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10/27/2003

Researcher Gives Insights on Persistence of HIV

Kate Traynor

An understanding of the importance of viral persistence is critical to the care of patients infected with HIV, says virologist Robert F. Siliciano.

Past research led by Siliciano, a professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, indicates that, even when antiretroviral therapy controls a patient's actively replicating virus, HIV persists in an inactive form in resting memory CD4+ T cells.

Siliciano, during a seminar last week at the National Institutes of Health in Bethesda, Md., described this reservoir of latently infected cells as "a kind of library of all of the previous forms of the virus that have been present at high levels" in the patient. The reservoir, he explained, contains both wild-type viruses that have not developed resistance to antiretroviral agents and drug-resistant viruses that have arisen during treatment.

"HIV evolved in a fundamentally unique way," Siliciano said. "It's not survival of the fittest; for HIV, it's survival of everything," he explained. "It's survival of all major forms, and it's active replication of the forms that are the fittest under the current conditions."

"If you don't understand this, you will make serious mistakes in treating patients," Siliciano said.

Current government guidelines (PDF) acknowledge the importance of considering the permanence of the viral reservoir when treating HIV-infected patients. The guidelines describe the pool of latently infected cells as a barrier to viral eradication, which cannot be achieved with current antiretroviral drugs. Treatment goals in the guidelines center on suppressing viral replication and keeping HIV-infected patients as healthy as possible for as long as possible.

The guidelines also call for delaying antiretroviral therapy in asymptomatic patients to postpone both the emergence of resistant virus and the exposure of patients to antiretroviral drugs, which must be taken for the rest of the patient's life.

"The guidelines...initially suggested treating people as you caught the infection, very early," Siliciano said. "Now this has really come into question, since the idea that you can eradicate the infection is essentially no longer accepted."

Since the advent of highly active antiretroviral therapy (HAART) in the mid-1990s, it is possible to virtually eliminate actively replicating virus from HIV-infected patients. When not replicating, the virus cannot mutate into variants resistant to the patient's antiviral regimen.

"If we can overcome the effects of drug toxicity," Siliciano predicted, "it should be possible to maintain patients in a state of virologic suppression for life."

Although there is presumably some activation and movement of memory cells out of the reservoir even during well-controlled infections, Siliciano argued that the process occurs "at such a low level that each little burst of replication dies out, and you don't accumulate [resistance] mutations."

But when conditions are right—such as if antiretroviral therapy is halted or poorly inconsistently taken—the virus emerges from the reservoir to generate a renewed active infection.

"You have to keep in mind that this reservoir preserves highly fit drug-sensitive viruses that will reemerge if treatment is stopped," Siliciano said. "This becomes clinically significant in some studies of patients who are failing treatment or are taken off treatment for whatever reason. What happens is that after a couple of weeks, the level of viremia increases, the CD4 count begins to drop more rapidly, and the patients go downhill. And this is coincident with the appearance of wild-type virus."

In other words, the wild-type virus is generally more harmful to patients than any less-efficiently replicating resistant forms, making control of the wild-type virus of paramount importance to patient care.

Siliciano said that learning about the evolutionary fitness of HIV variants can influence treatment decisions. He described a "worst-case scenario" in which a patient is infected with highly drug-resistant HIV that is "just as fit as the wild-type virus" harbored in the patient's reservoir.

"In this case," he said, "treatment really has no benefit," because wild-type virus will overgrow in the absence of drugs and resistant mutants will grow in the presence of therapy—with either viral type causing equal harm to the patient.

Siliciano said that a better clinical situation exists when the resistant virus "is less fit than the wild-type virus present in the same patient."

"In this setting," he said, "you might begin to think about whether you can reduce the number of drugs the patient is taking, since none of the drugs is actually doing anything in real time to inhibit the [resistant] virus. What they're doing, essentially, is keeping down this more fit" wild-type virus.

Siliciano briefly addressed the issue of structured interruptions of treatment for HIV-infected patients. The current HIV treatment guidelines recommend against so-called drug holidays and call for careful monitoring of patients if therapy needs to be interrupted.

"When you think about interruption, you have to think carefully about how you want to do it and what are all the potential possible viruses that could emerge, and what the best thing is for your patient," Siliciano said.

A recently reported study of four-month drug holidays in patients infected with multidrug-resistant HIV found that the practice led to increased rates of disease progression and death in patients who temporarily stopped therapy.

"I think this could have been totally predicted from the biology" of the virus, Siliciano said.

Ultimately, Siliciano said, clinicians must turn to the research community for guidance about beneficial changes to patients' drug regimens. "We need to provide them with a research basis for those decisions," he said.