Specific Tropism of HIV-1 for Microglial Cells in Primary Human Brain Cultures

Abstract

Human immunodeficiency virus (HIV) frequently causes neurological dysfunction and is abundantly expressed in the central nervous system (CNS) of acquired immunodeficiency syndrome (AIDS) patients with HIV encephalitis or myelopathy. The virus is found mostly in cells of the monocyte-macrophage lineage within the CNS, but the possibility of infection of other glial cells has been raised. Therefore, the effects of different HIV-1 and HIV-2 strains were studied in primary cultures of adult human brain containing microglial cells, the resident CNS macrophages, and astrocytes. These cultures could be productively infected with macrophage-adapted HIV-1 isolates but not with T lymphocyte-adapted HIV-1 isolates or two HIV-2 isolates. As determined with a triple-label procedure, primary astrocytes did not express HIV gag antigens and remained normal throughout the 3-week course of infection. In contrast, virus replicated in neighboring microglial cells, often leading to their cell fusion and death. The death of microglial cells, which normally serve immune functions in the CNS, may be a key factor in the pathogenesis of AIDS encephalitis or myelopathy.

Pathogenesis of ovine lentiviral encephalitis: Derivation of a neurovirulent strain by in vivo passage

“…In vitro studies demonstrated that this brain-adapted virus replicated more ef®ciently in microglia and less ef®ciently in GSM than the parental virus. HIV tropism for microglia has also been demonstrated in vitro and has been shown to be determined by the same regions of the env that determine macrophage tropism (Sharpless et al, 1992;Watkins et al, 1990).…”

Cell death in HIV dementia

“…11 Infection of other cell types may also occur but remains controversial. While the infection of macrophages and microglia is a productive infection with formation and release of viral particles, 12 infection of astrocytes may result in viral latency and small amounts of virus are only released upon stimulation by cytokines. 13 Prominent dendritic pruning 14 , loss of synapses 15 and cell death 16,17 may occur in neurons.…”

Neuropathogenesis of Simian Immunodeficiency Virus infection in macaque monkeys

“…As with HIV-1, the target for SIV infection in vivo and in vitro (Desrosiers et al, 1991;Lackner et al, 1991;Ringler et al, 1989;Wyand et al, 1988) is the CD4 molecule expressed on lymphocytes and monocyte/macrophages. Moreover, as with HIV-1, SIV isolated from encephalitic brains has been shown to be macrophage-tropic (Desrosiers et al, 1991;Simon et al, 1992Simon et al, , 1994Watkins et al, 1990;Wiley and Budka, 1991). Even when animals are infected with molecularly cloned lymphotropic virus (eg SIVmac239), approximately 30% of infected animals develop highly macrophage-competent variants (Desrosiers et al, 1991).…”