# Anti-HIV-1 recall responses from brain-resident memory CD8+ T-cells (bTRM) and reactive gliosis-mediated neurotoxicity > **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $385,000 ## Abstract PROJECT SUMMARY/ABSTRACT Although patients on successful combination antiretroviral therapy (cART) show sustained viral suppression in the cerebrospinal fluid (CSF) as well as plasma, “blips” indicative of transient HIV replication are often found with more frequent CSF testing. Recent studies link persistent immune activation, neuroinflammation, and CSF viral escape in cART-treated individuals to increased disease progression, as well as an increased risk for HAND. In this application, it is proposed that in patients on optimal cART, HAND is driven by recall immune responses to small amounts of antigen produced during this transient CSF viral escape. Over the previous funding period of this grant, we have described a population of CD8(+)CD103(+)CD127(+) memory T-cells which remain as permanent residents within the brain following viral infection. Building on these findings, we used a heterologous prime-boost strategy in which mice are immunized with recombinant adenovirus vectors expressing the HIV-1 p24 capsid protein (rAd5-p24), followed by a CNS boost using Pr55Gag/Env virus-like particles (HIVLPs). This approach allowed us to develop an innovative experimental model in which the murine brain becomes populated by resident CD8(+) memory T-cells specific for immunodominant HIV-1 Gag epitopes. In addition, subsequent anti-HIV-1 recall responses can then be induced in response to stimulation using defined peptide epitopes. This novel approach allows us to investigate the neuroimmune pathogenesis of recall immune responses in a powerful, yet convenient and inexpensive small animal model. Despite its importance to understanding and treating HAND, nothing is currently know about how anti-HIV-1 recall responses from brain-resident memory CD8(+) T-cells (bTRM) trigger tissue-wide innate immune responses which drive reactive gliosis-mediated neurotoxicity. Experiments proposed in this application will fill this gap in knowledge. The central hypothesis to be tested is that adaptive, anti-HIV-1 recall responses from bTRM trigger tissue-wide innate immune responses from reactive glia that promote inflammation-induced synaptic damage, neurotoxicity, and long-term neurocognitive impairment. The studies will first determine whether anti-HIV-1 recall responses from CD8(+)CD103(+)CD127(+) bTRM induce reactive gliosis and trigger broad innate neuroinflammatory responses. Experiments proposed in Aim #2 will go on to determine whether these anti- HIV-1 recall responses trigger synaptodendritic damage, neurotoxicity, and long-term neurological sequelae. Finally in Specific Aim #3, which is more translational, we will determine whether anti-HIV-1 recall response- driven neuroinflammation can be ameliorated through immunomodulatory approaches. Although patients on successful cART show sustained viral suppression, antiviral treatment alone does not fully protect against neurocognitive impairment. Still, partial protection by cART does indicate a direct connection to ... ## Key facts - **NIH application ID:** 10076865 - **Project number:** 5R01NS038836-23 - **Recipient organization:** UNIVERSITY OF MINNESOTA - **Principal Investigator:** James R Lokensgard - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $385,000 - **Award type:** 5 - **Project period:** 2000-01-01 → 2022-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10076865 ## Citation > US National Institutes of Health, RePORTER application 10076865, Anti-HIV-1 recall responses from brain-resident memory CD8+ T-cells (bTRM) and reactive gliosis-mediated neurotoxicity (5R01NS038836-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10076865. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*