Abstract HIV infection of the nervous system results in chronic infection, inflammation, neuropsychiatric problems and cognitive decline in up to 50% of people living with HIV with no effective treatments to-date. Inflammation appears early in the disease process and causes progressive neuronal damage due, in part, to factors released by activated microglia and macrophages. In cultured neurons and mice, expressing the HIV gp120 transgene these factors induce intracellular calcium accumulation, cytoskeletal damage and focal swelling, in a fashion similar to early Alzheimer’s disease (AD) pathology, suggesting a common substrate for disease progression. Age-dependent accumulation of the p75 neurotrophin receptor occurs early in disease and is thought to contribute to pathogenesis by shifting the balance of neurotrophin signaling away from protective, regenerative pathways. Treatment of aging and gp120 transgenic mice with a small non-peptide p75NTR ligand, LM11A-31, suppressed cholinergic degeneration, inflammation and neuronal damage. In cats chronically infected with feline immunodeficiency virus, ten weeks of oral treatment with LM11A-31 prevented degeneration, improved cognitive behaviors, reduced anxiety and CSF viral titers in the absence of any adverse effects on systemic viremia, PBMC FIV burden, or CD4:CD8 T cell ratios. Since p75NTR is normally expressed at very low levels in adult brain but is upregulated in response to injury or disease, it provides a unique target for therapy with minimal potential for off-target effects. The drug is orally bioavailable, crosses the blood brain barrier and has no significant adverse effects in humans at therapeutic concentrations. To explore the potential of LM11A-31 as a disease modifying neuroprotective treatment, the proposed studies will establish the safety and tolerability of LM11A-31 treatment in a small cohort of stable virally-suppressed participants with HIV and mild neurocognitive impairment. Safety measures will be supplemented with exploratory characterization of traditional and novel biomarkers for early detection of inflammation and neurodegeneration in CSF and blood. A novel fMRI Hcorr analysis will be used to provide a sensitive measure of early immune and p75NTR activation with the potential to identify individuals in early stages of neurodegeneration. Serial neuropsychological test results will provide preliminary data and facilitate transition to a subsequent efficacy trial for prevention of cognitive decline. These studies are expected to show that LM11A-31 is safe to use in people living with HIV and to lay the groundwork for a larger efficacy trial designed to demonstration protection from neuronal damage and cognitive decline.

Project Narrative Data from in vitro studies and various animal models of aging and neurodegenerative disease have uniformly indicated that a novel ligand targeted to the p75 neurotrophin receptor offers significant neuroprotection by stabilizing neurons at early stages of disease and by suppressing inflammatory activity. The ligand, LM11A-31, is orally bioavailable crosses the blood brain barrier and had no significant adverse actions in phase 1 studies thereby providing a potential disease modifying intervention for the treatment of HIV-associated neurocognitive disorders. The proposed studies will establish the safety of LM11A-31 in people with HIV on antiretroviral therapy and will establish the foundations for a larger efficacy trial in people living with HIV.