YKL-40
2008; Elsevier BV; Volume: 173; Issue: 1 Linguagem: Inglês
10.2353/ajpath.2008.080389
ISSN1525-2191
Autores Tópico(s)Mosquito-borne diseases and control
ResumoThis Commentary explores the possible role for YKL-40, a secreted mammalian chitinase-like protein, as a predictive biomarker for SIV encephalitis (SIVE) and HIV encephalitis (HIVE). This Commentary explores the possible role for YKL-40, a secreted mammalian chitinase-like protein, as a predictive biomarker for SIV encephalitis (SIVE) and HIV encephalitis (HIVE). Human immunodeficiency virus type 1 (HIV-1) affects more that 32 million people worldwide1UNAIDS/WHO report highlights epidemic resurgence.AIDS Alert. 2007; 22: 1-3Google Scholar and induces central nervous system-associated neurological dysfunction in at least 30% of infected individuals.2Sacktor N McDermott MP Marder K Schifitto G Selnes OA McArthur JC Stern Y Albert S Palumbo D Kieburtz K De Marcaida JA Cohen B Epstein L HIV-associated cognitive impairment before and after the advent of combination therapy.J Neurovirol. 2002; 8: 136-142Crossref PubMed Scopus (473) Google Scholar Cognitive disorders range from mild impairment of executive functions to frank dementia (HIV-associated dementia; HAD), and these are collectively termed HIV-associated neurocognitive disorders (HAND).3Antinori A Arendt G Becker JT Brew BJ Byrd DA Cherner M Clifford DB Cinque P Epstein LG Goodkin K Gisslen M Grant I Heaton RK Joseph J Marder K Marra CM McArthur JC Nunn M Price RW Pulliam L Robertson KR Sacktor N Valcour V Wojna VE Updated research nosology for HIV-associated neurocognitive disorders.Neurology. 2007; 69: 1789-1799Crossref PubMed Scopus (1950) Google Scholar Although the incidence of HAD has decreased with the use of highly active anti-retroviral therapy (HAART), it is only partially neuroprotective. The persistence and increasing prevalence of less severe HAND syndromes remains a serious concern, and the assessment of the risk of developing progressive disability in treated individuals is a clear priority. In underdeveloped countries where HAART availability is limited, increasing life expectancy remains the primary goal of HIV treatment, but our experience in the United States forewarns of the likelihood of increasing cognitive disability in these surviving populations.4Brew BJ Gonzalez-Scarano F HIV-associated dementia: an inconvenient truth.Neurology. 2007; 68: 324-325Crossref PubMed Scopus (13) Google Scholar In this issue of The American Journal of Pathology, Bonneh-Barkay et al5Bonneh-Barkay D Bissel SJ Wang G Fish KN Nicholl GCB Darko SW Medina-Flores R Murphey-Corb M Rajakumar PA Nyaundi J Mellors JW Bowser R Wiley CA YKL-40, a marker of SIV encephalitis, modulates the biological activity of basic fibroblast growth factor.Am J Pathol. 2008; 173 (xxx-xxx)Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar use one of several pigtailed macaque models to investigate a possible role for YKL-40, a secreted mammalian chitinase-like protein, as a predictive biomarker for simian immunodeficiency virus (SIV) encephalitis (SIVE), the primate homologue of HIV encephalitis (HIVE). Elevations in cerebrospinal fluid (CSF) YKL-40 preceded death due to SIVE by up to 8 weeks and correlated with CSF SIV viral RNA (viral load), indicating that YKL-40 could potentially serve as a biomarker for SIVE. Defining the neuropathogenesis of HIV infection is critical for developing effective neuroprotective strategies, and identifying appropriate animal models and biomarkers of immunodeficiency virus neuropathogenesis is a significant challenge. The macaque models (Macaca mulatta, rhesus; Macaca nemestrina, pigtail) of SIV infection currently provide the best opportunity not only for studying the virus-triggered pathways of neurodegeneration that lead to cognitive dysfunction, but also for testing biomarker validity and neuroprotective treatments. The SIVE model used by Bonneh-Barkay et al5Bonneh-Barkay D Bissel SJ Wang G Fish KN Nicholl GCB Darko SW Medina-Flores R Murphey-Corb M Rajakumar PA Nyaundi J Mellors JW Bowser R Wiley CA YKL-40, a marker of SIV encephalitis, modulates the biological activity of basic fibroblast growth factor.Am J Pathol. 