Viral Reservoir Seen 'Strikingly' Soon After HIV Infection

Pam Harrison

August 08, 2014

MELBOURNE, Australia — A viral reservoir of HIV is established soon after infection, and is present long before the virus can be detected in the blood, new research shows.

"In an animal model of HIV infection, we found that the viral reservoir is established in tissue within days of infection — much earlier than anyone had anticipated before," said Dan Barouch, MD, director of the Center for Virology and Vaccine Research at the Beth Israel Deaconess Medical Center in Boston.

"Even very early antiretroviral therapy was insufficient for curing the viral reservoir," he said during a news conference here at the 20th International AIDS Conference.

"If these data are translatable to humans, then as soon as one is able to diagnose a patient with HIV, even with the lowest levels of plasma virus, the reservoir has already been established," he explained.

The study results were published online July 20 in Nature.

Dr. Barouch and colleagues initiated suppressive antiretroviral therapy in 20 adult rhesus monkeys on days 3, 7, 10, or 14 after the animals were infected with the simian form of HIV (SIV). A subcutaneous injection of tenofovir, emtricitabine, and dolutegravir was administered daily for 24 weeks.

This rhesus monkey study has a 'remarkable parallel' to the recent events of the Mississippi baby.

Treatment initiated on day 3 "blocked the emergence of viral RNA and proviral DNA in peripheral blood, and substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa," compared with treatment initiated later, the investigators report. It also abrogated the induction of SIV-specific humoral and cellular immune responses.

The virus rebounded in all animals after the 24-week fully suppressive therapy was discontinued. However, the viral rebound was slower in monkeys started on therapy on day 3 than in those started on day 7, 10, or 14.

"This strikingly early seeding of the refractory viral reservoir raises new challenges for HIV-1 eradication strategies," the investigators note.

Clearly, the early initiation of antiretroviral therapy is not enough to eradicate the HIV reservoir, said Dr. Barouch.

He suggested that the use of monoclonal antibodies and therapeutic vaccines to boost the immune system's ability to eradicate the virus in the plasma might be effective.

Reservoir activators such as romidepsin have been shown to drive enough latent HIV out its reservoir for the virus to become detectable in blood with standard HIV assays, as reported by Medscape Medical News.

This strategy is now being coupled with a therapeutic vaccine to try to clear newly detectable virus from the blood.

This rhesus monkey study has a "remarkable parallel" to the events of the Mississippi baby, Dr. Barouch pointed out.

The Mississippi baby recently tested positive for HIV after being off antiretroviral therapy for 27 months. Until the positive test, the child had absolutely no evidence of HIV infection.

It is likely that the HIV reservoir was established before the initiation of antiretroviral therapy, which was started when the baby was only 30 hours old, speakers here suggested.

Measuring the Reservoir

Before the latent HIV reservoir can be eradicated, clinicians must be able to measure it.

"Right now, the assays we have to measure it are expensive, require a lot of blood, and we are not exactly sure what they measure," Nicolas Chomont, PhD, from the Vaccine & Gene Therapy Institute of Florida in Port Sainte Lucie, said during the news conference.

A reported scientific priority for the International AIDS Society has been to develop assays that can measure the size of the reservoir.

Dr. Chomont's team has come up with a novel assay they call the Tat/Rev Induced Limiting Dilution Assay, or TILDA.

He presented findings demonstrating that TILDA is relatively inexpensive, fast (<2 days to run), reproducible, and sensitive, during the Towards an HIV Cure symposium held in conjunction with the AIDS conference.

"It requires only 10 mL of blood," which is an important consideration in the treatment of neonates at high risk for HIV infection, he explained. And because the assay requires only "very basic instrumentation," it can be used in pretty much any laboratory in the world, he added.

With TILDA, "we have been able to confirm the benefit of early antiretroviral therapy," Dr. Chomont reported. "Our next step is to use the assay in a clinical trial to assess eradication strategies."

He said his team plans to make TILDA available to the HIV scientific community as soon as possible.

There are 3 big issues researchers need to solve before eradication strategies can be tested in full, said Steven Deeks, MD, professor of medicine, at the University of California, San Francisco.

"First, we need to know where the virus lives," he said during the news conference. The case of the Mississippi baby suggests that a virus living in a single cell in some reservoir somewhere in the body is all that is needed for the virus to take off, he explained.

"Second, we need to be able to measure the virus better." Dr. Deeks speculated that there are probably dozens of patients around the world with no detectable virus who may or may not be cured. Until the reservoir can be evaluated, there is no way of knowing if any eradication strategy has been effective, he noted.

Last, "we need to translate some of the early pilot studies we've heard about into real clinical studies to see if we can advance the cure agenda," Dr. Deeks said.

"The immune system really can't control the amount of virus people have now," he said. But, "if we can get rid of 99% of it and boost the immune system, the extra immune power may be all we need to control what's left.

"It's going to require combination approaches, including the use of vaccines, to get there," he said.

This study was supported by various organizations, including the US Military Research and Material Command and the US Military HIV Research Program. Dr. Barouch and Dr. Deeks have disclosed no relevant financial relationships. Dr. Chomont's work is supported by various organizations, including the National Institutes of Health.

20th International AIDS Conference. Presented July 21, 2014.


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