In its quest for a first-rate scientific director, NIAID didn't have to go far afield-it found just what it needed in its own back yard: noted immunologist Thomas Kindt. Recognized for his contributions to the understanding of human T-cell leukemia virus-1 (HTLV-1), Kindt joined NIAID in 1977 and went on to become the chief of the Laboratory of Immunogenetics. Before arriving at NIH, Kindt, who received his Ph.D. from the University of Illinois at Urbana-Champaign in 1967, held academic appointments at The Rockefeller University and Cornell University Medical College in New York. He has received numerous scientific awards, including the Elliot Osserman Award from the Israel Cancer Research Fund and has advised the Howard Hughes Research Scholars Program. Kindt offers this description of his research.
Our laboratory studies the human retrovirus HTLV-1. Although most of the 10 to 20 million people infected with HTLV-1 worldwide suffer no overt disease, about 5% are afflicted with an acute and often fatal leukemia, a debilitating neurologic disease, or one of a variety of chronic conditions ranging from arthritis to uveitis. In certain areas of the world, such as southern Japan, the prevalence of HTLV-1 infection may be as high as 20%. This problem of endemic HTLV-1 infection, along with the recent increase in the infection rate in the United States, mainly among intravenous drug users, makes HTLV-1 a significant health threat.
We would like to understand why HTLV-1 infection produces such variable responses in different individuals. What events or factors dictate the difference between asymptomatic infection and fatal or chronic disease? Possible candidates include the nature of the cell infected; mutations in the virus genome, which spans approximately 9 kilobases (kb); variations in host-virus interactions; the genetic background of the infected subject; or some combination of these parameters.
We have developed in vitro and in vivo systems to learn more about how HTLV-1 exerts its highly variable effects on the host. The laboratory rabbit, which is highly susceptible to HTLV-1 infection, is an animal model that mimics human infection in several ways. As its name implies, HTLV-1 infects T cells, and rabbit T-cell lines infected with HTLV-1 survive in culture indefinitely. We have administered HTLV-1-infected T- cell lines to rabbits and monitored the animals to see whether they develop disease or asymptomatic infections. In an effort to determine what is responsible for the divergent outcomes, we then studied the characteristics of the various HTLV-1-infected cell lines, along with the structure of the integrated virus, or provirus, and the functions of the provirus' component genes.
To date, we have identified HTLV-1 cell lines that cause acute disease in rabbits that is similar to human leukemia and, in other cases, chronic cutaneous lymphoma. We are now examining these lines in detail to ascertain how they differ from lines that give rise to asymptomatic infection. We have observed certain small differences in gene expression between the so-called lethal and nonlethal cell lines, but none of those differences absolutely correlates with the disease-causing potential of the infected cell. We have cloned proviruses from such lethal and nonlethal lines, and, through direct injection, have used those DNA clones to infect normal human and rabbit cells in vitro and rabbits in vivo. In a further effort to pinpoint the genes that control HTLV-1's pathogenicity, we are now ex-changing different component genes among the viruses from the lethal and nonlethal cell lines to create chimeric HTLV-1 strains.
Our current data suggest that a major factor in pathogenicity is the expression of certain, as-yet-unidentified cellular genes-expression that is very likely induced by infection with the lethal virus. Our in vitro studies show that expression of such genes predisposes the cell to overcoming host resistance. One route by which this occurs is by the apoptosis, or programmed death, of host T cells, which are presumably the cells that keep the infected cells in check.
In the future, our lab, which includes R. Mark Simpson, Tongmao Zhao, Mary Ann Robinson, Michel Leno, and Florence Bowers, will concentrate on exploring the effects of genes from lethal and nonlethal viruses on the expression of host cellular genes. First, both viral and cellular genes that exert either a positive or negative effect on pathogenesis will be identified by screening HTLV-1-infected cell lines by in vitro molecular and cellular methods. When candidate genes are found, nonlethal HTLV-1-infected cell lines transfected with these pathogenesis-promoting genes and lethal HTLV-1-infected cell lines transfected with pathogenesis-suppressing genes can be tested for in vivo effects.
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