2008; 173 (xxx-xxx)Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar uses pigtailed macaques infected with a viral swarm (SIV/Delta B670) that efficiently produces immune suppression but varies in frequency and time to onset of SIVE. In this sense, it mimics the temporal variability of HAND progression. Another closely related pigtail SIVE model (used by Clements, Zink and colleagues6Mankowski JL Clements JE Zink MC Searching for clues: tracking the pathogenesis of human immunodeficiency virus central nervous system disease by use of an accelerated, consistent simian immunodeficiency virus macaque model.J Infect Dis. 2002; 186: S199-S208Crossref PubMed Scopus (73) Google Scholar) uses the B670 swarm with co-infection with a CNS-adapted molecularly cloned SIV strain, SIV/17E-Fr, and more consistently produces SIVE in a shorter length of time (∼90% SIVE development in ∼84 days6Mankowski JL Clements JE Zink MC Searching for clues: tracking the pathogenesis of human immunodeficiency virus central nervous system disease by use of an accelerated, consistent simian immunodeficiency virus macaque model.J Infect Dis. 2002; 186: S199-S208Crossref PubMed Scopus (73) Google Scholar). This might be related to a more consistent loss of natural killer cell activity demonstrated in this effective model of SIV neuropathogenesis.6Mankowski JL Clements JE Zink MC Searching for clues: tracking the pathogenesis of human immunodeficiency virus central nervous system disease by use of an accelerated, consistent simian immunodeficiency virus macaque model.J Infect Dis. 2002; 186: S199-S208Crossref PubMed Scopus (73) Google Scholar Finally, rhesus macaques infected with other SIV strains (SIVmac239, SIV mac251, SIVmE660), with or without depletion of CD8+ T lymphocytes before SIV inoculation, are also used.7Harrington PR Connell MJ Meeker RB Johnson PR Swanstrom R Dynamics of simian immunodeficiency virus populations in blood and cerebrospinal fluid over the full course of infection.J Infect Dis. 2007; 196: 1058-1067Crossref PubMed Scopus (20) Google Scholar, 8Gold LH Fox HS Henriksen SJ Buchmeier MJ Weed MR Taffe MA Huitron-Resendiz S Horn TF Bloom FE Longitudinal analysis of behavioral, neurophysiological, viral and immunological effects of SIV infection in rhesus monkeys.J Med Primatol. 1998; 27: 104-112Crossref PubMed Scopus (44) Google Scholar, 9Bissel SJ Wang G Trichel AM Murphey-Corb M Wiley CA Longitudinal analysis of monocyte/macrophage infection in simian immunodeficiency virus-infected. CD8+ T-cell-depleted macaques that develop lentiviral encephalitis.Am J Pathol. 2006; 168: 1553-1569Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Each of these models replicates some features of SIVE and several demonstrate associated neurobehavioral abnormalities, making them useful for SIV neuropathogenesis studies. Notably, by magnetic resonance spectroscopy (MRS), several macaque studies have also demonstrated characteristic brain metabolite alterations observed in individuals with HAND, further validating these macaque models.10Gonzalez RG Cheng LL Westmoreland SV Sakaie KE Becerra LR Lee PL Masliah E Lackner AA Early brain injury in the SIV-macaque model of AIDS.Aids. 2000; 14: 2841-2849Crossref PubMed Scopus (63) Google Scholar In HIV neuropathogenesis studies, examination of autopsied brains of affected individuals suggest that significant and varying levels of irreversible structural damage often precede the presentation of cognitive disorders. Thus, defining the events that precede neurological symptoms and identifying "at risk" HIV-infected individuals are essential for developing rational neuroprotective approaches. A central strategy for defining such events lies in identifying expression of predictive biomarkers in the CSF compartment during different stages of SIV and HIV infection.11Price RW Epstein LG Becker JT Cinque P Gisslen M Pulliam L McArthur JC Biomarkers of HIV-1 CNS infection and injury.Neurology. 