Changes in monocyte/macrophage neurotoxicity in the era of HAART: implications for HIV-associated dementia.
OBJECTIVE
To determine changes in CD14/CD69 cells of HIV seropositive patients with HIV-1 associated dementia (HAD) on highly active antiretroviral therapy (HAART) and to determine the effect of soluble factors from cultured monocyte/macrophage (M/M phi) on neural cell functional proteins.


METHODS
Whole blood from patients with HAD, HIV seronegative subjects, and HIV seropositive subjects with no dementia (HIV-ND) was analyzed for CD14/CD69 cells using flow cytometry. M/M phi were isolated and cultured, and supernatants tested for neurotoxicity. Modulation of neural cell proteins and mitogen-activated protein kinases in response to supernatant exposure was examined by Western blot.


RESULTS
CD14/CD69 levels from HAART-treated HAD subjects were significantly elevated over those from HIV-ND subjects and controls. However, levels were significantly lower than those reported in similarly selected HAD subjects tested prior to the HAART era. Treatment of neural cells with M/M phi-derived culture supernatants from HAART-treated HAD subjects was not associated with cell death, but resulted in a trend towards lower activation of the JNK, AKT, and ERK kinases, decreased expression of SNAP-25, and increased expression of neurofilament light than was observed after treatment with HIV-ND M/M phi supernatants.


CONCLUSIONS
The clinical phenotype of HAD appears to be evolving from a subacute dementing disease to a more protracted disorder. Decreased CD14/CD69 levels may reflect changes in some aspects of the pathophysiology of brain injury in the era of HAART. Changes in neural cell signaling, structural and functional proteins may represent more subtle neurotoxicity, manifested in cell dysfunction rather than frank cell death.
Kusdra
Leonard
L
Department of Laboratory Medicine, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA.
McGuire
Dawn
D
Pulliam
Lynn
L
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000503:physiopathology*; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D023241:Antiretroviral Therapy, Highly Active; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D018023:HIV Seronegativity; D006679:HIV Seropositivity / Q000188:drug therapy; D006801:Humans; D037181:Lectins, C-Type; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008264:Macrophages / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D050825:Synaptosomal-Associated Protein 25; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017077:Culture Media, Conditioned; D037181:Lectins, C-Type; D018950:Lipopolysaccharide Receptors; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D050825:Synaptosomal-Associated Protein 25; D000099192:CD69 Antigens; C494208:SNAP25 protein, human; C044882:neurofilament protein L