Researchers Explore Agents that Reduce CD4 Cell Reservoir and Activate Latent HIV

A gold compound, auranofin, can kill memory CD4 T-cells that harbor latent HIV, thereby depleting the viral reservoir, according to a recent study. Other researchers used a high-throughput screen to identify compounds that can flush latent virus out of reservoir cells.

Over the past few years a growing body of research has looked at ways to cure HIV, aiming either to completely eradicate the virus or produce a "functional cure" that enables people with HIV to safely stop antiretroviral therapy (ART).

One of the key obstacles to reaching this goal is the fact that HIV genetic material (known as proviral DNA) can integrate itself and remain dormant in a "reservoir" of resting cells -- primarily long-lived memory CD4 T-cells -- where it is unreachable by current antiretroviral drugs. Researchers have proposed reducing this reservoir by either activating resting cells to "purge" or "flush out" latent virus, or by killing off resting cells that contain integrated viral DNA.

New Activating Agent

A study described in the April 15, 2011, advance online edition of the Journal of Biological Chemistry took the first approach, looking for compounds that could activate and purge latent HIV.

Sofiya Micheva-Viteva from Los Alamos National Laboratory and colleagues devised a cell-based system to model HIV latency in the laboratory. They used this model with a high-throughput screen to identify small molecules that could antagonize, or reverse, HIV latency.

They identified a compound dubbed antiviral 6 (AV6) that reproducibly activated latent proviral DNA from different lymphocyte-based laboratory cell lines and from latently infected primary (taken from people) resting CD4 T-cells. AV6 did not, however, cause dangerous generalized T-cell proliferation or activation. Furthermore, they also showed that AV6 complemented the ability of a previously known histone deacetylase (HDAC) inhibitor to activate latent HIV.

Based on these results, the investigators concluded, "This is a proof of concept showing that [a high-throughout screen] employing a cell-based model of HIV-1 latency can be utilized to identify new classes of compounds with novel activities that can be used in concert with other persistence antagonists with the aim of viral clearance."

Auranofin

As described in the April 18, 2011, advance online edition of AIDS, Mark Lewis, Andrea Savarino, and colleagues tried the second approach, testing whether auranofin (brand name Ridaura) -- a gold compound used to treat rheumatoid arthritis -- could help deplete the reservoir of T-cells harboring HIV.

The researchers first exposed primary human CD4 T-cells to auranofin in a laboratory study. They found that auranofin promoted cell differentiation, changing the phenotype (markers identifying cell function) of naive, central memory, and transitional memory T-cells. The compound also caused cell death, which was more pronounced for memory cells -- the type most likely to contain latent virus.

They next tested whether auranofin could reduce the viral DNA reservoir in a pilot study of 6 macaque monkeys infected with SIV, a primate relative of HIV. At the start of the experiment the macaques had stably suppressed viral load on standard ART consisting of tenofovir (Viread, also in the Truvada and Atripla coformulations), emtricitabine (Emtriva), and the integrase inhibitor raltegravir (Isentress).

Auranofin significantly decreased viral DNA in peripheral blood cells of monkeys on 3-drug ART, though the effect was transient. The gold compound shortened the lifespan and reduced the population size of central memory CD4 T-cells, while not significantly diminishing the naive CD4 T-cell population. Overall CD4 cell counts remained stable.

When ART was intensified by adding ritonavir-boosted darunavir (Prezista), the decrease in SIV DNA was sustained through 11 weeks in auranofin-treated monkeys, but not in a control group on intensified ART alone. Macaques on intensified ART were then treated with the HDAC inhibitor vorinostat at week 10 to see if it could flush out any remaining latent virus. Viral rebound did not occur in monkeys that took auranofin, although it did in control monkeys.

After all treatment was suspended, monkeys that had received auranofin experienced delayed and lower-level viral load rebound after about 7 weeks, compared with less than 2 weeks for control monkeys. One animal maintained a low viral load and stable high CD4 count for nearly a year, Savarino reported.

"These findings represent a first step towards a remission of primate lentiviral infections," the study authors optimistically concluded.

Nevertheless, in a press release describing the research, Savarino cautioned that people with HIV should not yet try this approach using off-label auranofin. "I strongly recommend that people living with HIV/AIDS do not buy the drug from uncontrolled sources such as the e-Bay and start self-treatment outside highly medicalized settings," he stated.

Investigator affiliations:

Micheva-Viteva study: Los Alamos National Laboratory, Los Alamos, NM; Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, Piscataway, NJ; Memorial Sloan-Kettering Cancer Center, New York, NY; PTC Therapeutics, Inc., South Plainfield, NJ.

Lewis study: BIOQUAL, Inc., Rockville, MD; VGTI-Florida, Port St. Lucie, FL; Cenci-Bolognetti Foundation, Dept of Public Health Sciences, Sapienza University of Rome, Rome, Italy; IRCCS San Raffaele Pisana, Rome, Italy; Cenci-Bolognetti Foundation, Dept of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy; Istituto Superiore di Sanità, Rome, Italy.

4/29/11

References

S Micheva-Viteva, Y Kobayashi, LC Edelstein, et al. High-throughput screening uncovers a compound that activates latent HIV-1 and acts cooperatively with a HDAC inhibitor. Journal of Biological Chemistry (abstract). April 15, 2011 (Epub ahead of print).

MG Lewis, S Dafonseca, N Chomont, et al. Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension. AIDS (abstract). April 18, 2011 (Epub ahead of print).

Other Source
A Savarino. Gold-based Drug to Hit HIV Reservoirs. Press release. April 20, 2011.