Scientists Report New Lead in the Regulation of HIV Coreceptor

Scientists have learned that when people are sexually exposed to HIV-1, they receive one strain of the virus, known as M-tropic, that causes the initial and mostly asymptomatic infection of the immune system. A second strain, known as T-tropic, becomes prevalent several years later and marks the onset of AIDS.

In the October issue of the Journal of Immunology*, government scientists report that they may have discovered one of the factors behind this deadly switch from M- to T-tropic virus. They found in laboratory studies that different cytokines, ubiquitous secreted proteins that the immune system uses to communicate, influence the display of the protein CXCR4 on the surface of certain immune cells.

Previous work has shown that T-tropic virus binds to CXCR4 as one of two proteins that it needs to latch onto and infect human T cells. M-tropic virus, conversely, uses the CCR5 protein as its coreceptor, marking a key difference in how the two strains infect cells.

"This finding potentially takes the HIV coreceptor story one step further," said J. Paul Zoeteweij, Ph.D., lead author on the paper and a scientist in the Dermatology Branch at the National Cancer Institute (NCI). "It suggests that some cytokines have a hand in regulating how much CXCR4 makes it to the cell surface."

According to Andrew Blauvelt, M.D., senior author on the paper and a scientist with NCI's Dermatology Branch, the finding also suggests that in people who are HIV positive, if certain cytokines become prevalent and tell immune cells to make CXCR4, it would be advantageous for the switch from M- to T-tropic virus.

"It has been shown in previous studies that T-tropic virus is predominant later in the disease and, quite independently of this finding, that there is change in the types of cytokines that people produce as they progress to AIDS," said Blauvelt. "Until now, there has been little data linking these two events. Our finding suggests a possible link."

However, Blauvelt and his colleagues warned that the link is still only speculative and would require a multiyear study in people to confirm.

In the study published this month, the scientists used Langerhans cells isolated from skin. Langerhans cells, scavenging immune cells that also are present on genital surfaces, are thought to be the first immune cells that HIV-1 encounters during sexual transmission. Studies indicate that after Langerhans cells become infected with M-tropic virus, they migrate to the lymph nodes, where the virus may spread to other immune cells.

Hana Golding, Ph.D., second author on the study and a scientist at the Center for Biological Evaluation and Research at the Food and Drug Administration, said Langerhans cells offer a unique perspective in studying HIV-1. "Langerhans cells are capable of displaying either CCR5 or CXCR4 on their surfaces," said Golding. "Thus, they are ideal for studying the effects of cytokines on the production of these proteins."

In a series of experiments, Golding and colleagues exposed cultured Langerhans cells to a panel of 14 different cytokines. The dose of each cytokine was carefully regulated, and other tests detected no ambient levels of naturally occurring cytokines that might interfere with the experiment.

The scientists found that while the cytokines had little effect on the production of the M-tropic CCR5 protein, they did have a measurable effect on the T-tropic CXCR4 protein. For instance, the scientists found some cytokines -- interferons -- seemed to shut down the production of CXCR4, while other cytokines -- IL-4 and TGF-beta1 -- increased the expression of CXCR4 on the cell surface, an indication that cytokines play a role in regulating the production of this protein.

This raised an obvious question. Does the cytokine-induced increase in CXCR4 have an effect on the ability of T-tropic virus to bind to Langerhans cells? If so, it would suggest, in theory, that changes in cytokine production could play a role in people in the switch to T-tropic virus. The question also was interesting because Langerhans cells constantly migrate to the lymph nodes during the course of HIV infection and could serve to spread T-tropic virus to other immune cells.

Consistent with their previous experiments, the scientists found that when they exposed pure populations of Langerhans cells in culture to TGF-beta1 -- an inducer of CXCR4 production -- fusion between a surface protein from the T-tropic virus and CXCR4 occurred much more frequently. Conversely, when Langerhans cells were exposed to gamma-interferon, which was known to inhibit CXCR4 production, the HIV protein bound much less to the cells.

"These experiments suggest that by exploring further the role of cytokines in regulating the production of CXCR4 on immune cells, it may be possible to identify important cellular targets that could be exploited to stop the switch to T-tropic virus and the onset of AIDS," said Blauvelt.

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*The title of this study is "Cytokines Regulate Expression and Function of the HIV Coreceptor CXCR4 on Human Mature Dendritic Cells." The authors are J. Paul Zoeteweij, Hana Golding, Howard Mostowski, and Andrew Blauvelt." Journal of Immunology, October 1, 1998.