Population Briefs | June 2004, Vol. 10, No. 2 | Biomedical Research: Combating HIV on Multiple Fronts

Population Briefs: Reports on Population Council Research

June 2004, Vol. 10, No. 2

Biomedical Research
Combating HIV on Multiple Fronts

Despite accounting for only approximately 1 percent of circulating immune system cells, dendritic cells are among the first such cells that encounter HIV following sexual or mother-to- child transmission of the virus by virtue of their position within the mucosa and throughout the body. These little-known cells are vital to both the initiation and control of immune responses. Unfortunately, the encounter between dendritic cells and HIV does not end as it should, with immunity to the virus. Paradoxically, the meeting instead spurs an increase in viral replication.

Population Council immunologist Melissa Pope has studied dendritic cells and HIV for more than a decade. Her work may lead to identification of ways to prevent HIV infection by targeting activated dendritic cells with a vaccine to launch an attack against HIV, or by using a microbicide to block the mucosal transmission of HIV. The term “microbicide” refers to a range of products, in cream, gel, film, or suppository form, that would substantially reduce the transmission of HIV—and possibly other sexually transmitted infections—when applied prior to sexual intercourse.

HIV: A formidable foe
Pope’s research has shown that HIV impairs dendritic cells in a number of ways. The virus enters dendritic cells and uses them to travel from the mucosa to areas of the body where it may infect other immune system cells. Normally, dendritic cells engulf pathogens and degrade them into protein fragments, called antigens. They display the antigens on their cell membranes. Other immune system cells recognize the antigens and launch a potent immune response. Crucially, HIV fails to stimulate dendritic cells to display these antigens optimally. Research by Pope and her collaborators shows that at the beginning of the infection process, mature and immature dendritic cells transport the virus without themselves becoming infected; later immature dendritic cells become infected and replicate HIV.

Recent work done by Pope and her colleagues may give insight into ways to fight HIV. Individual particles of HIV enter dendritic cells and other cells when proteins on the surface of HIV bind to specific molecular receptors on the surface of cells. Pope and her collaborators investigated HIV binding to cells in human cervical tissue, which had been removed from women undergoing planned hysterectomies. The team used small molecules known to attach to the cellular receptors that are favored by HIV. This strategy blocked the binding of HIV to these receptors, thus preventing the fusion of HIV to the cell. The scientists also attempted to neutralize proteins on the surface of HIV itself. They found that different receptors play a role in the infection of cervical cells, which do not migrate, and of dendritic cells, which do. The migratory nature of dendritic cells can ferry HIV into the body where it can infect and decimate other cells of the immune system. “Microbicidal preparations should target the receptors that are exploited by HIV in both of these instances and target proteins on the surface of HIV as well,” says Pope.

Toward a vaccine
An effective vaccine would induce activated dendritic cells to launch a proper immune response against HIV. In the best case, a vaccine could be used by people before or after HIV infection and would result in immunity that could pass from mother to child during pregnancy. Because dendritic cells are so scarce in the periphery of the body, increasing the number of circulating dendritic cells may be a key step in producing a workable vaccine. Pope and her colleagues investigated the effects of Flt3L, a molecule that has been shown to trigger the movement of dendritic cells (and their precursors) from the bone marrow into the rest of the body. “We found that although the standard treatment with Flt3L for 10 to 14 days increased the percentage of circulating dendritic cells in monkeys, treatment for as little as five to seven days was as effective, if not more so, at increasing the dendritic cell count,” says Pope. “Dendritic cell levels peak about four days after the week-long treatment, not immediately after, which is when researchers typically monitor the number of cells.”

In addition to potentially enhancing an HIV vaccine, increasing the numbers of circulating dendritic cells will facilitate the study of the role of dendritic cells in HIV infection.

“Our research is illuminating ways of keeping dendritic cells from transporting or becoming infected with HIV, while at the same time improving their ability to initiate a powerful attack on the virus,” concludes Pope.

Sources
Hu, Qinxue, Ines Frank, Vennansha Williams, John J. Santos, Patricia Watts, George E. Griffin, John P. Moore, Melissa Pope, and Robin Shattock. 2004. “Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue,” Journal of Experimental Medicine 199(8): 1065–1075.

Teleshova, Natalia, Jennifer Jones, Jessica Kenney, Jeanette Purcell, Rudolf Bohm, Agegnehu Gettie, and Melissa Pope. 2004. “Short-term Flt3L treatment effectively mobilizes functional macaque dendritic cells,” Journal of Leukocyte Biology 75(6): 1102–1110.

Turville, Stuart G., John J. Santos, Ines Frank, Paul U. Cameron, John Wilkinson, Monica Miranda-Saksena, Joanne Dable, Hella Stössel, Nikolaus Romani, Michael Piatak Jr., Jeffrey D. Lifson, Melissa Pope, and Anthony L. Cunningham. 2004. “Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells,” Blood 103(6): 2170–2179.

Outside funding
Elizabeth Glaser Pediatric AIDS Foundation and the U.S. National Institutes of Health

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