Of the cytopathic retroviruses that affect mammals, including HIV-1, many selectively infect CD4+ T cells and cause immunosuppressive syndromes. These diseases destroy both the thymus and the small and large intestines, after infecting and killing T-lineage cells in both tissues. A mutant of the murine leukemia retrovirus MoMuLV-TB, called ts1, causes this syndrome in susceptible strains of mice. In FVB/N strain mice that are infected at birth, thymic atrophy, CD4+ T cell loss, intestinal collapse, body wasting, and death occur by approximately 30-40 days postinfection (dpi). Apoptosis of ts1-infected T-lineage cells, in the thymus, peripheral lymphoid system and intestines is caused by accumulation of the ts1 mutant viral envelope preprotein gPr80(env), which is inefficiently cleaved into the mature viral proteins gp70 and PrP15E. We show here that ts1 infection in the small intestine is followed by loss of intestinal epithelial cell (IEC) thyroid-stimulating hormone (TSH) and cell cycling gradients (along the crypt-villus axes), accumulation of gPr80(env) in intestinal cells, apoptosis of developing T cells in the lamina propria (LP), and intestinal collapse by approximately 30 dpi. In infected mice treated with the antioxidant drug monosodium luminol (GVT), however, normal intestinal epithelial cell gradients are still in place at 30 dpi, and IECs covering both the crypts and villi contain large amounts of the antioxidant transcription factor Nrf2. In addition, no apoptotic cells are present, and accumulated gpr80(env) is absent from the tissue at this time. We conclude that GVT treatment can make ts1 a noncytopathic virus for intestinal lymphoid cells, as it does for thymocytes [25]. As in the thymus, GVT may protect the intestine by reducing oxidant stress in infected intestinal T cells, perhaps by prevention of gPr80(env) accumulation via Nrf2 upregulation in the IECs. These results identify GVT as a potential therapy for intestinal diseases or inflammatory conditions, including HIV-AIDS, in which oxidative stress is a triggering or exacerbating factor.