Suppression of neurocognitive damage in LP‐BM5‐infected mice with a targeted deletion of the TNF‐α gene

Brain levels of TNF‐α increase in many inflammatory conditions, including HIV‐1 infection, and may contribute to neurodegenerative processes. The paucity of agents that can selectively and potently block TNF‐α processing or its receptors has led us to investigate the role of TNF‐α in chronic neurodegeneration associated with retroviral infection using mice with targeted deletions of the TNF‐α gene. Infection of wild‐type C57BL/6 mice with the LP‐BM5 murine leukemia retrovirus mixture leads to the development of a severe immunodeficiency as well as cognitive deficits and neuronal damage. TNF‐α‐(‐/‐) mice infected with LP‐BM5 developed a systemic immunopathology indistinguishable in severity from that observed in contemporaneously infected wild‐type mice. In contrast, the performance of infected TNF‐α‐(‐/‐) mice in the γ‐maze and Morris water maze was not different from that of uninfected TNF‐α‐(‐/‐) mice. The extent of glial activation in the striatum, as indicated by the increase in density of peripheral benzodiazepine receptors, was equivalent in both groups of LP‐BM5‐infected mice. However, the decrease in striatal MAP‐2 expression, a marker of neurodegeneration observed in infected wild‐type mice, was not found in infected TNF‐α‐(‐/‐) mice. While the loss of TNF‐α appeared to have no effect on the course or severity of the central or peripheral immunopathology resulting from LP‐BM5 infection, the behavioral and biochemical manifestations were substantially curtailed in the TNF‐α‐(‐/‐) mice. These findings directly support a role for TNF‐α in the neurodegenerative processes associated with viral infections such as HIV‐1.—Iida, R., Saito, K., Yamada, K., Basile, A. S., Sekikawa, K., Takemura, M., Fujii, Wada, H. H., Seishima, M., Nabeshima, T. Suppression of neurocognitive damage in LP‐BM5‐infected mice with a targeted deletion of the TNF‐α gene. FASEBJ. 14, 1023–1031 (2000)