2007; 69: 1781-1788Crossref PubMed Scopus (71) Google Scholar Investigation of the expression of CNS biomarkers and their relationship to SIV replication and development of SIVE in macaque models is thus clearly justified. Markers of glial cell activation or virus replication are likely to be good candidates for predictive biomarkers of ensuing neuronal damage due to HIV replication. In addition, certain neuronal markers might predict ongoing injury as well as risk for progression of injury and cognitive decline. It is critical, however, to identify markers that predict neurodegeneration at stages of HIV infection that allow for therapeutic intervention. Macrophage-associated markers such as YKL-40 are likely to be altered during the course of SIV/HIV infection through both direct and indirect effects of viral replication. Because productive HIV infection is restricted to cells that express both CD4 and an appropriate chemokine receptor (CCR5 or CXCR4), the macrophage/microglia population is the primary target of HIV infection in the brain. The importance of HIV replication in brain macrophages for neuropathogenesis is supported by the observation that HIV swarms evolve toward enhanced macrophage tropism within the CNS compartment, and specific HIV envelope variants are associated with increased macrophage tropism and the presence of HAND.12Dunfee RL Thomas ER Gorry PR Wang J Taylor J Kunstman K Wolinsky SM Gabuzda D The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia.Proc Natl Acad Sci USA. 2006; 103: 15160-15165Crossref PubMed Scopus (132) Google Scholar To use predictive biomarkers effectively, one must understand not only the pattern of HIVE but also the course of brain HIV infection. Brain infection occurs early (weeks) after systemic infection and is associated with immune activation of both infected and noninfected glia (macrophages/microglia, astrocytes). Macrophage activation occurs both systemically and within the CNS, as evidenced by elevations of plasma sCD14 (lipopolysaccharide receptor) and the appearance of macrophage activation markers in the CNS.13Ryan LA Zheng J Brester M Bohac D Hahn F Anderson J Ratanasuwan W Gendelman HE Swindells S Plasma levels of soluble CD14 and tumor necrosis factor-alpha type II receptor correlate with cognitive dysfunction during human immunodeficiency virus type 1 infection.J Infect Dis. 2001; 184: 699-706Crossref PubMed Scopus (79) Google Scholar Macrophage infiltration into the CNS is enhanced through increased monocyte chemoattractant protein-1 (MCP-1/CCL-2) expression during infection, and this promotes a general enhancement of CNS immune activation.14Eugenin EA Osiecki K Lopez L Goldstein H Calderon TM Berman JW CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanism of HIV-CNS invasion and Neuro AIDS.J Neurosci. 2006; 26: 1098-1106Crossref PubMed Scopus (313) Google Scholar Neuronal damage likely begins later and progresses throughout the course of infection, resulting in both irreversible and reversible cognitive impairment. Although the predictive value of the CSF HIV viral load is uncertain, elevated CSF viral loads are associated with increased risk of HAND.15Sevigny JJ Albert SM McDermott MP McArthur JC Sacktor N Conant K Schifitto G Selnes OA Stern Y McClernon DR Palumbo D Kieburtz K Riggs G Cohen B Epstein LG Marder K Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia.Neurology. 2004; 63: 2084-2090Crossref PubMed Scopus (169) Google Scholar, 16Ellis RJ Gamst AC Capparelli E Spector SA Hsia K Wolfson T Abramson I Grant I McCutchan JA Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources.Neurology. 2000; 54: 927-936Crossref PubMed Scopus (171) Google Scholar Similar relationships between early virus replication, immune activation and ensuing neuronal damage are also found in the various macaque models of SIVE used by Bonneh-Barkay and colleagues5Bonneh-Barkay D Bissel SJ Wang G Fish KN Nicholl GCB Darko SW Medina-Flores R Murphey-Corb M Rajakumar PA Nyaundi J Mellors JW Bowser R Wiley CA YKL-40, a marker of SIV encephalitis, modulates the biological activity of basic fibroblast growth factor.Am J Pathol. 2008; 173 (xxx-xxx)Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar and other groups, suggesting that multiple biomarkers of these processes might be useful and accessible in the CSF. In their study of YKL-40 (a glycosyl 1 hydrolase family member and a previously identified biomarker of tissue inflammation and neoplasia17Johansen JS Jensen BV Roslind A Nielsen D Price PA Serum YKL-40, a new prognostic biomarker in cancer patients?.Cancer Epidemiol Biomarkers Prev. 2006; 15: 194-202Crossref PubMed Scopus (247) Google Scholar), Bonneh-Barkay and colleagues5Bonneh-Barkay D Bissel SJ Wang G Fish KN Nicholl GCB Darko SW Medina-Flores R Murphey-Corb M Rajakumar PA Nyaundi J Mellors JW Bowser R Wiley CA YKL-40, a marker of SIV encephalitis, modulates the biological activity of basic fibroblast growth factor.Am J Pathol. 