HIV-1 gp120 Impairs Spatial Memory Through Cyclic AMP Response Element-Binding Protein

Jenny Shrestha; Maryline Santerre; Charles N S Allen; Sterling P Arjona; Carmen Merali; Ruma Mukerjee; Kumaraswamy Naidu Chitrala; Jin Park; Asen Bagashev; Viet Bui; Eliseo A Eugenin; Salim Merali; Marcus Kaul; Jeannie Chin; Bassel E Sawaya

doi:10.3389/fnagi.2022.811481

HIV-1 gp120 Impairs Spatial Memory Through Cyclic AMP Response Element-Binding Protein

Front Aging Neurosci. 2022 May 9:14:811481. doi: 10.3389/fnagi.2022.811481. eCollection 2022.

Authors

Jenny Shrestha^{1

2}, Maryline Santerre^{1

2}, Charles N S Allen^{1

2}, Sterling P Arjona^{1

2}, Carmen Merali³, Ruma Mukerjee^{1

2}, Kumaraswamy Naidu Chitrala², Jin Park⁴, Asen Bagashev¹, Viet Bui^{1

2}, Eliseo A Eugenin⁵, Salim Merali³, Marcus Kaul^{6

7

8}, Jeannie Chin⁴, Bassel E Sawaya^{1

2

9

10

11}

Affiliations

¹ Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States.
² Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States.
³ Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, United States.
⁴ Memory and Brain Research Center, Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States.
⁵ Department of Neuroscience, Cell Biology, and Anatomy, The University of Texas Medical Branch, Galveston, TX, United States.
⁶ Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States.
⁷ Department of Psychiatry, University of California, San Diego, San Diego, CA, United States.
⁸ Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States.
⁹ Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.
¹⁰ Department of Cancer and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.
¹¹ Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States.

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.

Keywords: CREB protein; HIV; mitochondria; neurodegeneration; rolipram.

Abstract

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