Downregulation of CCR5 on brain perivascular macrophages in simian immunodeficiency virus‐infected rhesus macaques

• Published in: Brain and behavior 2023-08, Vol.13 (8), p.e3126-n/a
• Main Authors: Hattler, Julian B., Irons, Derek L., Luo, Jiangtao, Kim, Woong‐Ki
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antigens; Brain - pathology; Brain research; CCR5; CD8 T lymphocytes; Clathrin - metabolism; Down-Regulation; Encephalitis - metabolism; endocytosis; Euthanasia; HIV; Human immunodeficiency virus; Immune system; Infections; Laboratory animals; Macaca mulatta - metabolism; Macrophages; Original; Pathogenesis; perivascular macrophages; Proteins; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; Receptors, Chemokine - metabolism; Simian Acquired Immunodeficiency Syndrome - metabolism; Simian Acquired Immunodeficiency Syndrome - pathology; Simian Immunodeficiency Virus - metabolism; SIV
• ISSN: 2162-3279; 2162-3279
• DOI: 10.1002/brb3.3126

Background C‐C chemokine receptor 5 (CCR5) is a major coreceptor for Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) cell entry; however, its role in brain pathogenesis is largely understudied. Thus, we sought to examine cell type‐specific protein expression of CCR5 during SIV infection of the brain. Methods We examined occipital cortical tissue from uninfected rhesus macaques and SIV‐infected animals with or without encephalitis using immunohistochemistry and immunofluorescence microscopy to determine the number and distribution of CCR5‐positive cells. Results An increase in the number of CCR5+ cells in the brain of SIV‐infected animals with encephalitis was accounted for by increased CD3+CD8+ cells expressing CCR5, but not by increased CCR5+ microglia or perivascular macrophages (PVMs), and a concurrent decrease in the percentage of CCR5+ PVMs was observed. Levels of CCR5 and SIV Gag p28 protein expression were examined on a per‐cell basis, and a significant, negative relationship was established indicating decreased CCR5 expression in productively infected cells. While investigating the endocytosis‐mediated CCR5 internalization as a mechanism for CCR5 downregulation, we found that phospho‐ERK1/2, an indicator of clathrin‐mediated endocytosis, was colocalized with infected PVMs and that macrophages from infected animals showed significantly increased expression of clathrin heavy chain 1. Conclusions These findings show a shift in CCR5‐positive cell types in the brain during SIV pathogenesis with an increase in the number of CCR5+ CD8 T cells, and downregulated CCR5 expression on infected PVMs, likely through ERK1/2‐driven, clathrin‐mediated endocytosis. In this study, we provide in vivo evidence that SIV infection downregulates CCR5, one of the two major HIV/SIV coreceptors, in the brain of rhesus macaques, likely through clathrin‐mediated endocytosis. This is a clinically relevant information, which explains why CCR5 inhibition prevents new infections, but is not effective at suppressing viral replication from cells that have been already infected.