2008; 173 (xxx-xxx)Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar examined the protein's expression in the CSF and brain tissue of pigtailed macaques infected with SIV. Using the technique of surface-enhanced laser desorption/ ionization time-of-flight mass spectroscopy (SELDI-TOF-MS) to analyze CSF, the investigators found that four distinct spectral peaks were unique to SIVE, while four other peaks were found to be unique to animals without SIVE. Additionally, 14 peaks common between these groups demonstrated relative increases or decreases between the two groups. Among these, YKL-40 was identified and found to be elevated fivefold in CSF in SIVE cases versus non-encephalitis cases. These findings were confirmed by Western blot analysis of brain tissue. Although the origin and functions of YKL-40 in the CNS are unknown, YKL-40 is found in many non-neural cell types associated with inflammation and accompanying extracellular matrix (ECM) damage, including macrophages,17Johansen JS Jensen BV Roslind A Nielsen D Price PA Serum YKL-40, a new prognostic biomarker in cancer patients?.Cancer Epidemiol Biomarkers Prev. 2006; 15: 194-202Crossref PubMed Scopus (247) Google Scholar it can bind to oligosaccharides in the hyaluronic synthetic pathway and to collagen (see references within Bonneh-Barkay et al17Johansen JS Jensen BV Roslind A Nielsen D Price PA Serum YKL-40, a new prognostic biomarker in cancer patients?.Cancer Epidemiol Biomarkers Prev. 2006; 15: 194-202Crossref PubMed Scopus (247) Google Scholar), it has mitogenic effects in synovial cells and chondrocytes, and it can suppress pro-inflammatory cytokine and matrix metalloproteinase production. Thus, the association between YKL-40, inflammation, and macrophages might have particular relevance for neuroinflammation associated with HAND. In their study, the investigators present evidence that significant elevations of CSF YKL-40 consistently precede (2 to 8 weeks) the animal's death due to SIVE, and these elevations correlate with the CSF viral load in animals that develop SIVE but not in those who do not. Plasma levels of YKL-40 did not change from baseline in infected animals, suggesting that virus-induced YKL-40 expression and any resulting effects occur primarily within the CNS during viral replication, possibly qualifying YKL-40 as a compartmentalized predictive biomarker for SIVE. A potential link between elevated YKL-40 expression and the pathogenesis of SIVE neuronal damage was suggested by in vitro experiments demonstrating YKL-40 displacement of ECM-bound basic fibroblast growth factor (bFGF) and inhibition of bFGF-induced hippocampal neuronal axon sprouting. The displacement and inhibition of neurotrophic factors from the ECM by YKL-40 was proposed as a novel and indirect mechanism of SIV-induced neuronal damage. A further link to HIV neuropathogenesis was provided by examination of CSF from HIV-infected individuals, which showed significantly elevated CSF YKL-40 levels in those with >10,000 CSF HIV RNA copies/ml. Although the frequency of HIVE and HAND in the cases studied was not specified, high CSF viral loads are associated with increased risk of HIVE and HAND (see16Ellis RJ Gamst AC Capparelli E Spector SA Hsia K Wolfson T Abramson I Grant I McCutchan JA Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources.Neurology. 2000; 54: 927-936Crossref PubMed Scopus (171) Google Scholar and references therein). Because CSF YKL-40 is elevated in macaques before development of SIVE, YKL-40 could be a uniquely predictive biomarker for the development of HAND. If the predictive value of CSF YKL-40 expression is further validated in longitudinal studies of CNS HIV infection, this would represent a major step in progressing toward the eventual development of effective neuroprotective adjunctive therapies to HAART. The search for biomarkers of HIV-induced neurodegeneration and/or glial activation in both primate models and human cohorts has been an arduous and only partially successful undertaking. Ideally, the most desirable marker would meet the criteria of high sensitivity and specificity along with high predictive value for identifying high-risk individuals before development of irreversible neurological damage. To date, a number of variably reliable CSF markers of either pathological damage or cognitive dysfunction have been identified.11Price RW Epstein LG Becker JT Cinque P Gisslen M Pulliam L McArthur JC Biomarkers of HIV-1 CNS infection and injury.Neurology. 