Jan. 7, 1999 A team of California AIDS researchers has found the first direct clinical evidence that HIV does more than kill off T cells in the body's immune system. The skillful virus also prevents the production of new, healthy versions of these vital cells.
The scientists--from the Gladstone Institute of Virology and Immunology at UC San Francisco and from UC Berkeley--report their research results in the January issue of Nature Medicine. The study involved 21 patients.
"These studies focus our attention on the ways that HIV infection might stop the production of new T cells," said Joseph M. McCune, MD, PhD, senior study investigator and associate professor within the Gladstone Institute at UCSF. "To treat the disease, not only do we need potent anti-retroviral drugs to stop the virus from spreading and destroying T cells, we may also need additional therapies to ensure that T-cell production starts anew."
The findings are significant in understanding the puzzle of T-cell turnover in the HIV population, an area that has remained controversial among leading AIDS researchers who have proposed different theories to explain why T-cell counts decrease during the course of HIV disease.
Scientists use "turnover" to describe the natural process of T-cell death and new cell production that takes place in all individuals but that is altered after HIV infects the body. The precise mechanism that HIV uses to derail the different parts of this process have been unclear, but the end result is a collapse of the immune system that makes the body vulnerable to the opportunistic infections that cause full-blown AIDS.
It had been previously thought by many investigators that HIV decreased the T-cell count by causing the destruction of these cells. The new studies indicate that a more important contribution to disease may be the ability to stop T-cell production.
Using a new diagnostic tool, the research team determined the rates of production of two types of T cells--CD4 and CD8--that are major players in the immune system and prime targets of HIV. The technique was developed by McCune and Marc Hellerstein, MD, PhD, the lead investigator of the study and an associate professor at UCSF and at UC Berkeley.
"We found that the virus had an impact on both the rate of T-cell production and the rate of their destruction," Hellerstein said. "But it was the body's ability to produce new cells that was most important in determining T-cell counts."
Study participants included both men and women, and all were patients in the General Clinical Research Center at San Francisco General Hospital Medical Center. They represented three groups: HIV-negative and healthy, HIV-positive who had not undergone anti-HIV drug treatment, and HIV-positive who had completed a 12-week course of effective treatment with the potent antiretroviral drugs known as protease inhibitors after previously being untreated.
Major findings include:
For the first time, the daily rate of production of normal CD4 and CD8 T cells was directly measured in HIV-negative adults.
In untreated HIV-positive patients, CD4 and CD8 cells were being destroyed at a more rapid pace than in HIV-negative subjects and the body did not compensate by increasing the rate of production above the normal rate. Accordingly, the T-cell count decreased.
In HIV-positive patients whose virus was suppressed by potent therapy and whose T-cell counts increased, the rate of new cell production increased dramatically. The rise in new cell production was responsible for the increase in T-cell counts.
Warner Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology, called the findings surprising and noted that, "They promise to reshape our view of T-cell dynamics in HIV infection. These results have important implications on new approaches to therapy aimed at augmenting T- cell production rather than simply blocking T-cell destruction."
Crucial to the study was the new diagnostic tool that makes it possible to mark any human cell with a nontoxic label at the time of cell division and then to use the label to directly measure the numbers of new cells produced.
In this study, the label was incorporated in a specially formulated glucose solution that was administered to patients intravenously. After passing through complex biochemical pathways, the label attaches itself to the DNA of dividing cells.
The researchers took periodic blood samples from patients during the infusion and during the next two- to three-weeks. With the label serving as a marker for newly divided cells, they analyzed samples by using a cell sorter to isolate pure populations of circulating T cells and a mass spectrometer to measure the number of labeled cells.
Because the labeling was carried out in living people, the results serve as the first direct clinical evidence of cell production in the human bloodstream. In the past, cell generation could not be directly measured in clinical studies because techniques involved radioactive or toxic chemicals unsuitable for human consumption.
Based on the study findings and previous work, McCune said it appears that HIV may disrupt T-cell production in two key ways.
First, virus infection may short-circuit the division of memory T cells, whose function is to ward off foreign invaders that the body encountered in earlier years. Without a continuous supply of these cells, the immune system doesn't "remember" that it can successfully fight off previous enemies, and a person becomes susceptible to a variety of infections.
Second, virus infection may prevent the production of new T cells from the bone marrow and the thymus, the major organs of T-cell production.
In either case, the immune system would collapse and the HIV-infected patient would become immunodeficient, McCune explained.
"It remains unclear whether all HIV-infected patients will be able to increase T-cell production and restore their immune systems after treatment. For those who cannot, additional therapies may be required," he said.
Study co-investigators are Mary B. Hanley, BS; Eric Wieder, PhD; Diane Schmidt, BS, from UCSF and the Gladstone Institute; Derek Macallan, MD, PhD; Steven Deeks, MD, and Rebecca Hoh, RD, UCSF; Richard Neese, PhD, UCSF and UC Berkeley; and Denise Cesar, BS; Scott Siler, PhD, and Christina Papagoorgopoulos, PhD, UC Berkeley.
The research was supported by grants from the National Institutes of Health, the UCSF Center for AIDS Research, SpectruMedix, Inc., and the UCSF/Macy's Center for Creative Therapies and by funds from the J. David Gladstone Institutes.
The Gladstone Institute of Virology and Immunology, founded in 1991, focuses its research on HIV and AIDS. The Institute is one of three that make up the J. David Gladstone Institutes, a private biomedical research institute affiliated with UCSF and named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing interest in medical education and research.
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