Edited by: Neeraja Sankaran
G. Pantaleo, C. Graziosi, J.M. Demarest, L. Butini, M. Montroni, C.H. Fox, J.M. Orenstein, D.P. Kotler, A.S. Fauci, "HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease," Nature, 362:355-8, 1993. (Cited in 293 publications through January 1995)
J. Embretson, M. Zupancic, J.L. Ribas, A. Burke, P. Racz, K. Tenner-Racz, A.T. Haase, "Massive covert infection of helper T lymphocytes and macrophages by HIV during incubation period of AIDS," Nature, 362:559-62, 1993. (Cited in 252 publications through January 1995)
Comments by Giuseppe Pantaleo,National Institute of Allergy andInfectious Diseases, Bethesda, Md.;Janet Embretson, Schwegman, Lundberg & Woessner, P.A., Minneapolis
These two publications, ranked among 1993's 10 most-cited papers (K.Y. Kreeger, The Scientist, April 4, 1994, page 15), have continued to amass a high number of citations.
Although they are the products of work from independent research groups in different laboratories in Bethesda, Md., and Minneapolis, the two papers complement each other, the authors agree. In both instances, the researchers reported on HIV activity during the early, asymptomatic phases of infection.
"Until [these papers were published] it was commonly accepted that the clinically asymptomatic phase of HIV infection was also microbiologically inactive," says Guiseppe Pantaleo, a visiting scientist at the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health in Bethesda.
"Our paper was among the first ones to demonstrate that even during the period when HIV infection is clinically silent, the disease is active and the viral load in lymphoid tissue is significantly higher compared to that in peripheral cells."
The high level of interest in these papers continues, Pantaleo offers, because the findings "completely changed our view of the disease. Our whole approach to dealing with it changed since we realized that we need to treat HIV infection as early as we can. However, at the present time there are no drugs available for long-term therapies for HIV infections."
Since the papers' publication, "other new papers have clearly confirmed that the disease is very active. I am pleased to see that the results have been corroborated worldwide," he comments.
"Until three or four years ago we did not even have techniques to accurately estimate viral load. Techniques like polymerase chain reaction--PCR--really changed things. We can now accurately measure viral load and thus monitor progression of the disease."
The results have several important implications for AIDS research, he claims. For instance, the high viral load of the lymphoid tissue "may help to explain the progressive depletion of CD4+ T cells and the loss of related function even when there is clinical latency."
The research "also suggests that the lymphoid tissue is the primary site for virus replication and for the initial replication of infection." Recent studies showing the appearance of the simian immunodeficiency virus (SIV) in the lymph nodes as early as five days after infection support this suggestion.
Janet Embretson was a postdoc in Ashley Haase's laboratory at the University of Minnesota when her team's paper was published.
Embretson, who also attended law school during her graduate years, continues to stay informed on this and other research as an associate attorney with the Minneapolis-based patent law firm of Schwegman, Lundberg, and Woessner. She notes that the development of powerful new methods enabled scientists to look at old problems in new, more effective ways. "PCR in situ is a very powerful technique, although I must admit that when I first went to Dr. Haase's lab, I was a skeptic about its value."
What turned the skeptic into a believer, she says, was the fact that the technique "allows you to look at individual cells and thus, yields answers to questions about infection that you couldn't get from any other methods. We discovered that 20 percent of all CD4+ cells in the lymph node were actually infected with HIV even during the early stages of infections."
Haase's group found that a large number of helper T cells as well as macrophages in the lymphoid system harbored viral DNA, thereby forming a large intracellular reservoir of HIV, contributing to the immune depletion in the late stages of disease. "[Pantaleo's] work on viral DNA was a population analysis, vs. ours, which was at the level of the individual cell," Embretson remarks. "Using a double labeling technique, we were able to pinpoint which cell types had viral DNA and which ones had viral RNA. We defined a spatial context to the course of events in the disease."
Since the paper was released, Embretson says, "people are building on these results," in their attempts to develop more effective treatments and vaccines against AIDS. (For a review, see J. Coffin, Science, 267:483-89, 1995.) "In order to fight the disease, you have to know everything possible about it," she maintains. Together, the authors agree, these two reports underscore the need for the earliest possible intervention in order to check the progression of AIDS.