Alcohol Abuse Enhances Neuroinflammation and Impairs Immune Responses in an Animal Model of Human Immunodeficiency Virus-1 Encephalitis

Potula, Raghava; Haorah, James; Knipe, Bryan; Leibhart, Jessica; Chrastil, Jesse; Heilman, David; Dou, Haoran; Reddy, Rindha; Ghorpade, Anuja; Persidsky, Yuri

doi:10.2353/ajpath.2006.051181

Cited by 54 publications

(58 citation statements)

References 64 publications

(58 reference statements)

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“…We previously demonstrated specific antiviral cellular responses in this model and presence of CD8 ϩ T lymphocytes in areas containing MDM in the brain. 28,29,36 The presence of virus-specific cytotoxic T lymphocytes (CTL) ( Figure 9C) resulted in significant elimination of HIV-1 MDM as compared to control animals (injected with MDM intracerebrally without prior PBL transfer). 28,36,37 Astrogliosis and microglial reaction ( Figure 9D) were evident in these animals, being proportional to the level of mononuclear cell infiltration.…”

Section: Resultsmentioning

confidence: 99%

“…The following Abs were used to detect total OCC and CLD5 (TJs, 1:50; Zymed, South San Francisco, CA), phosphorylated forms of OCC/CLD5 (using novel antibodies described in this report), vimentin (all human leukocytes, 1:50; DAKO, Carpinteria, CA), CD4/ CD8 (human lymphocytes, 1:25; DAKO), CD68 (human MDM, 1:100; DAKO), vWF (BMVECs, 1:100; DAKO) (data not shown), glial fibrillary acid protein (astrocytes, 1:100; DAKO), Iba1 (microglia, 1:500; Wako Corp., Osaka, Japan), HIV-1 p24 antigen (1:10, DAKO). 28,29 Mouse neurons were labeled with mAbs for the neurofilament (NF, 1:100; DAKO). 30 For immunofluorescence, Alexa fluor-594-conjugated secondary Abs (at 1:400 dilution, Invitrogen) were introduced to the tissue sections at room temperature for 1 hour.…”

Section: Histopathologymentioning

confidence: 99%

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Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells

Yamamoto

Ramirez

Sato

et al. 2008

The American Journal of Pathology

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203

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Critical to the proper maintenance of blood-brainbarrier (BBB) integrity are the endothelial tight junctions (TJs). Posttranslational modifications of essential endothelial TJ proteins, occludin and claudin-5, contribute and possibly disrupt BBB integrity. Our previous work has shown that Rho kinase (RhoK) activation mediates occludin and claudin-5 phosphorylation resulting in diminished barrier tightness and enhanced monocyte migration across BBB in the setting of human immunodeficiency virus-1 encephalitis (HIVE). To determine whether RhoK can directly phosphorylate TJ proteins, we examined phosphorylation of cytoplasmic domains of recombinant claudin-5 and occludin by RhoK. We found that RhoK predominately phosphorylated two sites on occludin (T382 and S507) and one site on claudin-5 (T207). The blood-brain-barrier (BBB) is composed of specialized nonfenestrated brain microvascular endothelial cells (BMVECs) connected by tight junctions (TJs) in an impermeable monolayer devoid of transcellular pores.1 TJs are composed of claudins and occludin (OCC, integral membrane proteins) and intracellular proteins, zonula occludens (ZO-1 to ZO-3).2 OCC (65-kDa protein) is highly expressed in BMVECs, and it is consistently found along the cell borders of brain endothelium.3,4 OCC is composed of four transmembranous domains with the carboxyl and amino terminals oriented to the cytoplasm and two extracellular loops (44 amino acids and 45 amino acids) spanning the intercellular cleft.5 OCC content is much lower in endothelial cells outside of the central nervous system 6,7 suggesting its active role in BBB function. The phosphorylation state of OCC regulates its association with the cell membrane and barrier permeability, and multiple phosphorylation sites have been identified on OCC serine and threonine residues.8 -10 The cytoplasmic C-terminal domain provides the connection of OCC with the cytoskeleton via accessory proteins, ZO-1 and ZO-2. 11Up to 24 claudins (20-to 24-kDa proteins) sharing the high sequence homology in the first and fourth transmembranous domains and extracellular loops have been identified in mammals.12 Contiguous staining for claudins is found along endothelial cell borders in and outside the central nervous system. BMVECs express predominantly claudin-3 and -5 (CLD5).3,13 The homophilic and heterophilic interactions between the extracellular loops of clauSupported in part by the National Institutes of Health (research grants P01 NS043985, R01 AA015913, and R01 MH65151 to Y.P.; R01 MH072539 to T.I.; and National Center for Research Resources P20RR15635 to T.I. and R.L.C.).M.Y. and S.H.R. contributed equally in this study.

