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

Abstract

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 ccr5. 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 ccr2 and ccr5 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 ccr2 and ccr5, 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 ccr2/ccr5 down-regulation, suggesting that the phenotype is heritable.

Distinct lipid profile, low-level inflammation, and increased antioxidant defense signature in HIV-1 elite control status

“…We did not see any of these two features in our cohort. Recently, reduced frequencies and surface levels of CCR2 on CD4 + T cells were described in a subset of EC samples (but not in all) ( Gonzalo-Gil et al., 2019 ). Although we did not see any difference in frequencies of CCR2 + CD4 + T cells, we noticed a reduction of CCR2 surface expression levels on CD4 + T cells in EC.…”

The CD8+T Cell Noncytotoxic Antiviral Responses

“…In addition to CD8 + T cells mediating antiviral activity, the NGS approaches could also be relevant to elucidate the intracellular pathway(s) creating the antiviral state elicited by CAF in CD4 + cells. In one study, RNA-Seq analysis was performed on the CD4 + cells of ECs ( 376 ). Although this particular study focused on subjects who were resistant to R5-tropic virus infection, this NGS approach may help to determine how the transcriptome of target cells is affected by CNAR/CAF in future experiments.…”

CCR5 Promoter Polymorphism −2459G > A: Forgotten or Ignored?

“…CCR5 cell surface expression vis-à-vis disease phenotype [10,11]. In addition, they suggest a possible role of these polymorphisms in HIV pathogenesis, where the promoter activity may regulate bystander CD4+ T cell apoptosis and loss [11,12].…”

“…Recent studies have advanced our understanding regarding the relationship between these polymorphisms and transcriptional regulation of the CCR5 promoter, and how this relationship affects CCR5 cell surface expression vis-à-vis disease phenotype [ 10 , 11 ]. In addition, they suggest a possible role of these polymorphisms in HIV pathogenesis, where the promoter activity may regulate bystander CD4+ T cell apoptosis and loss [ 11 , 12 ].…”