AIDSWEEKLY Plus, Monday, 30 June 1997
Daniel J. DeNoon, Senior Editor
A new approach to AIDS therapy would cause HIV infected cells to kill themselves.
The approach is based on studies indicating that HIV causes infected cells to lose a surface molecule known as Fas ligand. Interaction of Fas with its ligand triggers cellular suicide, a phenomenon known as apoptosis or programmed cell death.
Apoptosis is a normal process used by the body to delete cells that are no longer needed. Recent work suggests that this process is also used to rid the body of virus-infected cells before the virus can replicate.
"We propose an adjunctive therapy that is not predicated on inhibiting the activity of a viral protein," wrote Scott Sieg and colleagues of Case Western Reserve University. "Since the deficiency in Fas ligand seems to favor viral production, the replacement of Fas ligand activity in HIV infected individuals may decrease the amount of virus in vivo and thereby provide benefit to patients."
Sieg et al. put forward their proposal in the Proceedings of the National Academy of Sciences ("Fas Ligand Deficiency in HIV Disease," PNAS, 1997;94(11):5860-5).
They noted that several viruses have evolved means of inhibiting apoptosis. These include Epstein-Barr virus, adenovirus, cowpox virus, myxoma virus, papillomavirus, parainfluenza virus type 3, and herpes simplex virus type 2.
The researchers found that Fas ligand is expressed on peripheral blood mononuclear cells (PBMC) from healthy individuals. But they found that Fas ligand was undetectable on PMBCs from people with HIV infection. Unlike the PBMCs from the healthy donors, the PBMCs from people with HIV infection had no demonstrable Fas-ligand activity.
Sieg et al. then treated PBMCs from four HIV infected patients with anti-Fas IgM antibody, which is known to mediate Fas-induced apoptosis.
"Treatment with this antibody represents a reconstitution of Fas ligand activity in the patients' PBMCs," Sieg et al. wrote.
Addition of antibody to the PBMCs from HIV infected patients resulted in >90 percent inhibition of viral production. Lymphocyte function was unaffected.
"We suggest that the deficiency in Fas ligand activity may play an important role in the pathogenesis of HIV disease," Sieg et al. wrote. "We propose that HIV infection of patients depresses Fas ligand expression on monocytes in vivo and thereby enhances the survival of cells that actively produce virus."
Reconstitution of Fas activity, the authors suggested, selectively induces apoptosis of cells that are actively producing HIV.
They noted that previous studies have shown that Fas antigen expression on CD4(+) and CD8(+) T cells increases with progression of HIV disease.
"Consequently, therapy based on reconstituting Fas ligand activity in HIV infected patients would optimally be instituted early in the disease process before the accumulation of significant numbers of susceptible uninfected T lymphocytes," Sieg et al. wrote.
Liver cells express the Fas receptor, but Sieg et al. noted that Fas ligand has been administered to mice without toxicity. They recommended that any future therapy attempting Fas ligand reconstitution be formulated to minimize liver toxicity.
The corresponding author for this study is David Kaplan, The Institute of Pathology, Case Western Reserve University, Biomedical Research Building, 2109 Adelbert Road, Cleveland, Ohio 44106-4943.
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