Inhibiting GCPII in EcoHIV-infected mice to improve cognitive performance

Human Immunodeficiency Viruses (HIV) are lentiviruses that cause a chronic, progressive infection, which can ultimately lead to acquired immunodeficiency syndrome (AIDS). Despite the development of antiretroviral therapy (ART), which has improved and extended the lives of people living with HIV (PLH), these individuals often experience neurocognitive deficits, especially in working memory and executive function. These domains are linked to brain circuits regulated by N-acetyl-aspartyl glutamate (NAAG), the most prevalent brain dipeptide. NAAG is cleaved by the enzyme glutamate carboxypeptidase II (GCPII) into N-acetyl aspartate (NAA) and glutamate. Inhibition of GCPII has been shown to elevate brain NAAG levels and improve learning and memory in both rodents and primate models. Using magnetic resonance spectroscopy (MRS) data in PLH, we recently reported that higher brain NAAG levels were associated with better attention/working memory, cognitive function and verbal fluency. These data suggest that brain NAAG may serve as a biomarker of cognition in PLH, and modulation of brain NAAG could represent a novel therapeutic strategy. To explore this potential, we utilized EcoHIV-infected mice as a mouse model of HIV as these mice have been shown to have cognitive performance deficits. Mice were infected with EcoHIV and received daily treatment of either vehicle or the GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA; 100 mg/kg IP) beginning 3 weeks post-infection. After 2 weeks of treatment, mice underwent behavioral tests, including open field (OF), novel object recognition test (NORT), light-dark box (LDB), social interaction test (SIT) and fear conditioning (FC). We found no difference in locomotion activities measured by OF, recognitive function measured by NORT, or anxiety-like behaviors measured by LDB in EcoHIV-infected mice comparing to age-matched WT controls. However, EcoHIV-infected mice displayed social avoidance behavior in the SIT and significant impairments in cued fear memory in the FC, both of which were reversed by 2-PMPA treatment. After completing the behavioral tests, we measured NAAG levels in the cerebrospinal fluid (CSF) and found that treatment with 2-PMPA significantly increased NAAG levels in the CSF of EcoHIV-infected mice. In conclusion, inhibiting GCPII with 2-PMPA increases NAAG levels in the CSF and improves specific cognitive and social deficits in EcoHIV-infected mice. Further studies are needed to elucidate the precise molecular mechanisms of these effects. This work was supported by P30 CAHN Pilot 90108414 (MH), P30 CAHN Pilot 90101781 (XZ) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.