UNIFYING HYPOTHESIS FOR THE PATHOGENESIS OF HIV-ASSOCIATED DEMENTIA COMPLEX, VACUOLAR MYELOPATHY, AND SENSORY NEUROPATHY

Neurological diseases associated with HIV infection include dementia, vacuolar myelopathy, and sensory neuropathy. Although in vitro studies suggest that other nervous system cell types could harbor HIV, immuno histochemical and in situ hybridization studies have indicated that on ly macrophages/microglia are significantly infected in the central ner vous system. In the peripheral nervous system, even HIV-infected macro phages are rare. Therefore, theories regarding the pathogenesis of HIV -associated neurologic disorders have centered around the elaboration of substances that may be toxic to neurons, oligodendrocytes or myelin . These potential toxins include HIV proteins, cellular metabolites, a nd cytokines. In this review we present evidence that there are large numbers of macrophages/microglia present in the nervous system of pati ents with these diseases and that they produce tumor necrosis factor ( TNF)-alpha. The large increase in macrophage activity late in HIV infe ction may be due to the diminution in production by CD4-positive T cel ls of cytokines such as interleukin (IL)-4 and IL-10 which are inhibit ors of macrophage activities. We hypothesize that HIV-associated demen tia complex, vacuolar myelopathy, and sensory neuropathy are directly or indirectly related to the increased numbers of macrophages found in brain, spinal cord, and peripheral nerve. Future therapies may be dir ected towards inhibition of macrophage functions.