"Compliance" is the medically correct word for a patient sticking closely and patiently to a prescribed course of treatment. "Goofing off" is what too many HIV-positive patients do when they quit their highly effective antiretroviral therapy - triple-cocktail HAART - because it's so highly effective that they feel fine, and compliance is an increasing nuisance.

That's where they make their big - possibly fatal - mistake. Just because pre-AIDS symptoms are gone doesn't mean that the AIDS virus itself has vanished, along with those forgotten symptoms. Like a gang of mobsters that holes up and hunkers down in a hideaway till danger blows over, the AIDS virus hides out and re-emerges when the HAART threat goes away. HAART targets the immune system's T cells, which in turn are targeted by the invading HIV.

"What we suspect," observed virologist/molecular biologist George Pavlakis, "is that the AIDS virus hides in many different places. I don't believe there's a single type of cell, a single long-term reservoir. The virus can be found, even during the most aggressive anti-retroviral therapy, in T cells. Now we have new evidence that under the same aggressive HAART, natural killer [NK] cells are also hidden and latent. These, too, act in long-term viral reservoirs.

"So the simple message," he continued, "is that if we want to improve the highly active anti-AIDS therapy, we have to deal not only with the latent T cells but also natural killer cells. In addition to that, we have evidence that the properties - the biologies - of these NK cells are not exactly like the T cells. So if one designs a therapeutic strategy focusing just on T cells, it may not do any good - considering the NK cells."

Not By T Cells Alone To Clobber HIV Latency

Pavlakis heads the Human Retrovirus Section at the National Cancer Institute. He is senior author of a paper in today's Proceedings of the National Academy of Sciences (PNAS), dated May 14, 2002. It is titled: "Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy."

"We report in this article," he told BioWorld Today, "having found a new type of white blood cell that can be infected by HIV. It was not known before that this distinct NK population, which exists in all healthy humans, is also present in HIV-infected people," he explained, "but unlike other NK cells, a subset of NK cells express molecules on their surface that are not traditionally associated with natural killers. In addition to CD4," Pavlakis went on, "they express all the necessary receptors - such as CCR5 and CXCR4 - that enable the virus to enter the human body. These cells are infected by HIV and generate infectious progeny. Importantly, we determined that HIV-1 DNA remains in NK cells even after two years of aggressive HAART drug. Scientists had observed similar cellular hideaways for HIV virus several years ago in T cells.

"All the white and blood cells come from common progenitors - hematopoietic stem cells," Pavlakis pointed out. "But the natural killer cells specialize. They are effector cells of the innate immune system. That means they orchestrate the immune response's first line of defense against a lot of invaders - microorganisms - but not only that. The NK cells also participate heavily in cell/non-cell recognition.

"For example, they can determine whether a cancer cell is abnormal. If it is, they have the license to kill it. They are killers that are not restricted by specific antigens, the way the adoptive immune system operates. They are very important in defending against viruses - and also cancer. NKs continuously sniff around the surface of the cells and recognize if there is anything abnormal on the surface that they touch. If so, they directly kill it - by injecting molecules such as perforin that terminate the cells. It's exactly the same mechanism that cytotoxic T cells use. NKs are very efficient and direct killers."

After discovering and isolating the specialized natural killer cells in vitro - in cell culture - Pavlakis and his co-authors followed their fate in vivo - in the blood of HIV-positive patients on HAART. "We did two things in the patients," he recounted. "We separated their NK and T cells by laboratory methods, and tested them to see whether they had the virus integrated into their viral DNA. The answer was yes: All the patients had virus in their NK cells, and in their T cells. Then we said: Okay, we can find the viral DNA, but are we able to rescue the virus from these cells?' That answer, too, was yes: We could recover virus from their T cells, and NK cells. This told us that in these patients, despite the HAART drug treatment, we had not solved the problem; we still found infected NK cells."

Tackling Humongous Worldwide Pandemic'

"Of course," Pavlakis pointed out, "the problem in AIDS is that once you stop the drug the virus comes right back. That's why you need to continuously provide this kind of heavy drug regimen. If one could find a way to eliminate long-term viral reservoirs, that would be a tremendous step for AIDS research and treatment. I don't think we're going to come easily to that stage," he added, "but the first thing we have to do is at least describe the boundaries of the problem. Where is the virus that remains? That's one of the main questions our PNAS paper addresses.

"We have a very happy collaboration with the co-authors, our clinical colleagues," Pavlakis allowed, "and we hope to greatly expand this patient study. Despite all the attention and efforts in the AIDS field, there is still a tremendous possibility for new types of drugs against that disease. It continues to be a humongous worldwide pandemic. AIDS numbers keep going up. I'm not the first one to sound the alarm, but we should not forget that we have not conquered AIDS. We are in desperate need of better therapies, and I think that the biotech business has tremendous opportunities, even today, to come up with new drugs. So AIDS should not be overlooked. There is still a tremendous problem."

Pavlakis concluded: "We recently signed an agreement with Wyeth for DNA vaccines against AIDS."