Neurokinin-1 Receptor (NK1-R) Expression in the Brains of SIV-Infected Rhesus Macaques

Vinet-Oliphant, Heather; Álvarez, Xavier; Buza, Elizabeth L.; Borda, Juan T.; Mohan, Mahesh; Aye, Pyone P.; Tuluc, Florin; Douglas, Steven D.; Lackner, Andrew A.

doi:10.2353/ajpath.2010.091109

Cited by 23 publications

(15 citation statements)

References 29 publications

(47 reference statements)

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“…Elevated levels of substance P have been observed in the serum of HIV infected patients and simian immunodeficiency virus-infected rhesus macaques (Douglas et al, 2001, 2008a,b; Lai et al, 2001; Vinet-Oliphant et al, 2010). Viral levels correlate with the amount of substance P released by immune cells and it has been suggested that this neuropeptide may facilitate viral replication by increasing the expression of receptors including CCR5 that are required for HIV infection of host cells (Bost, 2004a; Manak et al, 2010).…”

Section: Evidence For the Involvement Of Substance P In Cns Disordersmentioning

confidence: 99%

The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

Johnson

Young

Marriott

2017

Front. Cell. Neurosci.

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The inflammatory responses of resident central nervous system (CNS) cells are now known to play a critical role in the initiation and progression of an array of infectious and sterile neuroinflammatory disorders such as meningitis, encephalitis, Parkinson’s disease, Alzheimer’s disease and multiple sclerosis (MS). Regulating glial inflammatory responses in a timely manner is therefore critical in preserving normal CNS functions. The neuropeptide substance P is produced at high levels within the CNS and its selective receptor, the neurokinin 1 receptor (NK-1R), is abundantly expressed by neurons and is present on glial cell types including microglia and astrocytes. In addition to its functions as a neurotransmitter in the perception of pain and its essential role in gut motility, this tachykinin is widely recognized to exacerbate inflammation at peripheral sites including the skin, gastrointestinal tract and the lungs. Recently, a number of studies have identified a role for substance P and NK-1R interactions in neuroinflammation and described the ability of this neuropeptide to alter the immune functions of activated microglia and astrocytes. In this review article, we describe the expression of substance P and its receptor by resident CNS cells, and we discuss the ability of this neuropeptide to exacerbate the inflammatory responses of glia and immune cells that are recruited to the brain during neurodegenerative diseases. In addition, we discuss the available data indicating that the NK-1R-mediated augmentation of such responses appears to be detrimental during microbial infection and some sterile neurodegenerative disorders, and propose the repurposed use of NK-1R antagonists, of a type that are currently approved as anti-emetic and anti-anxiolytic agents, as an adjunct therapy to ameliorate the inflammatory CNS damage in these conditions.

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Section: Evidence For the Involvement Of Substance P In Cns Disordersmentioning

confidence: 99%

The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

Johnson

Young

Marriott

2017

Front. Cell. Neurosci.

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“…Depressive symptoms have been associated with poor HIV-related outcomes, such as rapid progression of HIV disease, higher mortality rates, poor adherence to cART, and higher HIV viral loads (Evans et al, 2002; Horberg et al, 2008; Ickovics et al, 2001; E Shacham, Nurutdinova, Satyanarayana, Stamm, & Overton, 2009; Vinet-Oliphant et al, 2010). Depression has also been associated with high-risk behaviors: alcohol use in both HIV-infected and HIV-negative individuals (Sullivan, Goulet, Justice, & Fiellin, 2011) and illicit drug use (Berger-Greenstein et al, 2007; Bing et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Depression severity is associated with increased risk behaviors and decreased CD4 cell counts

et al. 2014

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Depression is a common comorbidity among HIV-infected individuals. We studied the relationship between depressive symptoms, risk behaviors (risky-sexual behavior, tobacco, alcohol and illicit drug use) and HIV outcomes. This cross-sectional study conducted in 2009 at Washington University HIV Clinic included screening for depression with patient health questionnaire (PHQ-9), survey of sexual behavior, illicit drug, alcohol and tobacco use within 30 days. Sociodemographics, plasma HIV RNA levels, CD4 cell counts and sexually transmitted disease (STD) test results were obtained from medical records. Multivariate logistic and linear regression models were used to assess the association between depressive symptoms severity and risk behaviors, HIV outcomes and combination antiretroviral therapy (cART) adherence. A total of 624 persons completed the assessment, of whom 432 (69%) were male and 426 (68%) African American. The median CD4 cell count was 410 cells/mm3 and 479 (77%) were on cART of whom 112 (23%) had HIV RNA level > 400 copies/mL. Overall, 96 (15%) had symptoms of major depressive disorder. Depressive symptom severity was associated with increased likelihood of high-risk drinking (Odds Ratio (OR), 2.4; 95% Confidence Interval (CI), 1.1–5.1), current tobacco use (OR, 1.8; 95%CI, 1.1–2.9), illicit drug use (OR, 1.7; 95%CI, 1.0–2.8) and risky-sexual behavior (OR, 1.5; 95%CI, 0.8–2.7). Sub-optimal cART adherence (visual analogue scale < 95%) was also associated with depressive symptoms severity (p< 0.05). After adjustment for age, sex, race, receipt of cART and cART adherence, depressive symptoms severity was independently associated with lower CD4 cell count (p< 0.05) but not with higher HIV RNA level (p= 0.39). Depression adversely affects HIV-infected individuals, requiring greater effort at utilizing multidisciplinary interventions.

