Human immunodeficiency virus-1 (HIV-1) is detected early in central nervous system (CNS) and causes neuroinflammation leading to the initiation and expansion of neuronal injury and death. In USA alone, 40% of about 1 million HIV-1 infected individuals are likely to acquire HIV-1 related CNS impairment. The innate immune mechanisms underlying HIV-1 neuropathogenesis and CNS impairment have been understudied. Mannose binding lectin (MBL), coded by MBL2 gene, is an active phase protein that mounts innate immune response against risk of infections by recognizing mannose residues present on the surface of pathogens (e.g. viruses, bacteria) and initiating the complement pathway by activating MBL- associated serine proteases (MASPs). MBL binds to high mannose N-linked glycan residues of HIV-1 gp41/120 and elicits cytokine responses and macrophage mediated HIV-1 opsonization. Thus, lower MBL expression or function can result in neuroinflammation and anomalous accumulation of viral proteins and immune complexes in brain leading to neurotoxicity and neurocognitive impairment. Recently, in about 1000 HIV-1 infected children we showed that the presence of MBL2 genetic variants resulting in expression of non-functional MBL was associated with more rapid progression of CNS impairment. Although effects of MBL2 variants on susceptibility of HIV-1 and disease progression are known;their association with the progression of CNS impairment is a new finding. The proposed research seeks to extend this new finding by studying the association of MBL expression and function to the susceptibility and progression of HIV-1 related neuroinflammation and CNS impairment. Our overarching hypothesis is that lower expression and altered function of MBL impairs MBL-mediated complement activation, related cytokine responses;scavenger opsonization function and leads to increased susceptibility to HIV-1 infection and neuroinflammation, accumulation of viral/complement proteins or autoantigens in brain, and eventually neurocognitive impairment. Additionally, variant MBL2/MASP-2 alleles alter expression and function of MBL in CNS. For these studies, we will determine the MBL, MASPs and complement protein levels in paired CSF/plasma from HIV infected impaired/unimpaired adults (N=2385) from HIV Neurobehavioral Research Center (HNRC, UCSD);and post-mortem brain tissues (N=45) from National NeuroAIDS Tissue Consortium (NNTC, Rockville, MD) using highly sensitive multiplex ELISAs, innate immune response microarray analyses during HIV infection, quantitative PCR validation, genotyping, immunohistostaining and fluorescence microscopy techniques. These studies will help to understand the novel role of MBL and related innate immunity complement biomarkers in HIV related neuroinflammation and neurocognitive impairment;and might suggest avenues for development of effective therapeutics such as recombinant human MBL.

Public Health Relevance

Proposed studies will determine the novel role of mannose binding lectin, an important component of complement-mediated innate immunity and pathogen phagocytosis, in susceptibility of HIV-1 infection in brain and related neuroinflammation, viral protein accumulation and neurocognitive impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085608-05
Application #
8393063
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2009-04-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$348,737
Indirect Cost
$123,017
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Teodorof, C; Divakar, S; Soontornniyomkij, B et al. (2014) Intracellular mannose binding lectin mediates subcellular trafficking of HIV-1 gp120 in neurons. Neurobiol Dis 69:54-64
Grant, Igor; Franklin Jr, Donald R; Deutsch, Reena et al. (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82:2055-62
Singh, Kumud K; Wang, Yan; Gray, Kathryn P et al. (2013) Genetic variants in the host restriction factor APOBEC3G are associated with HIV-1-related disease progression and central nervous system impairment in children. J Acquir Immune Defic Syndr 62:197-203
Singh, Kumud K; Nathamu, Satyanarayana; Adame, Anthony et al. (2011) Expression of mannose binding lectin in HIV-1-infected brain: implications for HIV-related neuronal damage and neuroAIDS. Neurobehav HIV Med 3:41-52
Kwok, Janet Y; Vaida, Florin; Augst, Ryan M et al. (2011) Mannose binding lectin mediated complement pathway in multiple sclerosis. J Neuroimmunol 239:98-100
Singh, Kumud K; Gray, Ping Kathryn; Wang, Yan et al. (2011) HLA alleles are associated with altered risk for disease progression and central nervous system impairment of HIV-infected children. J Acquir Immune Defic Syndr 57:32-9
Spector, Stephen A; Singh, Kumud K; Gupta, Saurabh et al. (2010) APOE epsilon4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors. AIDS 24:1471-9
Heaton, R K; Clifford, D B; Franklin Jr, D R et al. (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75:2087-96