Soluble and cell-associated insulin receptor dysfunction correlates with severity of HAND in HIV-infected women.
BACKGROUND
Blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HIV-associated neurocognitive disorders (HAND). These abnormalities may occur as a result of chronic HIV infection, long-term use of combined antiretroviral treatment (CART), aging, genetic predisposition, or a combination of these factors, and may increase morbidity and mortality in this population.


OBJECTIVE
To determine if changes in soluble and cell-associated insulin receptor (IR) levels, IR substrate-1 (IRS-1) levels, and IRS-1 tyrosine phosphorylation are associated with the presence and severity of HAND in a cohort of HIV-seropositive women.


RESULTS
This is a retrospective cross-sectional study using patient database information and stored samples from 34 HIV-seropositive women and 10 controls without history of diabetes from the Hispanic-Latino Longitudinal Cohort of Women. Soluble IR subunits [sIR, ectodomain (α) and full-length or intact (αβ)] were assayed in plasma and CSF samples by ELISA. Membrane IR levels, IRS-1 levels, and IRS-1 tyrosine phosphorylation were analyzed in CSF white cell pellets (WCP) using flow cytometry. HIV-seropositive women had significantly increased levels of intact or full-length sIR in plasma (p<0.001) and CSF (p<0.005) relative to controls. Stratified by HAND, increased levels of full-length sIR in plasma were associated with the presence (p<0.001) and severity (p<0.005) of HAND. A significant decrease in IRS-1 tyrosine-phosphorylation in the WCP was also associated with the presence (p<0.02) and severity (p<0.02) of HAND.


CONCLUSIONS
This study provides evidence that IR secretion is increased in HIV-seropositive women, and increased IR secretion is associated with cognitive impairment in these women. Thus, IR dysfunction may have a role in the progression of HAND and could represent a biomarker for the presence and severity of HAND.
NeuroAIDS Specialized Neuroscience Research Program, University of Puerto Rico, San Juan, Puerto Rico.
Yamil
Y
Gerena
Richard L
RL
Skolasky
Joyce M
JM
Velez
Dianedis
D
Toro-Nieves
Raul
R
Mayo
Avindra
A
Nath
Valerie
V
Wojna
D015526:AIDS Dementia Complex / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000328:Adult; D003430:Cross-Sectional Studies; D016208:Databases, Factual; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D006679:HIV Seropositivity / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008875:Middle Aged; D009483:Neuropsychological Tests; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D012189:Retrospective Studies; D012720:Severity of Illness Index
D055504:Insulin Receptor Substrate Proteins; D011972:Receptor, Insulin