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“…Double-and triple-label confocal microscopy was performed to colocalize SIV RNA with cell type-specific markers to determine the immunophenotype of infected cells, as described previously (47 (24,28,34,47,50,51). After incubation with the primary antibodies (anti-CD3, anti-OPD4/CD45RO [which only detects CD45RO on CD4 ϩ T cells {34}], anti-CD68, anti-CD163, or anti-BrdU) and subsequent washes, the appropriate species-specific secondary antibodies were applied (Alexa Fluor 488-or 633-conjugated goat anti-rabbit or goat anti-mouse IgG1 or goat anti-rat [Invitrogen, Carlsbad, CA]).…”

Section: Methodsmentioning

confidence: 99%

“…Tissue samples collected at biopsy or necropsy were fixed in Z-Fix (Anatech, Battle Creek, MI) and embedded in paraffin, and 5-m-thick sections were cut from select tissues and adhered to charged glass slides. SIV RNA in situ hybridization (ISH) was then performed, as described previously (24,28,47,48), using SIV RNA sense/antisense probes tagged with digoxigenin (DIG) and obtained from Lofstrand Laboratories (Gaithersburg, MD) or provided by Jake Estes (AIDS and Cancer Virus Program at the Frederick National Laboratory of Cancer Research) (49). The chromogens used were nitroblue tetrazolium (NBT)-5-bromo-4-chloro-3-indolylphosphate (BCIP) for light microscopy or liquid permanent red for fluorescence microscopy.…”

Section: Methodsmentioning

confidence: 99%

Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif

Breed

Elser

Torben

et al. 2015

J Virol

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Deletion of Gly-720 and Tyr-721 from a highly conserved GYxxØ trafficking signal in the SIVmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed ⌬GY, leads to a striking perturbation in pathogenesis in rhesus macaques (Macaca mulatta). Infected macaques develop immune activation and progress to AIDS, but with only limited and transient infection of intestinal CD4؉ T cells and an absence of microbial translocation. Here we evaluated ⌬GY in pig-tailed macaques (Macaca nemestrina), a species in which SIVmac239 infection typically leads to increased immune activation and more rapid progression to AIDS than in rhesus macaques. In pig-tailed macaques, ⌬GY also replicated acutely to high peak plasma RNA levels identical to those for SIVmac239 and caused only transient infection of CD4 ؉ T cells in the gut lamina propria and no microbial translocation. However, in marked contrast to rhesus macaques, 19 of 21 pig-tailed macaques controlled ⌬GY replication with plasma viral loads of <15 to 50 RNA copies/ml. CD4 ؉ T cells were preserved in blood and gut for up to 100 weeks with no immune activation or disease progression. Robust antiviral CD4 ؉ T cell responses were seen, particularly in the gut. Anti-CD8 antibody depletion demonstrated CD8؉ cellular control of viral replication. Two pig-tailed macaques progressed to disease with persisting viremia and possible compensatory mutations in the cytoplasmic tail. These studies demonstrate a marked perturbation in pathogenesis caused by ⌬GY's ablation of the GYxxØ trafficking motif and reveal, paradoxically, that viral control is enhanced in a macaque species typically predisposed to more pathogenic manifestations of simian immunodeficiency virus (SIV) infection. IMPORTANCE The pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) reflects a balance between viral replication, host innate and adaptive antiviral immune responses, and sustained immune activation that in humans andAsian macaques is associated with persistent viremia, immune escape, and AIDS. Among nonhuman primates, pig-tailed macaques following SIV infection are predisposed to more rapid disease progression than are rhesus macaques. Here, we show that disruption of a conserved tyrosine-based cellular trafficking motif in the viral transmembrane envelope glycoprotein cytoplasmic tail leads in pig-tailed macaques to a unique phenotype in which high levels of acute viral replication are followed by elite control, robust cellular responses in mucosal tissues, and no disease. Paradoxically, control of this virus in rhesus macaques is only partial, and progression to AIDS occurs. This novel model should provide a powerful tool to help identify host-specific determinants for viral control with potential relevance for vaccine development.

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Neurokinin-1 Receptor (NK1-R) Expression in the Brains of SIV-Infected Rhesus Macaques

Cited by 23 publications

References 29 publications

The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

The Therapeutic Potential of Targeting Substance P/NK-1R Interactions in Inflammatory CNS Disorders

Depression severity is associated with increased risk behaviors and decreased CD4 cell counts

Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif

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