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Chemokine receptor CCR5 and CXCR4 expression in HIV-associated kidney disease
Frank Eitner1, Yan Cui1, Kelly L Hudkins1
1Department of Pathology, University of Washington, Seattle, Washington.
Abstract:
The chemokine receptors CCR5 and CXCR4 have been identified as essential coreceptors for entry of HIV-1 strains into susceptible cells. Direct infection of renal parenchymal cells has been implicated in the pathogenesis of HIV-associated renal disease, although data are conflicting. The localization of CCR5 and CXCR4 in kidneys with HIV-associated renal disease is unknown. Formalin-fixed, paraffin-embedded renal biopsies from patients with HIV-associated nephropathy (HIVAN) (n = 13), HIV-associated immune complex glomerulonephritis (n = 3), HIV-associated thrombotic microangiopathy (n = 1), and HIV-negative patients with collapsing glomerulopathy (n = 8) were analyzed in this study. Cellular sites of expression of CCR5 and CXCR4 were identified by immunohistochemistry and by in situ hybridization. The presence of HIV-1 was detected by immunohistochemistry and by in situ hybridization. Expression of both chemokine receptors CCR5 and CXCR4 was undetectable in intrinsic glomerular, tubular, and renovascular cells in all analyzed cases. In the presence of tubulointerstitial inflammation, CCR5 and CXCR4 expression was localized to infiltrating mononuclear leukocytes. HIV-1 protein was undetectable by immunohistochemistry in all cases of HIV-associated renal disease. HIV-1 RNA was identified in one case of HIVAN but was restricted to infiltrating leukocytes. HIV-1 RNA was not detected in intrinsic renal cells in all analyzed cases. Identifying the cellular expression of HIV-coreceptors CCR5 and CXCR4 may help to clarify which tissues are permissive for direct HIV infection. These data do not support a role of productive HIV-1 infection of renal parenchymal cells in the pathogenesis of HIV-associated renal disease.
Insights
Chemokine receptors CCR5 and CXCR4 are not found in kidney cells of patients with HIV-associated renal disease. These findings suggest HIV-1 does not directly infect kidney parenchymal cells in these conditions.
Area of Science:
- Nephrology
- Virology
- Immunology
Background:
- Chemokine receptors CCR5 and CXCR4 are crucial for HIV-1 entry into cells.
- Direct HIV-1 infection of renal parenchymal cells is a proposed mechanism in HIV-associated nephropathy, but evidence is conflicting.
- The expression of CCR5 and CXCR4 in the kidneys of patients with HIV-associated renal disease remains unclear.
Purpose of the Study:
- To determine the cellular localization of chemokine receptors CCR5 and CXCR4 in renal biopsies from patients with HIV-associated renal disease.
- To investigate the presence of HIV-1 in renal parenchymal cells and infiltrating leukocytes.
- To clarify the role of direct HIV-1 infection in the pathogenesis of HIV-associated renal disease.
Main Methods:
- Immunohistochemistry and in situ hybridization were used to detect CCR5, CXCR4, and HIV-1.
- Analysis was performed on renal biopsies from patients with HIV-associated nephropathy, immune complex glomerulonephritis, thrombotic microangiopathy, and HIV-negative controls.
- Cellular expression of chemokine receptors and HIV-1 was assessed in intrinsic renal cells and infiltrating leukocytes.
Main Results:
- CCR5 and CXCR4 expression was undetectable in intrinsic glomerular, tubular, and renovascular cells in all cases.
- In cases with tubulointerstitial inflammation, CCR5 and CXCR4 were expressed on infiltrating mononuclear leukocytes.
- HIV-1 protein was not detected in any HIV-associated renal disease cases; HIV-1 RNA was found only in infiltrating leukocytes in one case of HIVAN, not in intrinsic renal cells.
Conclusions:
- These findings do not support the hypothesis of productive HIV-1 infection of renal parenchymal cells in HIV-associated renal disease.
- CCR5 and CXCR4 expression in the kidneys is primarily associated with infiltrating leukocytes, not intrinsic renal cells.
- The cellular localization of HIV-coreceptors suggests that direct HIV-1 infection of kidney cells is unlikely to be a major factor in the pathogenesis of HIV-associated renal disease.