AUTHOR=Shrestha Jenny , Santerre Maryline , Allen Charles N. S. , Arjona Sterling P. , Merali Carmen , Mukerjee Ruma , Chitrala Kumaraswamy Naidu , Park Jin , Bagashev Asen , Bui Viet , Eugenin Eliseo A. , Merali Salim , Kaul Marcus , Chin Jeannie , Sawaya Bassel E. TITLE=HIV-1 gp120 Impairs Spatial Memory Through Cyclic AMP Response Element-Binding Protein JOURNAL=Frontiers in Aging Neuroscience VOLUME=14 YEAR=2022 URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.811481 DOI=10.3389/fnagi.2022.811481 ISSN=1663-4365 ABSTRACT=

HIV-associated neurocognitive disorders (HAND) remain an unsolved problem that persists despite using antiretroviral therapy. We have obtained data showing that HIV-gp120 protein contributes to neurodegeneration through metabolic reprogramming. This led to decreased ATP levels, lower mitochondrial DNA copy numbers, and loss of mitochondria cristae, all-important for mitochondrial biogenesis. gp120 protein also disrupted mitochondrial movement and synaptic plasticity. Searching for the mechanisms involved, we found that gp120 alters the cyclic AMP response element-binding protein (CREB) phosphorylation on serine residue 133 necessary for its function as a transcription factor. Since CREB regulates the promoters of PGC1α and BDNF genes, we found that CREB dephosphorylation causes PGC1α and BDNF loss of functions. The data was validated in vitro and in vivo. The negative effect of gp120 was alleviated in cells and animals in the presence of rolipram, an inhibitor of phosphodiesterase protein 4 (PDE4), restoring CREB phosphorylation. We concluded that HIV-gp120 protein contributes to HAND via inhibition of CREB protein function.