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Section: Resultsmentioning

confidence: 99%

Section: Histopathologymentioning

confidence: 99%

Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells

Yamamoto

Ramirez

Sato

et al. 2008

The American Journal of Pathology

Self Cite

203

147

View full text Add to dashboard Cite

show abstract

“…A comparative description of previous mouse models of NeuroAIDS is presented in the Supplemental table, S1 (available at http://ajp.amjpathol.org). [1][2][3][4]6,7,[62][63][64][65][66][67][68][69][81][82][83][84][85][86][87][88][89][90] What is reported now can permit future studies of viral neuropathogenesis studies in rodents and for investigations of novel antiretroviral and adjunctive therapies.…”

Section: Discussionmentioning

confidence: 99%

Links between Progressive HIV-1 Infection of Humanized Mice and Viral Neuropathogenesis

Gorantla

Makarov

Finke-Dwyer

et al. 2010

The American Journal of Pathology

112

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“…Huntington's disease: Peinemann et al 2005; Parkinson's disease: Cools et al 2006). Animal models have demonstrated that chronic alcohol consumption induces neuro-inflammation and oxidative stress that can exacerbate the progress of the HIV infection (Potula et al 2006). Evidence for a functional effect of immunocompromise progression in our comorbid patients emerged from the correlation between high viral loads and poor Stroop-nonmatch performance, indicating that severity of HIV infection is related to the degree of disability to disengage attention from an incorrectly cued color to the correct color to resolve a Stroop conflict.…”

Section: Discussionmentioning

confidence: 99%

“…There is also postmortem evidence of structural disruption of frontal and parietal cortical sites and connections between cortices relevant to processes of selective attention in patients with longterm alcohol abuse (Kril et al 1997) and in vivo evidence of such disruption in those with immunodeficiency virus infection (Hardy and Hinkin 2002). Despite the efficiency of highly active antiretroviral therapies (HAART) in reducing viral burden, alcohol can impair immune responses that would otherwise reduce neuro-inflammation and neurodegeneration (Brailoiu et al 2006;Chao et al 2003;Hammoud et al 2005;Potula et al 2006). …”

mentioning

confidence: 99%

Callosal Compromise Differentially Affects Conflict Processing and Attentional Allocation in Alcoholism, HIV, and Their Comorbidity

Schulte

Müller‐Oehring

Javitz

et al. 2007

Brain Imaging and Behavior

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Diffusion tensor imaging was used to study the combined effects of HIV-infection and alcoholism (ALC) on corpus callosum (CC) integrity in relation to processes of attentional allocation and conflict resolution assessed by a novel Stroop Match-to-Sample task. We tested 16 ALC, 19 HIV, 20 subjects with combined disorder and 17 controls. In ALC, low fractional anisotropy and high mean diffusivity throughout the CC correlated with poor Stroop-match performance, i.e., when the cue-color matched the color of the Stroop stimulus. By contrast, in the two HIV groups DTI relations were restricted to the genu and poor Stroop-nonmatch performance, i.e., when the cue-color was in conflict with the Stroop stimulus color. These results suggest that disruption of callosal integrity in HIV-infection and alcoholism differentially affects regionally-selective interhemispheric-dependent attentional processing. We speculate that callosal degradation in these diseases curtails the opportunity for collaboration between the two hemispheres that contributes to normal performance in HIV or alcoholic patients with higher callosal integrity. KeywordsDiffusion tensor imaging; HIV infection; Alcoholism; Stroop; Selective attention; Corpus callosum A frequent comorbidity in individuals infected with human immunodeficiency virus (HIV) is alcohol use disorder (Justice et al. 2006;Lefevre et al. 1995;Meyerhoff 2001;Molina et al. 2006;Winsauer et al. 2002). Each disorder exerts adversive effects on cognitive function and brain structure, some different and some overlapping. Although both disorders affect attention, each can selectively disrupt different component processes of this NIH Public Access Author ManuscriptBrain Imaging Behav. Author manuscript; available in PMC 2009 April 8. Published in final edited form as:Brain Imaging Behav. 2008 ; 2(1): 27-38. doi:10.1007/s11682-007-9014-z. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript complex cognitive process. Chronic alcoholism adversely disrupts executive control mechanisms relying on prefrontal and parietal attentional brain systems (Nixon et al. 1988;Sullivan et al. 2000;Tapert et al. 2001). Lack of executive function control over attentional systems has also been reported in patients infected with human immunodeficiency virus (HIV) (Chao et al. 2004;Hinkin et al. 1999;McArthur 2004;Sahakian et al. 1995).The Stroop Color Word Test (Stroop 1935) is a widely used paradigm to study selective attentional processes that require conflict resolution and response inhibition between competing stimulus attributes (Bush et al. 2003;Carter et al. 1999;Fan et al. 2003;MacDonald et al. 2000;Salo et al. 2001). The Stroop phenomenon describes slower responses when subjects are asked to name the ink color of a word printed in a color incongruent with the word's meaning (e.g., the word "red" written in blue ink) relative to when the word's meaning and ink color are the same (e.g., the word "red" written in red ink). When the relevant color-attribute and the irrelevant word-...

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Alcohol Abuse Enhances Neuroinflammation and Impairs Immune Responses in an Animal Model of Human Immunodeficiency Virus-1 Encephalitis

Cited by 54 publications

References 64 publications

Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells

Phosphorylation of Claudin-5 and Occludin by Rho Kinase in Brain Endothelial Cells

Links between Progressive HIV-1 Infection of Humanized Mice and Viral Neuropathogenesis

Callosal Compromise Differentially Affects Conflict Processing and Attentional Allocation in Alcoholism, HIV, and Their Comorbidity

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