Human immunodeficiency virus infection of human brain capillary endothelial cells occurs via a CD4/galactosylceramide-independent mechanism.

Abstract

Neuropathologic studies of AIDS patients have shown that brain capillary endothelial cells are a cellular target for human immunodeficiency virus (HIV) in vivo. We have established in vitro cultures of primary human brain capillary endothelial (HBCE) cells. Using this model system, we have shown a signifcant HIV infection of HBCE cells that is productive yet noncytopathic. The infection is mediated by a cellular interaction with gpl20 that does not involve CD4 or galactosylceramide. HIV infection of HBCE cells may contribute to AIDS-associated neuropathology by disturbing the physiology of the endothelium and directly or indirectiy facilitating dissemination of virus to the central nervous system. AIDS patients develop a characteristic neuropathology accompanied by motor, sensory, and cognitive disorders (see ref. 1 for a review). Human immunodeficiency virus (HIV) has been cultured from the brain, spinal cord, and cerebrospinal fluid ofAIDS patients (2-4). Examination ofpostmortem brain sections by immunocytochemistry, in situ hybridization, and electron microscopy has identified cells of the macrophage lineage as the principal cellular target for HIV (5-12). Viral proteins and nucleic acids are also localized in brain capillary endothelial cells of AIDS patients (7,9,13,14) and simian immunodeficiency virus-infected rhesus macaques (15). HIV is detected at lower frequency in astrocytes (9,10,13,16).While HIV infection is clearly associated with pathological changes and neurological impairment, the relationship between tissue infection and disease manifestation remains unclear. Central nervous system (CNS) pathology could arise from direct infection of brain tissue by HIV or from the indirect effects of systemic or local viral infection such as the production of neurotoxic viral (17-21) or virally induced cellular proteins (22,23) and cytokines (24,25). The brain endothelium is a dynamic interface that functions as a potentially immunoreactive surface for the modulation of immune and inflammatory responses (27,28). Endothelial cells form an integral part of the blood-brain barrier (BBB), a selectively permeable transport barrier for substance exchange across capillary walls (29, 30). Infection of human brain capillary endothelial (HBCE) cells may alter the immunoreactivity of the endothelium or compromise the integrity of the BBB. These perturbations could contribute to immunopathological processes and allow neurotoxic substances access to the brain. In addition, HIV infected endothelium may constitute an entry portal for HIV into the CNS.We report here on the development of an in vitro system to examine the interaction of HIV with HBCE cells. We have developed and characterized pure cultures of primary HBCE cells and have established that they can be productivelyThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.infected by HIV in vitro. The natur...

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

“…As previously reported, we found that BMECs lack the entry receptor CD4 as well as GalCer ( Fig. 1A and B) (23,54). We also found that BMECs express low levels of both coreceptors CCR5 and CXCR4 ( Fig.…”

“…Lastly, anti-CD4 antibodies (SIM2 and SIM.4) (100 l of culture supernatant per ml of each) failed to prevent HIV-1 attachment, entry, and transcytosis (Fig. 6), further suggesting that HIV-1 crosses the BBB in a CD4-independent manner as proposed previously (23,54). Note that we verified the potency of these entry inhibitors (Fig.…”

“…Several scenarios have been proposed for BBB transmigration of HIV-1 as cell-free virus. In one scenario, BMECs directly infected by HIV-1 release infectious particles into the brain (8,54,67,84). In an alternative scenario, HIV-1 enters BMECs from the blood, migrates through the cells, and is released into the CNS from the brain side of BMECs (10,11,47).…”

“…Given that BMECs lack the entry receptor CD4 (23,54), HIV-1 must use attachment and entry receptors distinct from CD4 to enter these cells. Several receptors have been reported to facilitate HIV-1 entry into CD4-negative cells.…”

Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by the p38 mitogen-activated protein kinase pathway

“…The blood-brain barrier (BBB) strictly regulates the transport of blood-borne cells and substances into the brain. Brain microvessel endothelial cells are a major component of the BBB and do not express CD4 receptor which HIV-1 uses to enter other cell types (Moses et al, 1993). Despite and absence of the CD4 receptor, HIV-1 can cross the BBB by two routes, the passage of cell free virus by adsorptive endocytosis (Banks et al, 2001) and the trafficking of infected immune cells across BBB (Persidsky et al, 1997).…”