Sensory neuropathy in human immunodeficiency virus/acquired immunodeficiency syndrome patients: protease inhibitor-mediated neurotoxicity.
OBJECTIVE
Human immunodeficiency virus-associated sensory neuropathy (HIV-SN) is a common and disabling disorder, often associated with antiretroviral therapy (ART) use. We investigated the clinical features and associated pathogenic determinants of HIV-SN in a neurological cohort of HIV-infected patients, together with a novel model of HIV-SN.


METHODS
HIV-infected patients with neurological disease were investigated in terms of clinical and laboratory aspects together with ART exposure focusing on symptomatic HIV-SN. Rat-derived dorsal root ganglion (DRG) cultures, transgenic for human CD4 and CCR5 treated with ARTs or HIV infected, or both, were studied with respect to quantitative neuronal injury.


RESULTS
Among 221 patients assessed from 1998 to 2004, 120 had no sensory neuropathy, whereas 101 displayed HIV-SN, including 64 with distal sensory neuropathy and 37 with antiretroviral toxic neuropathy. HIV-SN patients exhibited significantly greater mean age, peak plasma viral loads, and exposure to neurotoxic dideoxynucleosides and protease inhibitors, including indinavir, saquinavir, or ritonavir. HIV-infected DRG cultures exposed to indinavir or didanosine showed significant neuronal atrophy, neurite retraction, and process loss, compared with controls. Indinavir was selectively cytotoxic to DRG macrophages compared with other ARTs.


CONCLUSIONS
Protease inhibitor exposure is an unrecognized risk factor for the development of HIV-SN, which may potentiate neuronal damage in HIV-infected DRGs, possibly through the loss of macrophage-derived trophic factors.
Pettersen
Jacqueline A
JA
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Jones
Gareth
G
Worthington
Catherine
C
Krentz
Hartmut B
HB
Keppler
Oliver T
OT
Hoke
Ahmet
A
Gill
M John
MJ
Power
Christopher
C
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000473:pathology; D000328:Adult; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D015704:CD4 Antigens / Q000235:genetics; D002478:Cells, Cultured; D015331:Cohort Studies; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000473:pathology; D015658:HIV Infections / Q000150:complications* / Q000473:pathology; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D015497:HIV-1; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D030781:Organisms, Genetically Modified; D051381:Rats; D017207:Rats, Sprague-Dawley; D019713:Receptors, CCR5 / Q000235:genetics; D012678:Sensation Disorders / Q000139:chemically induced* / Q000473:pathology
D015704:CD4 Antigens; D017320:HIV Protease Inhibitors; D019713:Receptors, CCR5