| Publication Abstract Display | | Type: Published Abstract | | Title: Lectin complement pathway activation is linked to immune complex deposition in HIV encephalitis. | | Authors: Nathamu S, Adame A, Dumoap W, Gouaux B, Moore D, Masliah E, Singh K, and the HNRC Group | | Year: 2012 | | Publication: 19th Conference on Retroviruses and Opportunistic Infections | | Volume: Issue: Pages: | | Abstract:Background: Mannose binding lectin (MBL) binds to the high-mannose N-linked glycans on the HIV-1 gp120 envelope protein and activates the complement pathway that leads to virus opsonization and phagocytosis. MBL deficiency is associated with HIV transmission and AIDS progression; however its role in HIV related neuroinflammation remains understudied. We hypothesized that MBL complement pathway is activated in HIV-infected brain by its binding to mannose residues present on gp120 protein and it leads to MBL-mediated immune complex deposition and augmented cytokine response in HIV encephalitis (HIVE).
Methods: Double immunofluorescence, confocal microscopy and western blot analyses were used to evaluate the expression and co-localization of MBL, MBL-associated serine protease-2 (MASP-2), C3d, membrane attack complex C5b-9, viral gp120, neuroinflammatory monocyte chemoattractant protein -1 (MCP-1) and brain cell markers in the frontal cortex of the post-mortem brain tissues from HIV negative healthy controls (n=5) and those with and without HIVE (n=15 each). Paired t tests were used to compare expression of markers in HIVE vs. non-HIVE cases.
Results: Co-localization and higher expression of MBL (twofold increase in HIVE vs. non-HIVE cases, p=0.0001) and MASP-2 (twofold increase in HIVE vs. non-HIVE, p=0.0003) were observed. MBL/MASP-2 -HIVE link was further enhanced by the co-localization of MBL/MASP-2 with higher expression of HIV-1 gp120 protein (2.5 fold increase in HIVE vs. non-HIVE, p=0.0012) and MCP-1 (1.95 fold increase in HIVE vs. non-HIVE, p=0.002). Finally, increased depositions of immune complexes such as MBL-C3d (1.5 fold increase in HIVE vs. non-HIVE, p=0.008), MBL-C5b9 (2.4 fold increase in HIVE vs. non-HIVE, p=0.0001) and MBL-IgG (2.4 fold increase in HIVE vs. non-HIVE, p=0.0002) were observed. Western blot analyses for these markers confirmed their higher expression in HIVE vs. non-HIVE cases. HIV negative healthy controls did not show altered expression of these markers.
Conclusions: Increased levels of the components of MBL complement activation pathway together with viral gp120 and MCP-1 proteins in HIV-1 infected brain suggest that lectin complement pathway is potentially involved in the innate immune response in HIVE. Furthermore, the deposition of MBL-mediated immune complexes in HIVE suggests that these aggregates may play a central role in axonal damage, neuroinflammation, and potential neurocognitive impairment in HIV-1 infected individuals. |
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