Scientists at the National Institute of Child Health and Human Development (NICHD) have developed a new model for studying the destructive effects of AIDS in live tissue samples. The critical events in the development of AIDS take place in lymphoid tissue, but AIDS research has been hampered by the fact that an animal model of HIV infection that readily mimics human AIDS does not exist. Scientists also lack readily available laboratory techniques for closely mimicking, in vitro, HIV infection in the body (in vivo).
The NICHD scientists have overcome this limitation by culturing and infecting pieces of tonsil, which is composed largely of lymphoid tissue, obtained from tonsillectomies. With this advance, they have helped illuminate one of the central questions of HIV pathology--what triggers the eventual development of AIDS in people who carry HIV?
The finding appears in the March issue of Nature Medicine, and was reported by scientists Svetlana Glushakova, Jean- Charles Grivel, Wendy Fitzgerald, Andrew Sylvester, Joshua Zimmerberg, and Leonid Margolis.
The laboratory model, which allows HIV to be studied in the tissue in which it is usually found, consists of tiny (1mm) cubes of tonsil cultured on wet collagen sponges. The cubes, which retain their viability and native architecture for several weeks, can be infected with HIV (which multiplies and spills into the surrounding medium), so that they mount a response to immunological challenge. Such responses are the hallmark of lymphoid tissue. Thus, just as they would in the body, the blocks of lymphoid tissue make antibodies to tetanus toxoid or diphtheria toxoid (which are used to immunize people against tetanus and diphtheria), and they do so with much greater efficiency than isolated immune cells, underscoring the importance of the cell's environment to the cell's proper functioning.
With the help of these cultured, immunologically responsive, tonsil blocks, the NICHD team has started to answer some of the basic questions about AIDS and HIV infection. HIV is transmitted by a form of the virus that can infect macrophages, scavenger cells that live in the body's tissues, and other immune cells known as CD4+ T lymphocytes. Viruses with this property are called M- tropic (M for macrophage) and are the predominant form of HIV found in a person's body early in the disease process. Later in the course of the disease, a different strain of the virus often predominates, and that strain is called "T-tropic," because it attacks T lymphocytes almost exclusively.
Researchers speculate whether AIDS develops partly because of the transition from M-tropism to T-tropism. In the Nature Medicine paper, the researchers present strong evidence that it is a change in the virus itself that leads to irreparable damage to the immune system.
Dr. Margolis and his coworkers showed that, after being infected with T-tropic viruses, the response of the tonsil blocks to immunological challenge is suppressed, whereas M- tropic viruses have the opposite effect, making the blocks secrete more antibody. This study supports the view that changes in the properties of HIV may contribute to the immunologic deterioration that leads to AIDS.
This is a useful tool for scientists to observe the development of immunodeficiency outside the body. The technique promises to provide important information about HIV pathogenesis and should be extremely useful in developing and testing therapies and vaccination strategies.