2007; 69: 1781-1788Crossref PubMed Scopus (71) Google Scholar Among these are the glial activation markers MCP-1/CCL-2 and other chemokines, neopterin, β-2 microglobulin, quinolinic acid, Fas, 4-hydroxynonenals and other associated reactive oxygen species,15Sevigny JJ Albert SM McDermott MP McArthur JC Sacktor N Conant K Schifitto G Selnes OA Stern Y McClernon DR Palumbo D Kieburtz K Riggs G Cohen B Epstein LG Marder K Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia.Neurology. 2004; 63: 2084-2090Crossref PubMed Scopus (169) Google Scholar, 18Cinque P Vago L Mengozzi M Torri V Ceresa D Vicenzi E Transidico P Vagani A Sozzani S Mantovani A Lazzarin A Poli G Elevated cerebrospinal fluid levels of monocyte chemotactic protein-1 correlate with HIV-1 encephalitis and local viral replication.Aids. 1998; 12: 1327-1332Crossref PubMed Scopus (211) Google Scholar, 19Sacktor N Haughey N Cutler R Tamara A Turchan J Pardo C Vargas D Nath A Novel markers of oxidative stress in actively progressive HIV dementia.J Neuroimmunol. 2004; 157: 176-184Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 20Brew BJ Dunbar N Pemberton L Kaldor J Predictive markers of AIDS dementia complex: CD4 cell count and cerebrospinal fluid concentrations of beta 2-microglobulin and neopterin.J Infect Dis. 1996; 174: 294-298Crossref PubMed Scopus (103) Google Scholar, 21Towfighi A Skolasky RL St Hillaire C Conant K McArthur JC CSF soluble Fas correlates with the severity of HIV-associated dementia.Neurology. 2004; 62: 654-656Crossref PubMed Scopus (21) Google Scholar, 22Heyes MP Brew BJ Martin A Price RW Salazar AM Sidtis JJ Yergey JA Mouradian MM Sadler AE Keilp J Rubinow D Markey SP Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status.Ann Neurol. 1991; 29: 202-209Crossref PubMed Scopus (495) Google Scholar and the neuronal markers neurofilament light chain (NFL)23Gisslen M Hagberg L Brew BJ Cinque P Price RW Rosengren L Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex.J Infect Dis. 2007; 195: 1774-1778Crossref PubMed Scopus (86) Google Scholar, 24Gisslen M Hagberg L Rosengren L Brew BJ Cinque P Spudich S Price RW Defining and evaluating HIV-related neurodegenerative disease and its treatment targets: a combinatorial approach to use of cerebrospinal fluid molecular biomarkers.J Neuroimmune Pharmacol. 2007; 2: 112-119Crossref PubMed Scopus (43) Google Scholar and tau protein.25Brew BJ Pemberton L Blennow K Wallin A Hagberg L CSF amyloid beta42 and tau levels correlate with AIDS dementia complex.Neurology. 2005; 65: 1490-1492Crossref PubMed Scopus (144) Google Scholar Each of these has been demonstrated to be associated with cognitive dysfunction in HIV-infected individuals, and MCP-1/CCL-2 (primarily derived from activated glia) and NFL have been found to be predictive of the development or worsening of HAND (CSF NFL: sensitivity 78%, specificity 67%).23Gisslen M Hagberg L Brew BJ Cinque P Price RW Rosengren L Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex.J Infect Dis. 2007; 195: 1774-1778Crossref PubMed Scopus (86) Google Scholar, 26Gonzalez E Rovin BH Sen L Cooke G Dhanda R Mummidi S Kulkarni H Bamshad MJ Telles V Anderson SA Walter EA Stephan KT Deucher M Mangano A Bologna R Ahuja SS Dolan MJ Ahuja SK HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels.Proc Natl Acad Sci USA. 2002; 99: 13795-13800Crossref PubMed Scopus (258) Google Scholar, 27Mellgren A Price RW Hagberg L Rosengren L Brew BJ Gisslen M Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection.Neurology. 2007; 69: 1536-1541Crossref PubMed Scopus (64) Google Scholar More recently, increases in CSF tocopherol and triglyceride C52 levels have also been shown to serve as predictive indicators of worsening HAND in individuals receiving HAART.28Bandaru VV McArthur JC Sacktor N Cutler RG Knapp EL Mattson MP Haughey NJ Associative and predictive biomarkers of dementia in HIV-1-infected patients.Neurology. 