Soluble and cell-associated insulin receptor dysfunction correlates with severity of HAND in HIV-infected women

Abstract

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.

Methods and 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.

Figure 1. Soluble insulin receptor full-length (sIRαβ) and HIV.

Soluble insulin receptor (sIR) intact or full-length (αβ) was measured in plasma (A) and CSF (B) of HIV-seropositive women (HIV+) (n = 34) and controls (HIV−) (n = 10, 5 with plasma and different 5 for CSF). The sIR subunits were determined using an ELISA Significantly higher levels of full-length sIR was observed in HIV-seropositive women in plasma and CSF when compared with controls (p<0.001 and p = 0.003 respectively). (MFI = Median Fluorescence Intensity).

Figure 2. Soluble insulin receptor full-length (sIRαβ) stratified by HAND.

Soluble insulin receptor (sIR) intact or full-length (αβ) subunit was measured by ELISA in plasma (A) and CSF (B) of HIV-seropositive women (HIV+) (n = 34) stratified by HAND into normal cognition (n = 11), asymptomatic impairment (n = 8), and symptomatic impairment (n = 15); and 10 HIV-negative controls (HIV−) (5 plasma were different women from 5 CSF). In plasma (A), levels of full-length sIR were significantly increased from controls in all HIV-seropositive women and it correlated with the severity of HAND (normal cognition [p = 0.003], asymptomatic impairment [p<0.001], and symptomatic impairment [p<0.001]). Also, women with symptomatic impairment had significant higher levels of full-length sIR when compared to those with normal cognition (p = 0.009). A similar trend was observed in CSF samples (B), although the only significant increased was observed in the women with symptomatic impairment when compared to controls. (MFI = Median Fluorescence Intensity).

Figure 3. Insulin Receptor Substrate 1 (IRS-1) tyrosine phosphorylation stratified by HAND.

Insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation was determined in CSF cell pellets of 23 HIV-seropositive women (HIV+) stratified by HAND (7 with normal cognition, 7 with asymptomatic impairment, and 9 with symptomatic impairment) using flow cytometry. A significant decrease in IRS-1 tyrosine phosphorylation was observed between HIV-seropositive women with normal cognition and symptomatic impairment (p = 0.02). (MFI = Median Fluorescence Intensity).