HIV is notorious for grinding down the immune system. But exactly how its primary target--a class of immune cells called CD4 T lymphocytes--is driven to extinction has been vociferously debated. One side argues that HIV slays the cells and exhausts an immune system that's frantically making replacements. The other side believes that the virus chokes off the supply line of CD4 cells. Now, results from a new technique, reported in the January issue of Nature Medicine, lend support to the notion that HIV interferes with T cell production.
To tackle this vexing question, a team led by immunologist Joseph McCune of the University of California (UC), San Francisco, and endocrinologist Marc Hellerstein of UC Berkeley used an innovative method (Science, 20 February 1998, p. 1133). They intravenously infused subjects with a solution of glucose--a precursor of deoxyribose, one of the chemical building blocks of DNA--in which the glucose molecules contain deuterium, a nonradioactive isotope of hydrogen. They then took blood samples at various times after the infusion had ended. As T cells divided, the deuterium-labeled DNA was progressively replaced by unlabeled DNA, allowing the team to calculate the production rate of new cells as well as their average life-span.
On average, T cells had shorter life-spans in untreated HIV-infected patients than in uninfected controls, suggesting that the virus was killing them off. But the production rate of T cells in infected patients was no higher than in controls, as would be expected if the immune system was working overtime to replace these destroyed cells. And patients taking antiviral drugs that drastically reduced their levels of HIV had higher T cell production levels than the control and untreated groups--the opposite of what would be expected if increased production were simply a response to T cell destruction by HIV. Instead, the authors propose, antiviral therapy leads to a "disinhibition" of the production machinery.
For some researchers, the new paper essentially resolves the controversy. In an accompanying article in Nature Medicine, immunologist Giuseppe Pantaleo of the Vaudois Hospital Center in Lausanne, Switzerland, summarily declares that the study "puts an end to four years of exciting (although often harsh) debate" over the issue. But proponents of the "immune exhaustion" model argue that untreated HIV-positive patients may still exhaust their immune systems, which must replenish their smaller pool of immune cells much faster than uninfected people do.
McCune says that if HIV is indeed interfering with production of new T cells, the findings might point to new strategies for enhancing this production. For example, T cells could be cultured outside the body for reintroduction later in the disease, or patients could be given signaling molecules called cytokines to prompt immune system cells to divide.