Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs.
Human immunodeficiency virus infection (HIV) at late stages of the disease is accompanied by neurological complications, including motor, behavioral and cognitive impairment. Using simian immunodeficiency virus (SIV)-infected rhesus monkeys, an animal model of HIV infection, we found that during the asymptomatic SIV infection dopamine (DA) deficits are early components of central nervous system (CNS) dysfunction. To investigate the role of the DA system in SIV infection and to restore the DA deficiency, we administered selegiline, an agent with DAergic and neuroprotective properties, to SIV-infected monkeys. Selegiline increased DA availability but induced CNS vacuolization, SIV encephalitic lesions, and enhanced CNS viral replication during early SIV infection. The pathological changes seem to be mediated by DA, as treatment with L-DOPA, the precursor of DA, had similar effects. We propose that any natural or induced DAergic dysregulation which results in increased DA availability may potentiate HIV-associated neurological disease (ND). Our findings raise new questions regarding the pathogenesis of HIV-ND and generate concerns about the safety of dopaminergic drugs in the clinical management of HIV-infected patients.
Institute for Pathology, University of Würzburg, Germany.
S
S
Czub
E
E
Koutsilieri
S
S
Sopper
M
M
Czub
C
C
Stahl-Hennig
J G
JG
Müller
V
V
Pedersen
W
W
Gsell
J L
JL
Heeney
M
M
Gerlach
G
G
Gosztonyi
P
P
Riederer
V
V
ter Meulen
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D018792:Encephalitis, Viral / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008253:Macaca mulatta; D018696:Neuroprotective Agents / Q000009:adverse effects; D012642:Selegiline / Q000009:adverse effects; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D012642:Selegiline; D004298:Dopamine