National Cancer Institute (NCI) researchers and their colleagues have identified a new hideout for the HIV virus, a discovery that could lead to new approaches to anti-retroviral therapies. A subset of natural killer (NK) cells has been found to remain infected with HIV, even after aggressive treatment. The findings indicate that NK cells, immune cells essential to the body's fight against viruses and tumors, may play an important role in HIV infection and should be considered as a target for therapy, in addition to T cells.

Scientists from NCI's Human Retrovirus Section and HIV and AIDS Malignancy Branch conducted the research in collaboration with scientists from the University of Athens School of Medicine and the Red Cross General Hospital, both in Athens, Greece. The study will be published in the May 14, 2002, edition of Proceedings of the National Academy of Sciences*. The research was also presented at the International AIDS Conference in Barcelona, Spain on July 11, 2002.**

Researchers found that a subset of NK cells express CD4, CCR5 and CXCR4, all known cell surface receptors for HIV that enable the virus to enter the body. These cells are infected by the HIV virus and generate infectious progeny. Importantly, the scientists found that HIV-1 DNA remains in NK cells even after two years of aggressive treatment with combinations of three anti-retroviral drugs. Scientists observed similar hideaways for the HIV virus several years ago in T cells, another type of immune cell that is the focus of many current anti-retroviral therapies.

The presence of HIV-1 in some NK cells was demonstrated with both in vivo and in vitro testing. For in vitro testing, researchers purified NK cells and infected them with HIV-1 that had been tagged by green fluorescent protein. Scientists were therefore able to identify infected cells and examine their characteristics. For in vivo tests, researchers isolated T cells and NK cells from patients infected with HIV and extracted all DNA from the cells. Polymerase chain reaction (PCR) was then used to examine the presence of HIV DNA within the different cells. The virus was also cultured from purified NK cells.

The findings from this study demonstrate that some currently available anti-retroviral therapies do not eliminate the HIV virus from an identified subset of NK cells. According to George Pavlakis, M.D., Ph.D., a senior scientist at NCI's Human Retrovirus Section and a member of the research team, recent protocols that aim to eliminate HIV from latently infected T cells may not be effective on NK cells.

One reason they may not be effective, according to the scientists, is that protease inhibitors are less effective in NK cells that have highly active p-glycoprotein (p-gp) drug efflux pumps. High p-gp transporter levels can interfere with the ability of protease inhibitors to block HIV replication because they rapidly remove the active drug from the cell.

"This new population of NK cells needs to be studied further because they are substantially different from T cells and they appear to remain infected for long periods of time," said Pavlakis. "Either these cells live for long periods and escape immune detection and killing by the virus, or they are continuously re-infected despite the strong antiviral drugs."

The researchers are continuing to examine the ongoing presence of HIV in this subset of NK cells. "Further experiments are needed to determine what exactly is going on in the body, but there is no question in my mind that we need to study these infected cells," added Pavlakis. "We have put forth the hypothesis that some cells may be more resistant to antiviral drugs and therefore may continue to propagate the virus."

The continuation of these studies may advance the understanding of drug resistance in both AIDS and cancer patients, according to Pavlakis. NK cells are important components of the body's immune system. Infection of NK cells may contribute to defects in innate immunity previously reported in AIDS patients.

** http://www.aids2002.com/

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