Overexpression of GRP78 confers protection against neurocognitive impairment in HIV-infected polydrug users

Aims: Due to the high prevalence of stress and neurocognitive impairment (NCI) in HIV infected and drug abuse patients worldwide, there is a need to study these disorders and their impact on the immune response. We hypothesize that HIV polydrug users (PDU) will have greater impact in stress and NCI leading to Endoplasmic Reticulum (ER) stress related T-lymphocyte protein and pro-inflammatory cytokine expression. To test this hypothesis, we will (1) identify stress levels and cytokine profiling in NCI in HIV+ and HIV−PDU, (2) detect biomarkers associated with NCI, stress and HIV polydrug use. Methods: The initial population analysis in this study was: 10 HIV+PDU+ and 10 HIV−PDU+. NCI and stress were respectively measured physiologically (homocysteine and cortisol levels) and psychologically (MOCA, IHDS andmodified PERI scale) in HIV+PDU. Immunoproteomics and flow cytometry were used to detect ER stress markers and cytokine profiling. Gene expression and western blots were used to validate the ER stress gene and protein expression. Results: HIV+PDU+ had elevated cortisol levels (1.25 g/dL) as compared to HIV−PDU+ (0.107 g/dL). Moreover, HIV+PDU+ with no NCI had an increase expression of proinflammatory cytokines. Immunoproteomics revealed the overexpression of ER stress marker GRP78 in HIV+PDU+NCI− participants. To compare significant differences between the HIV+PDU+NCI−/NCI+ groups, two-way ANOVA statistical analysis with 0.05 p value was used. Conclusions: Our findings showed that HIV infection in PDU contributes negatively in NCI, moreover, identification of GRP78 overexpression in HIV+PDUswith no NCI highlights its cytoprotective role and the identification of ER stress markers that may serve as candidates for early diagnostic of NCI HIV+, and polydrug use. Financial support:NIH andNIMHD (G12MD007583) (N Boukli) to the Universidad Central del Caribe) and K05DA015799 (J.C. Anthony, sponsor) to Michigan State University.