphoma. Research has shown that Zolinza successfully activates latent HIV in infected cells in the laboratory. A Phase 1/2 clinical trial to test its effects in HIV-positive adults on stable antiretroviral therapy regimens is currently recruiting participants. Studies in other patient populations have suggested that Zolinza causes side effects when used long-term, but physicians hope that prolonged treatment with the drug would not be necessary.

Prostratin, a chemical isolated from tree bark, is a traditional Samoan treatment for hepatitis. Researchers have found that it also activates latent HIV in the laboratory, although it works differently than HDAC inhibitors. Prostratin is still in pre-clinical studies but may be too toxic for use in humans.

Another class of drugs under investigation is DNA methylation inhibitors. This class of drugs is used to treat cancer and myelodysplastic syndromes (MDS), which are a group of blood conditions that are often considered cancerous.

In particular, Dacogen (decitabine), a drug approved to treat MDS, has been shown to activate latent HIV in cells from people with HIV. Results from other studies showed that Dacogen was more effective when used in combination with prostratin and an HDAC inhibitor.

Finally, researchers are also investigating the protein IL-7, which helps immune cells develop and survive. In a recent study, results showed that IL-7 was well-tolerated and led to an increase in HIV RNA in HIV patients, indicating that it may be successfully reactivating latent HIV. IL-7 is currently in a Phase 2 clinical trial to see if it can activate latent HIV when used with an intensified highly active antiretroviral regimen. The trial is recruiting participants in several European countries.

Results from several studies have shown that combining the above classes of drugs have a more pronounced effect on latent HIV.

“Whether these approaches will work alone, or require additional combination therapies is a question that we hope to be able to answer in the next few years,” said Dr. David Margolis, a professor of medicine at the University of North Carolina School of Medicine who participated in the LiveChat.

Treatment Intensification And Early Treatment

Two other methods Dr. Lewin and Prof. Rouzioux discussed for restricting or reducing the size of the latent HIV reservoir in people with HIV involve treatment intensification – adding additional anti-HIV drugs to a person’s regimen – and starting treatment early, right after infection.

Previous studies have looked at the effect of treatment intensification on remaining virus in HIV patients. However, despite the addition of drugs such as Fuzeon (enfuvirtide), Isentress (raltegravir), or extra protease inhibitors, many studies to date have not demonstrated a significant decline in viral load or amount of latent HIV in individuals with HIV.

An exception to this is results found in a recent small Spanish study, in which the additional use of the HIV entry inhibitor Selzentry (maraviroc) decreased the amount of latent HIV in study participants. However, the results will need to be confirmed with a larger trial. How Selzentry might decrease the amount of latent HIV is unknown.

In spite of the mostly negative results, researchers have not yet given up on treatment intensification as a strategy for fighting latent HIV.

“Intensification is still an open question. If you measure effect on detectable viremia (by the most sensitive methods), there does not appear to be any effect of intensification. However, it is still unclear whether intensification might impact cell-to-cell spread of HIV that never results in detectable viremia,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, during the LiveChat.

Early treatment of HIV may be an additional strategy to reduce and control latent HIV. Results from several studies have shown that the number of HIV-infected cells decrease significantly when antiretroviral therapy is initiated during the early, acute stage of HIV rather than the chronic, late stage of HIV.

Results from a recent study showed that 16 percent of patients who initiated early antiretroviral therapy and then discontinued therapy managed to maintain low viral loads. However, these findings conflict with findings from other studies, and the effect of early treatment on HIV infection needs to be further investigated.

“There appear to be several potential benefits to early therapy, before significant CD4 cell decline, but this is under clinical study now,” said Dr. Margolis.

“Patients treated within weeks of infection (acute) or months of infection (early) present some advantages for the initial attempts to eradicate infection, but our goal is to develop eradication therapies that can benefit all patients,” he added.

For more information, please see the review in the journal AIDS (abstract) or the Science LiveChat website. For more information about the potential for an HIV cure, please see Part 1 (general types of HIV cures), Part 3 (gene therapy and therapeutic vaccines), and Part 4 (obstacles to a cure) of this series.