Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS.
Difficulties in understanding the mechanisms of HIV neuropathogenesis include the inability to study dynamic processes of infection, cumulative effects of the virus, and contributing host immune responses. We used H magnetic resonance spectroscopy and studied monocyte activation and progression of CNS neuronal injury in a CD8 lymphocyte depletion model of neuroAIDS in SIV-infected rhesus macaque monkeys. We found early, consistent neuronal injury coincident with viremia and SIV infection/activation of monocyte subsets and sought to define the role of plasma virus and monocytes in contributing to CNS disease. Antiretroviral therapy with essentially non-CNS-penetrating agents resulted in slightly decreased levels of plasma virus, a significant reduction in the number of activated and infected monocytes, and rapid, near-complete reversal of neuronal injury. Robust macrophage accumulation and productive virus replication were found in brains of infected and CD8 lymphocyte-depleted animals, but no detectable virus and few scattered infiltrating macrophages were observed in CD8 lymphocyte-depleted animals compared with animals not receiving antiretroviruses that were sacrificed at the same time after infection. These results underscore the role of activated monocytes and monocyte infection outside of the brain in driving CNS disease.
Williams
Kenneth
K
Viral Pathogenesis, RE113 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. Kenneth_Williams@hms.harvard.edu
Westmoreland
Susan
S
Greco
Jane
J
Ratai
Eva
E
Lentz
Margaret
M
Kim
Woong-Ki
WK
Fuller
Robert A
RA
Kim
John P
JP
Autissier
Patrick
P
Sehgal
Prahbat K
PK
Schinazi
Raymond F
RF
Bischofberger
Norbert
N
Piatak
Michael
M
Lifson
Jeffrey D
JD
Masliah
Eliezer
E
González
R Gilberto
RG
D015526:AIDS Dementia Complex / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D004359:Drug Therapy, Combination; D006801:Humans; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D009000:Monocytes / Q000276:immunology*; D009474:Neurons / Q000276:immunology / Q000473:pathology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*
D044966:Anti-Retroviral Agents; D000911:Antibodies, Monoclonal