Have We Been Looking For HIV in All the Wrong Places?

Have researchers and doctors been looking for HIV in all the wrong places? That’s what the scientists involved in the Collaboratory of AIDS Researchers for Eradication (CARE) certainly believe. CARE is part of an National Institutes of Health-sponsored program, the Martin Delaney Collaboratory: Towards an HIV-1 Cure , named in honor of the late AIDS activist, Martin Delaney who founded Project Inform in 1985.

Speaking at last month’s Cure Conference — hosted by University of California San Diego AntiViral Research Center and CARE—Dr. David Margolis and Dr. Warner Greene both shared some startling statistics about the traditional reliance on blood by those testing for and treating HIV.

Blood tests reveal the viral load a patient’s bloodstream, but Margolis, who heads CARE, maintains that “only one percent” of a person’s T-cells are located in the bloodstream. The remainder of CD4 T-cells and the HIV that has infected them hides in tissue. 

Greene, a professor of Medicine Microbiology and Immunology at University of California San Francisco, was the person who first discovered that HIV is actually “a disease of the lymphoid tissue.” It was a discovery Green admits he stumbled upon accidently. Most of the research conducted over the past 30 years has revolved around studying and treating HIV in the bloodstream because blood is easier to access then human tissue.

But Greene’s team started using tissues from the lymphatic system (specifically spleen and tonsil tissue), which had recently been made available to researchers, which is when they discovered that “98 percent of CD4 T-cells reside there in lymphoid issues.”

By focusing on the lymphoid tissues, the researcher began to realize that HIV behaves differently in the spleen and tonsils than it does in the bloodstream. He says that only viewing HIV (and testing for HIV) in the blood has dramatically limited our understanding of HIV and impacted our ability to effectively eliminate HIV infections.

While earlier research suggested that CD4 T-cell death in an HIV-positive person occurs from a type of cell death called apoptosis, Greene’s team demonstrated that only a fraction of the cells were actually dying this way.  In contrast, he says, "19 out of 20” these T-cells in the lymphoid tissue dies by pyrotosis. 

As Greene explains, “the lifecycle of the virus within the cells occurs during the time when it’s trying to convert RNA to DNA by reverse transcription. What happens is there is the accumulation of small pieces of DNA in the cytoplasm of the infected cells that are [then] recognized and detected as foreign DNA by the cell.”

Mistaking the pieces of human DNA as foreign intrusion, the cell launches an immune response against that viral DNA. This ultimately leads to activation of the key enzyme, Caspase 1, and because it's “laden with inflammation” this is how 95 percent of the cells with HIV infection die.

As Greene wrote in a study published in the journal Nature, “This death pathway thus links the two signature events in HIV infection –– CD4 T-cell depletion and chronic inflammation –– and creates a vicious pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die.”  

The cells essentially commit suicide in a vain attempt to protect the larger host. Their deaths trigger the immune system to send even more CD4 T-cells, which repeat the cycle. Calling this, “death by friendly fire,” Greene says HIV turns our celluar defenses against us, causing the greatest number of CD4 T-cells that die in an HIV infection are killed by this cell "suicide," not “viral murder.”

So how can we stop this deadly cycle?

Greene had hoped to find the answer in the 40 species of monkeys in Africa found to have their own version of HIV. Research has shown that many of these monkeys have viral loads ten times higher than those found in untreated HIV patients, and yet they appear to have no illness associated with the high viral loads. Believing that these monkeys have been evolving for tens of thousands of years with the Simian Immunodeficiency Virus, Greene investigated how the simian immune system manages the SIV, and he discovered that the virus has remained unchanged over the decades. What did change was that the monkeys no longer have the inflammatory response they once did, the kind that is still triggered by HIV in humans.

Then Greene went back to patients infected with HIV and could see that the higher levels of CD4 T-cell death in lymphoid tissue suggested that blood cells weren’t sustaining an HIV infection long enough to trigger the inflammatory response.

“So, in fact we have circulating in our body CD4 T-cells that are highly effective at fighting the infection and the Caspace-1. Yet when these cells traffic into lymphoid issue they are rendered sensitive, they achieve just enough activation to sustain this form of infection and lead to the pyrotonic cell death.”

Researchers already know one way they can end that deadly immune system response.

“This cycle can be broken by Caspase-1 inhibitors,” Greene says, pointing to lab tests previously done as proof. A highly potent and selective Caspase-1 inhibitor already exists, in form of the drug called VX -765. Even more miraculously, VX-765 has already been through drug trials and has been shown to be safe in humans.

It just hasn’t been tested in the treatment of HIV. Still there's hope on the horizon. The drug was recently acquired by a new pharmaceutical company and the existence of human drug trials potentially could speed up the process toward achieving FDA approval.