Pitt-led study provides new understanding of HIV infections

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.”