The complement system, neuronal injury, and cognitive function in horizontally-acquired HIV-infected youth.
The complement system (C1q/C3) is a key mediator of synaptic pruning during normal development. HIV inappropriately induces C1q and C3 production in the brain, and reduces neuronal complement inhibition. HIV may thus alter neural connectivity in the developing brain by excessively targeting synapses for elimination. The resultant pattern of neuronal injury may fundamentally alter neurodevelopmental and cognitive processes differentially across ages. This study aimed to (1) measure the association between the cerebrospinal fluid (CSF) complement factors (C1q/C3) and a marker of neuronal injury (NFL) in HIV+ subjects; (2) quantify the differences in CSF C1q/C3 between HIV+ youth and older adults; and (3) define the relationship between CSF C1q/C3 and cognitive impairment in each age group. We performed a retrospective cross-sectional study of 20 HIV+ 18-24-year-old youth and 20 HIV+ 40-46-year-old adults with varying levels of cognitive impairment enrolled in the CNS Antiretroviral Therapy Effects Research study. We quantified C3, C1q, and NFL by ELISA in paired CSF/plasma specimens. We found that CSF C1q correlates with NFL in all subjects not receiving antiretroviral therapy (n = 16, rho = 0.53, p = 0.035) when extreme NFL outliers were eliminated (n = 1). There was no difference in plasma/CSF C1q or C3 between older adults and youth. In 18-24-year-old youth, a nearly significant (p = 0.052) elevation of CSF C1q expression was observed in cognitively impaired subjects compared to cognitively normal subjects. Further investigation into the role of the CNS complement system in the neuropathogenesis of HIV is warranted and should be considered in a developmentally specific context.
Division of Neurology, The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA, 19104, USA. mcguirej@email.chop.edu.|Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mcguirej@email.chop.edu.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mcguirej@email.chop.edu.
Jennifer L
JL
McGuire
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Alexander J
AJ
Gill
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.
Steven D
SD
Douglas
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Dennis L
DL
Kolson
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000502:physiology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy; D015922:Complement C1q / Q000134:cerebrospinal fluid*; D003176:Complement C3 / Q000134:cerebrospinal fluid*; D063132:Connectome; D003430:Cross-Sectional Studies; D018562:Disease Transmission, Infectious; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000635:transmission; D006801:Humans; D008297:Male; D008875:Middle Aged; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012189:Retrospective Studies; D013569:Synapses / Q000378:metabolism / Q000473:pathology
D019380:Anti-HIV Agents; D015415:Biomarkers; D003176:Complement C3; D016900:Neurofilament Proteins; C044882:neurofilament protein L; D015922:Complement C1q
Cognition; Complement; HAND; HIV; Neurofilament; Neuroinflammation; Youth