CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain

Edinger, Aimee L.; Mankowski, Joseph L.; Doranz, Benjamin J.; Margulies, Barry J.; Lee, Benhur; Rucker, Joseph; Sharron, Matthew; Hoffman, Trevor L.; Berson, Joanne F.; Zink, M. Christine; Hirsch, Vanessa M.; Clements, Janice E.; Doms, Robert W.

doi:10.1073/pnas.94.26.14742

Cited by 237 publications

(209 citation statements)

References 34 publications

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“…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.…”

Section: Cell Surface Expression Of Proteoglycans On Primary Humansupporting

confidence: 69%

“…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.…”

supporting

confidence: 62%

“…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.…”

mentioning

confidence: 99%

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Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Bobardt

Salmon

Wang

et al. 2004

J Virol

105

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As a neurotropic virus, human immunodeficiency virus type 1 (HIV-1) invades the brain and causes severe neuronal, astrocyte, and myelin damage in AIDS patients. To gain access to the brain, HIV-1 must migrate through brain microvascular endothelial cells (BMECs), which compose the blood-brain barrier (BBB). Given that BMECs lack the entry receptor CD4, HIV-1 must use receptors distinct from CD4 to enter these cells. We previously reported that cell surface proteoglycans serve as major HIV-1 receptors on primary human endothelial cells. In this study, we examined whether proteoglycans also impact cell-free HIV-1 invasion of the brain. Using an artificial BBB transmigration assay, we found that both heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) are abundantly expressed on primary BMECs and promote HIV-1 attachment and entry. In contrast, the classical entry receptors, CXCR4 and CCR5, only moderately enhanced these processes. HSPGs and CSPGs captured HIV-1 in a gp120-dependent manner. However, no correlation between coreceptor usage and transmigration was identified. Furthermore, brain-derived viruses did not transmigrate more efficiently than lymphoid-derived viruses, suggesting that the ability of HIV-1 to replicate in the brain does not correlate with its capacity to migrate through the BBB as cell-free virus. Given that HIV-1-proteoglycan interactions are based on electrostatic contacts between basic residues in gp120 and sulfate groups in proteoglycans, HIV-1 may exploit these interactions to rapidly enter and migrate through the BBB to invade the brain.

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Section: Cell Surface Expression Of Proteoglycans On Primary Humansupporting

confidence: 69%

supporting

confidence: 62%

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Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Bobardt

Salmon

Wang

et al. 2004

J Virol

105

View full text Add to dashboard Cite

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“…The types of receptors engaged by Env and how Env engages those receptors are factors that can influence viral tropism and pathogenesis. Thus, viruses that evolve from using CCR5 to using CXCR4 appear to be less adept at establishing infections in new hosts but are associated with accelerated disease progression in those with established infections (15), while decreased dependence on CD4 levels has been linked to macrophage tropism in the simian immunodeficiency virus system and neurotropism for both simian immunodeficiency virus and HIV (4,22,26,41). Theoretically, how well an Env binds to a coreceptor and how Env responds to receptor binding could also influence tropism and pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Reeves

Miamidian

Biscone

et al. 2004

J Virol

Self Cite

106

111

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An increasingly large number of antiviral agents that prevent entry of human immunodeficiency virus (HIV) into cells are in preclinical and clinical development. The envelope (Env) protein of HIV is the major viral determinant that affects sensitivity to these compounds. To understand how changes in Env can impact entry inhibitor sensitivity, we introduced six mutations into the conserved coreceptor binding site of the R5 HIV-1 strain YU-2 and measured the effect of these changes on CD4 and coreceptor binding, membrane fusion levels and rates, virus infection, and sensitivity to the fusion inhibitors enfuvirtide (T-20) and T-1249, the CCR5 inhibitor TAK-779, and an antibody to CD4. The mutations had little effect on CD4 binding but reduced CCR5 binding to various extents. In general, reductions in coreceptor binding efficiency resulted in slower fusion kinetics and increased sensitivity to TAK-779 and enfuvirtide. In addition, low CCR5 binding usually reduced overall fusion and infection levels. However, one mutation adjacent to the bridging sheet ␤21 strand, P438A, had little effect on fusion activity, fusion rate, infectivity, or sensitivity to enfuvirtide or T-1249 despite causing a marked reduction in CCR5 binding and a significant increase in TAK-779 sensitivity. Thus, our findings indicate that changes in the coreceptor binding site of Env can modulate its fusion activity, infectivity, and entry inhibitor sensitivity by multiple mechanisms and suggest that reductions in coreceptor binding do not always result in prolonged fusion kinetics and increased sensitivity to enfuvirtide.

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“…CCR5 is expressed on a number of hematopoietic cells, including lymphocytes, macrophages, and granulocytes, and also on non-hematopoietic cells [15][16][17][18]. CCR5 binds to multiple chemokines including CCL3, CCL4/ MIP-1b, and CCL5 [19,20].…”

Section: Introductionmentioning

confidence: 99%

Role of C‐C chemokine receptors 1 and 5 and CCL3/macrophage inflammatory protein‐1α in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects by compensatory chemokine production

et al. 2004

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The deposition of immune complexes induces an acute inflammatory response with tissue injury. Immune complex-induced tissue injury is mediated by inflammatory cell infiltration that is highly regulated by multiple chemokines. To assess the role of the chemokine receptors CCR1 and CCR5, and a ligand for these receptors CCL3/macrophage inflammatory protein1a, in this pathogenic process, the reverse passive cutaneous Arthus reaction was induced in mice lacking CCR1, CCR5, or CCL3. Edema was significantly attenuated in CCR1-deficient (CCR1 -/-) and CCL3 -/-mice but not CCR5 -/-mice, compared with wild-type mice. Numbers of infiltrating neutrophils and mast cells were reduced in CCL3 -/-and CCR1 -/-mice, respectively, compared with wild-type mice. CCR1 and CCR5 were expressed on neutrophils and mast cells. Remarkably, the intradermal mRNA expression of CCL5/RANTES, another ligand for CCR1 and CCR5, was increased in CCR5 -/-and CCL3 -/-mice, compared with wild-type mice, while the cutaneous CCL3 mRNA expression was augmented in CCR1 -/-and CCR5 -/-mice. These results indicate that CCR1, CCR5, and CCL3 cooperatively contribute to the cutaneous Arthus reaction, and also suggest that enhanced expression of CCL3 and CCL5 compensates for the loss of CCR1, CCR5, and CCL3 in the reaction.

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CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain

Cited by 237 publications

References 34 publications

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

Role of C‐C chemokine receptors 1 and 5 and CCL3/macrophage inflammatory protein‐1α in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects by compensatory chemokine production

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