Special Edition, Spring 2002

Immunology
Role of Dendritic Cells in HIV Infection Clarified

The immune system is made up of several kinds of cells that function in concert to provide humans and animals with protection against pathogens. Often, this system works flawlessly, quashing infections before they can kill their host. Sometimes, however, the system fails and infection prevails. This is what happens, for example, when people are infected with the human immunodeficiency virus (HIV), which causes AIDS.

Scientists have been investigating the immune system for decades, yet there is still much that remains unknown about its function. One of the least-understood members of the immune system family is the dendritic cell. Accounting for only about one percent of all immune system cells, dendritic cells, one type of leukocyte, are nevertheless vital to both the initiation and control of immune responses.

Immunologist Melissa Pope, who recently joined the Population Council’s Center for Biomedical Research, has studied the action of dendritic cells during HIV infection for the past decade. In parallel with human studies, Pope uses rhesus macaques and the simian immunodeficiency virus (SIV) to model human HIV infection. Her findings have contributed to one of the widely accepted theories for the mechanism of sexual transmission of HIV. Positioned within the mucosa, dendritic cells are one of the first white blood cells that meet HIV following sexual or perinatal transmission and may be pivotal for the onset and spread of infection. Ultimately, Pope’s work may identify ways to block the mucosal transmission of HIV with microbicidal formulations. This work may also provide clues in the search for an HIV vaccine.

Antigen-presenting cells
In their immature stage, dendritic cells engulf pathogens and degrade them into protein fragments. As they migrate via the afferent lymphatic system to the draining lymph tissues, immature dendritic cells evolve into mature dendritic cells. They then display the protein fragments from the degraded pathogens on their cell membranes. Other immune system cells, B-cells and T-cells, recognize proteins and protein fragments, also known as antigens, and launch a potent antigen-specific immune response. Thus, dendritic cells are known as “antigen-presenting cells.”

This chain of events does not appear to occur successfully when dendritic cells encounter HIV, however. When dendritic cells come across HIV and subsequently interact with T-cells, the encounter, rather than triggering a powerful immune response that should clear infection, spurs a great increase in viral replication. Pope’s lab is conducting parallel in vitro studies involving immature and mature dendritic cell subsets and SIV. With these studies, Pope and her team aim to understand the early events of dendritic cell–HIV interactions, with the goal of optimizing the presentation of HIV antigens on the surfaces of dendritic cells in order to activate T- and B-cell responses instead of facilitating virus spread.

Virus localization
These experiments have revealed that the virus becomes localized in different areas of dendritic cells depending on the cells’ maturity level. Pope and her colleagues noted a peripheral localization of the virus in immature dendritic cells, with small vacuoles containing one or two intact viral particles near the cell membrane. In mature dendritic cells they noted an intense intracellular localization of numerous intact viral particles in large vacuoles near the nucleus.

Pope and her team are investigating the implications of these two distinct localizations. They believe immature and mature dendritic cells may use different mechanisms to entrap viral particles. Understanding these uptake mechanisms is the first step in devising ways to block them, says Pope.

Their experiments further showed that dendritic cells do indeed process some of the virus and display antigens on their membranes to be presented to T-cells. Pope and her associates will now attempt to determine ways to boost this antigen presentation and, along with it, subsequent immune activation.

In addition to providing clues about virus uptake in dendritic cells for immune stimulation, these experiments may give insight to the ensuing spread of virus from dendritic cells to T-cells. Pope is investigating whether viral particles remain intact, not infecting the dendritic cells they occupy, until they get transmitted to T-cells, or whether dendritic cells eventually do become infected and spread newly formed virus to T-cells.

"We still have a lot to learn about the interactions between HIV, dendritic cells, and other immune cells," says Pope. "But this basic research, mapping out these microscopic cellular activities, lays the groundwork for the development of microbicides and vaccines that may one day save people's lives."  Originally published in Population Briefs 7(4), December 2001.

Sources
Frank, Ines and Melissa Pope. 2001. “Consequences of dendritic cell (DC)–immunodeficiency virus interactions: Chemically inactivated virus as a model for studying antigen presentation and virus transmission by primate DCs,” Immunobiology 204: 622–628.

Mehlhop, Erin, Loreley A. Villamide, Ines Frank, Agegnehu Gettie, Christine Santisteban, Davorka Messmer, Ralf Ignatius, Jeffrey D. Lifson, and Melissa Pope. 2002. “Enhanced in vitro stimulation of rhesus macaque dendritic cells for activation of SIV-specific T cell responses,” Journal of Immunological Methods 260(1–2): 219–234.

Pope, Melissa. 2000. “Mechanisms of mucosal immunity: How does the dendritic cell fit in?” AIDS Patient Care and STDs 14(4): 207–210.

Outside funding
The Elizabeth Glaser Pediatric AIDS Foundation, the National Institutes of Health, and the Rockefeller Foundation

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