Human immunodeficiency virus (HIV) dementia (HIVD), also called the AIDS dementia complex, is a primary disorder of the central nervous system (CNS) that affects about 20% of HIV-infected individuals (32
). Although the pathogenesis of HIVD has been the subject of many studies, there is no consensus on the cause of brain dysfunction. Neuropathological and virological studies have implicated brain microglial cells and microglia-derived giant cells as the principal CNS cells infected with HIV (3
), leading most investigators to believe that microglial cells are the central element in the development of this complication. Microglial cells may produce viral proteins that have neurotoxic properties, or perhaps HIV-infected cells are induced to secrete soluble neurotoxins like platelet-activating factor, tumor necrosis factor alpha, or nitric oxide (15
A key unanswered question in the development of HIVD is the role of viral strain variability. While only a proportion of infected individuals demonstrate CNS dysfunction, the relative contributions of viral and host factors are unknown. Data from a number of groups have indicated that HIV penetrates the CNS early during the course of systemic HIV infection (5
). For example, HIV can be isolated from the cerebrospinal fluid of 50% of individuals early in the course of infection, and HIV sequences obtained from the CNS segregate independently of sequences prevalent in the systemic circulation (11
). One potential explanation for the isolated evolution of HIV strains within the CNS is that replication within microglia results in adaptation of the virus for this cell type (36
Chemokine receptors, which were recently found to have an essential role in mediating HIV entry in conjunction with CD4, are responsible for some of the key differences in HIV cellular tropism (6
). Isolates using CXCR4 as a coreceptor replicate in peripheral blood lymphocytes and in some immortalized T-cell lines, whereas HIV type 1 (HIV-1) isolates that replicate in monocyte-derived macrophages (MDM) utilize CCR5, the second major HIV coreceptor discovered. Several other chemokine receptors, like CCR3, and orphan receptors such as STRL33 and GPR15 have been shown to have coreceptor activity with different assays (10
). The potential role of these and other chemokine receptors in HIV pathogenesis is yet to be explored.
Microglial cells express several chemokine receptors, including CCR3, CCR5, and CXCR4 (25
). Therefore, viruses could theoretically use any of these coreceptors to enter microglial cells. In fact, clearly T-cell line-tropic viruses like HIV-1HXB
will replicate in some microglial preparations (36
). However, for the most part, viruses that replicate in microglial cells also replicate in MDM (36
), and they would be expected to at the very least use CCR5 as a coreceptor. However, He and collaborators (25
) have recently suggested that utilization of CCR3 as a coreceptor is an important correlate of replication in fetal microglial cells, since some viruses obtained from the brain (JRFL and YU-2) (28
) were capable of utilizing CCR3 in a fusion assay, and antibodies against CCR3 inhibited infection of fetal microglial cells.
To determine the role of chemokine coreceptors in infection of adult microglial cells, we have obtained a small panel of brain isolates (20
), as well as other HIV strains that replicate well in cultured microglial cells. These viruses, as well as molecular clones of their envelope (env
) genes, have been used in infection and cell-to-cell fusion assays to determine their chemokine coreceptor utilization. The results demonstrate the predominant use of CCR5, at least among the major coreceptors so far identified, but with some use of CCR3 and CXCR4 by some envelope clones.