2007; 68: 1481-1487Crossref PubMed Scopus (93) Google Scholar These latter unique markers are thought to represent an endogenous CNS antioxidant response, and it is intriguing to speculate that this response occurs during early glial cell activation induced by HIV replication. Such early postinfection glial cell activation has been demonstrated by detection of early elevations of brain myoinositol, another marker of glial activation, by MRS studies of HIV-infected individuals.29Chang L Ernst T Leonido-Yee M Witt M Speck O Walot I Miller EN Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia.Neurology. 1999; 53: 782-789Crossref PubMed Google Scholar How YKL-40 compares with these glial and neuronal biomarkers in its predictive value for HAND remains to be determined. Many questions about the ultimate validity of CSF YKL-40 as a predictive marker for HIV-induced cognitive impairment remain, including the CNS cellular origins of YKL-40, its kinetics of expression, its association with neurodegenerative pathways, and its association with cognitive impairment in individuals receiving HAART and adjunctive neuroprotective therapies. In extraneural tissues, YKL-40 expression has been detected in macrophages in various inflammatory conditions and in many tumor types (reviewed17Johansen JS Jensen BV Roslind A Nielsen D Price PA Serum YKL-40, a new prognostic biomarker in cancer patients?.Cancer Epidemiol Biomarkers Prev. 2006; 15: 194-202Crossref PubMed Scopus (247) Google Scholar). However, the cellular origin of YKL-40 within the CNS is undefined, and this clearly requires clarification. This is especially critical because macrophage/microglial activation might occur before astrocyte activation, and markers selectively released by these distinct cell lineages might therefore have different predictive values. The Bonneh-Barkay study also presents evidence that differentiated macrophages express YKL-40 in vitro, and the investigators further suggest (in data not shown) that HIV-1 infection of macrophages rapidly induces transient elevations in YKL-40 expression, although the kinetics of YKL-40 expression in HIV-infected macrophages and other CNS cell types are as yet unknown. In these SIV-infected macaques, YKL-40 expression in the brain localized to perivascular macrophages (but not those in microglial nodules) and to areas surrounding activated astrocytes associated with microglial nodules, suggesting macrophage release and subsequent extracellular accumulation and association with astrocytes. This surprising accumulation is proposed to link YKL-40 directly to neurodegenerative pathways through interference with the neuronal binding and trophic activity of bFGF. The evidence for this is indirect, based on demonstration of bFGF displacement from ECM, perhaps through interactions with heparin sulfate in the ECM. However, the binding partners for YKL-40 are not completely defined, and YKL-40 apparently does not bind directly to the bFGF receptor. Despite these uncertainties, this suggests a role for YKL-40 in neuropathogenesis through interference with trophic functions of bFGF and perhaps other ECM-binding trophic factors. Because bFGF promotes the survival of neurons from multiple brain regions (neocortex, hippocampus, cerebellum, midbrain, others) and because expression of bFGF expression is altered in neurodegenerative diseases (Alzheimer's disease, AD; Parkinson's disease, PD), it may have a role in protecting the brain from pathological events.30Dono R Fibroblast growth factors as regulators of central nervous system development and function.Am J Physiol Regul Integr Comp Physiol. 