DESCRIPTION (provided by applicant): In mice infected with the ts1 retrovirus, a syndrome develops that resembles human HIV-AIDS in many respects. In infected mice, large amounts of the ts1 envelope preprotein gPr80env are retained in the endoplasmic reticulum (ER) of (a) infected central nervous system (CNS) astrocytes, and (b) thymocytes. Our recent publications identify this accumulation as the causative agent in astrocyte death leading to neurodegeneration in infected mice. We have also found that the redox balancing agent a-luminol (trade name Galavit) protects infected animals from paralysis and from thymic atrophy. The protective effect of Galavit is correlated, as expected, with an absence of virus replication in the CNS. To our surprise, however, Galavit-treated animals show substantial viral replication in the thymus, although thymic atrophy does not occur, and the treated animals remain healthy even after all control (untreated infected animals) have died. We propose here to determine whether and how ER stress, mitochondrial stress and oxidative stress resulting from gPr80env accumulation might contribute to thymocyte death and thymic atrophy in the ts1 -infected mouse. We further propose to determine how Galavit protects the thymus of treated infected animals. We suspect that the cytopathic effects of HIV-1 for human thymocytes and T cells, like those of ts1 for thymocytes and T cells of mice may be due to do retention of the HIV-1 envelope preprotein in the ER of specific cell types, and to oxidative stress responses by these cells to this accumulation. To our knowledge, we are the first to propose such a mechanism for T cell loss in AIDS. If Galavit protection of the te1 thymus is due to its prevention of oxidative stress and apoptosis in thymocytes, we will have identified the first drug that can fully protect T-lineage cells that are productively infected with a retrovirus. This will serve as promising evidence that HIV-AIDS infection might be approached in a similar fashion, by antioxidant prevention of cytopathic effects in cells that have been infected, and which cannot be "cured" of their latent virus. Studies of Galavit as an anti-HIV antiviral agent, or as an antioxidant therapy for prevention of HIV cytopathic effects, are the subject of another application in preparation.
|Effective start/end date||9/30/05 → 2/29/08|
- National Institutes of Health: $75,000.00
- National Institutes of Health: $73,238.00