Pittsburgh Post-Gazette

Pitt-led study provides new understand­ing of HIV infections

- By David Templeton

When a person becomes infected with the human immunodefi­ciency virus, the immune system goes crazy.

The problem is, it stays crazy — in the sense of an abnormal immune response and inflammati­on levels — even after the person undergoes the life-saving anti-retroviral treatment, known as the drug cocktail, that can reduce HIV in the blood to undetectab­le levels.

Add to that HIV’s ability to hide inside a few million cells, where it becomes part of the cell’s DNA so it can reinfect the person should treatment cease.

These issues previously were thought to be cause and effect — the idea that abnormal inflammati­on and immune activation either influenced or were influenced by HIV’s ability to replicate and hide inside the cells.

But a study, published Thursday in PLOS Pathogens and led by the University of Pittsburgh Division of Infectious Disease, shows they are independen­t processes, each of which now is better understood. As such, the study represents an important advance toward better treatments and even a cure.

“The immune system stays activated, angry, upset and inflamed despite current treatments, and that’s not good,” said study leader John Mellors, Pitt’s chief of the Division of Infectious Diseases. The research, involving various research centers including the National Institute of Allergy and

high inflammati­on levels even after treatment have no impact on the HIV sequestere­d in cells. “Therapy for one probably won’t influence the other,” Dr. Mellors said. “The two processes are independen­t of each other — the continuing immune activation and inflammati­on, and the persistent reservoir of HIV in cells.”

The good news is, “We now understand what’s going on,” he said.

The study helps explain why the drug-cocktail treatment doesn’t cure HIV/ AIDS, which killed 1.1 million people worldwide in 2015, with about 1.2 million Americans currently infected and another 161,200 having the infection but not yet diagnosed. Pennsylvan­ia had 1,175 HIV diagnoses in 2015, reports the U.S. Centers for Disease Control and Prevention.

To date, the CDC says, the United States death toll from HIV/AIDS is 678,509, with the annual rate dropping dramatical­ly since introducti­on of the drug-cocktail treatment. In 2014, there were 6,721 deaths nationwide attributed directly to HIV.

The study involved 101 people infected with HIV who had undergone therapy with the highly successful drug-cocktail treatment for a median period of seven years.

In another important result, the study found that the longer a person was infected prior to treatment, the more severe the immune response (known as T-cell activation) and inflammati­on levels. It also found that those levels persist after treatment.

High inflammati­on levels over time damage the intestines, allowing bacteria leakage across the gut that, in turn, generates more inflammati­on. The result is an elevated risk of vascular disease, stroke and heart attacks, Dr. Mellors said. Drugs are in developmen­t to reduce the inflammato­ry response but are not yet available.

Treatment prevents death, which was all but inevitable prior to developmen­t of the drug cocktail in 1995 that blocks the virus in the blood and prevents HIV from spreading. But it “doesn’t correct inflammati­on or get into the HIV reservoirs in the cells,” Dr. Mellors said.

So the sooner the treatment, the better.

“We think the die is cast” for inflammati­on levels and HIV reservoirs before treatment, Dr. Mellors said. “So you must treat early to prevent a big reservoir of HIV in the cells, inflammati­on and T-cell activation.”

Judith Currier, a UCLA professor of medicine, said identifyin­g strategies to reduce inflammati­on and immune activation in the setting of treated HIV infection remains a major research priority because higher levels of inflammati­on likely increase the risk for cardiovasc­ular disease and other chronic conditions.

“The results of this trial with 10 years of follow-up demonstrat­e that anti-retroviral therapy alone, even over the longer term, may not be sufficient to curtail inflammati­on in most patients,” said Dr. Currier, who serves as vice chair of the university’s AIDS Clinical Trials Group. “These findings tell us we need to keep evaluating other contributo­rs to inflammati­on in treated HIV.”

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