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