Cognitive deficits are a significant clinical problem associated with HIV infection (HIV-associated neurocognitive disorders or HAND). We have recently showed that decreasing the function of CCR5, a receptor that mediates HIV cellular entry, increases MAPK and CREB signaling, enhances long-term potentiation (LTP), and strengthens hippocampus-dependent memory (e.g., spatial and contextual learning), while manipulations that increase CCR5 function have the opposite effect.
These results demonstrate that CCR5 is a suppressor for synaptic plasticity and memory, and suggest the hypothesis that CCR5 over-activation by HIV viral proteins contribute to HAND. Consistent with this hypothesis, our laboratory found that the neuronal and cognitive deficits caused by an HIV coat peptide, known to bind and activate CCR5 (HIV Gp120 V3 loop peptide or HIV-V3 peptide) could be prevented by manipulations that decreased CCR5 function. Overall, our results demonstrate that CCR5 plays an important role in neuroplasticity and learning & memory, and indicate that over-activation of this receptor could contribute to HIV-associated neurocognitive disorders
Delayed increases in CCR5 are also critical for closing the temporal window for memory linking. This is accomplished by CCR5's role in decreasing the neuronal excitability of the neurons recruited to encode the first memory, thus ensuring that those neurons do not also encode the second memory. We have also discovered an age-related loss of memory linking that is due to increases in the expression of CCR5 in middle-aged mice. Remarkably, a FDA approved CCR5 inhibitor (Maraviroc) reverses deficits in memory linking in middle-aged mice. It is possible that the same treatment may also be effective in accelerated age-related cognitive deficits in individuals living with HIV
Key Publications:
Miou Zhou Stuart Greenhill Shan Huang Tawnie K Silva Yoshitake Sano Shumin Wu Ying Cai Yoshiko Nagaoka Megha Sehgal Denise J Cai Yong-Seok Lee Kevin Fox Alcino J Silva. CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory. DOI: http://dx.doi.org/10.7554/eLife.20985; Published December 20, 2016; Cite as eLife 2016;10.7554/eLife.209851. (PDF)
Yang Shen, Miou Zhou1, Denise Cai Daniel Almeida Filho, Giselle Fernandes, Ying Cai, Nury Kim, Deanna Necula, Chengbin Zhou, Andy Liu, Xiaoman Kang, Masakazu Kamata, Ayal Lavi, Shan Huang, Tawnie Silva, Won Do Heo, Alcino J. Silva. CCR5 closes the temporal window for memory linking. Nature (2022). https://doi.org/10.1038/s41586-022-04783-1 (link)