2003; 284: R867-R881PubMed Google Scholar Accordingly, because many growth factors are bound to components of the ECM,31Ruoslahti E Yamaguchi Y Proteoglycans as modulators of growth factor activities.Cell. 1991; 64: 867-869Abstract Full Text PDF PubMed Scopus (1168) Google Scholar loss of activity of bFGF (and perhaps other ECM-bound neurotrophic factors) due to enhanced YKL-40 activity could indeed represent a novel mechanism of SIV/HIV-induced neurodegeneration. Determining the potential role for YKL-40 in such processes requires much additional investigation. Furthermore, although loss of several neurotrophic factors has been demonstrated in primary neurodegenerative diseases such as AD and PD, this has not been established in HAND. Alternatively, it is possible that YKL-40 accumulation could perturb supportive functions of astrocytes or induce production of neurotoxins by astrocytes. These questions are clearly worth further investigation in macaque SIVE models, in in vitro models of HIV-induced neurodegeneration, and in HAND. Other major unanswered questions are whether predictive biomarkers such as YKL-40, MCP-1/CCL-2, NFL and others respond similarly and reliably to anti-retroviral therapy before the development of SIVE and neurobehavioral changes and whether macaque models will replicate responses of these markers in humans receiving HAART. As previously discussed, there are several macaque models used in studies of SIVE pathogenesis that could certainly be used to further test and validate a role for YKL-40 in neuropathogenesis and neurological outcomes in longitudinal studies. Along with a strong predictive value for HAND development, an ideal biomarker would also serve as an easily assayed predictor of neuroprotection in response to drug treatment regimens, not only in treatment-naive patients but also in patients already receiving HAART. Several CSF biomarkers such as MCP-1/CCL-2 and NFL are expressed at lower levels during HAART than before HAART, and these lowered levels are associated with improvement in HAND symptoms.27Mellgren A Price RW Hagberg L Rosengren L Brew BJ Gisslen M Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection.Neurology. 2007; 69: 1536-1541Crossref PubMed Scopus (64) Google Scholar Other potential biomarkers are under investigation in ongoing clinical trials. The relationship between CSF YKL-40 expression, HAART, and the development and progression of HAND also requires investigation in longitudinal studies. Moreover, the effects of adjunctive (non-HAART) neuroprotective therapies (antioxidants, NMDA receptor antagonists, trophic factors) on predictive biomarkers such as YKL-40 need to be studied to determine the value of these biomarkers for defining the neuroprotective efficacy of combination therapy. If HAART is only partially neuroprotective, how do we assess these adjunctive therapies in real time in infected individuals? We need to urgently pursue the development of simple, rapid, and widely available assays of biomarkers suitable for both treatment-naive and HAART patients. HAND might be unique among neurodegenerative disorders in expressing a significant level of reversibility long after symptoms first develop, and effective "restorative" treatment might be possible in currently affected individuals. If a biomarker is linked solely to levels of SIV/HIV replication as indicated by CSF viral load, and it "normalizes" concomitantly with HAART suppression of CSF viral load, how do we then identify those individuals who nonetheless develop or progress to HAND? How do we apply neuroprotective adjunctive strategies in those patients? Perhaps predictive CSF biomarkers such as YKL-40 and/or others will eventually serve as adjuncts or even as surrogates for conventional specialized methods of neuropsychological testing and neuroimaging techniques used in individuals at high risk for HAND. Much additional study is required before YKL-40 can be validated as a predictive biomarker for the development of HAND. We should strive to fully define such biomarkers because of the potential benefit to millions of HIV-infected individuals worldwide. YKL-40, a Marker of Simian Immunodeficiency Virus Encephalitis, Modulates the Biological Activity of Basic Fibroblast Growth FactorThe American Journal of PathologyVol. 173Issue 1PreviewHuman immunodeficiency virus encephalitis causes dementia in acquired immune deficiency syndrome patients. Using proteomic analysis of postmortem cerebrospinal fluid (CSF) and brain tissue from the simian immunodeficiency virus primate model, we demonstrate here a specific increase in YKL-40 that was tightly associated with lentiviral encephalitis. Longitudinal analysis of CSF from simian immunodeficiency virus-infected pigtailed macaques showed an increase in YKL-40 concentration 2 to 8 weeks before death from encephalitis. Full-Text PDF
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