UF scientists seek to close cell doors to HIV invasion

University of Florida researchers have identified a biochemical code that a form of HIV uses to access immune system cells and turn them into virus-making factories.

New targets for HIV treatment might be found by decoding the genetic makeup of this virulent version of the virus, which can pick a biochemical lock and break into cells called macrophages, UF scientists report this month in the Journal of Virology. Researchers had set out to identify genetic biomarkers of HIV-1, which emerges in the later stages of the disease.

"Most times when people think about HIV, they think about it infecting the T cells, the lymphocytes," said Maureen Goodenow, Ph.D., the study's senior author and the Stephany W. Holloway University Chair in AIDS Research at the UF College of Medicine. "When HIV enters the macrophage, it doesn't kill the cell, it uses it to create more virus. If we can stop that, we can stop the virus. Not kill it directly, but stop it from getting what it needs to complete its life cycle, a cell."

Guity Ghaffari, Ph.D., the study's lead author and an assistant professor in pediatrics at UF's College of Medicine, said specific forms of HIV-1 develop in late-stage AIDS.

"With the biomarker, we can predict the virus's emergence over time," Ghaffari said. "A long-term goal is to use this genetic information to design a vaccine that doctors can use in combination with antiretroviral medications."

All strains of HIV-1 can invade T cells, the body's infection-fighting cells also known as lymphocytes. But they vary in their ability to enter macrophages, the long-living white blood cells often considered the scavengers of the immune system. The HIV-1 viruses that can infect both types of immune cells share a genetic lineage that allows them to chemically access macrophages through a series of ordered interactions at the virus's outer coating, called its envelope, the researchers noted.

To identify how HIV-1 can enter macrophages, UF researchers took RNA and DNA samples from a group of 50 HIV-1 infected children and, through a series of steps, sequenced the DNA and analyzed the genetic makeup.

They found that a region on the surface of the virus, glycoprotein 120, dictates how viruses get into macrophages. To enter, the virus requires the presence of a molecule called CD4 and certain co-receptors, or "locks," CCR5 or CXCR4, on the macrophages' outer cell wall.

If the CD4 molecule is present, this type of HIV-1 virus can use it like a key to open the locks and enter the cell, said Goodenow, a professor and co-director of experimental pathology in the department of pathology, immunology and laboratory medicine.

"As it turns out, in contrast to getting into lymphocytes, getting into macrophages is relatively an incredibly complex interaction, and in some ways that is good because if it were a very simple interaction, you'd have only one shot to break that up. But in this case you can have lots and lots of targets, interactions that perhaps scientists will be able to block," Goodenow said.

Goodenow said the problem with HIV is that it mutates so much.

"If you block one interaction, the virus goes around it and uses some other kind of interaction," Goodenow said. "So if you can select for multiple interactions simultaneously, the idea is you can shut down the virus. And that is one of the overall treatment strategies, because drugs have been very effective, but the virus develops a resistance. So the more classes of drugs you can put together with a vaccine, the hope is that we can really interfere with the virus life cycle to control viral mutation."

Steven D. Douglas, M.D., a professor and associate chairman of pediatrics at the University of Pennsylvania and director of the clinical immunology laboratories at Children's Hospital of Philadelphia, said the research is a unique molecular approach to distinguishing a particularly virulent form of HIV-1.

"These findings of complex determinants in the HIV envelope and their interaction with (cell) receptors provide an important new drug target or new vaccine target for researchers to point their guns toward," Douglas said.