Transcriptional down-regulation of ccr5 in a subset of HIV+ controllers and their family members

• Published in: eLife 2019-04, Vol.8
• Main Authors: Gonzalo-Gil, Elena, Rapuano, Patrick B, Ikediobi, Uchenna, Leibowitz, Rebecca, Mehta, Sameet, Coskun, Ayse K, Porterfield, J Zachary, Lampkin, Teagan D, Marconi, Vincent C, Rimland, David, Walker, Bruce D, Deeks, Steven, Sutton, Richard E
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adult; Aged; AIDS; CC chemokine receptors; ccr2; CCR2 protein; ccr5; CCR5 protein; CD4 antigen; CD4-Positive T-Lymphocytes - chemistry; CD4-Positive T-Lymphocytes - virology; Cell activation; Cell surface; Cells, Cultured; Chemokines; Chromatin; Chromosome 3; Disease Resistance; Down-Regulation; Drug resistance; elite controllers; Family; Female; Flow cytometry; Gene expression; Gene regulation; Genomes; Genotype & phenotype; Health care; HIV; HIV Infections - immunology; HIV Long-Term Survivors; HIV-1 - growth & development; Human immunodeficiency virus; Humans; Infections; Infectious diseases; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - chemistry; Macrophages - virology; Male; Medicine; Microbiology and Infectious Disease; Middle Aged; Monocyte chemoattractant protein 1; Morphology; mRNA stability; Phenotypes; Receptors, CCR2 - biosynthesis; Receptors, CCR5 - biosynthesis; Transcription; Viral Tropism; viremic controllers; Young Adult
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.44360

HIV +Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4 +T cells with resistance specific to R5-tropic HIV, reversed after introduction of . R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4 +T cells of these EC/VCs had lower and RNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of and , despite having more accessible chromatin by ATAC-seq. Other nearby genes were also down-regulated, over a region of ~500 kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with / down-regulation, suggesting that the phenotype is heritable.