Differential Expression of CREM/ICER Isoforms Is Associated with the Spontaneous Control of HIV Infection

A rare subset of HIV-infected individuals, termed elite controllers (ECs), can maintain long-term control over HIV replication in the absence of antiretroviral therapy (ART). To elucidate the biological mechanism of resistance to HIV replication at the molecular and cellular levels, we performed RNA sequencing and identified alternative splicing variants from ECs, HIV-infected individuals undergoing ART, ART-naive HIV-infected individuals, and healthy controls. We identified differential gene expression patterns that are specific to ECs and may influence HIV resistance, including alternative RNA splicing and exon usage variants of the CREM/ICER gene (cyclic AMP [cAMP]-responsive element modulator/inducible cAMP early repressors). The knockout and knockdown of specific ICER exons that were found to be upregulated in ECs resulted in significantly increased HIV infection in a CD4⁺ T cell line and primary CD4⁺ T cells. Overexpression of ICER isoforms decreased HIV infection in primary CD4⁺ T cells. Furthermore, ICER regulated HIV long terminal repeat (LTR) promoter activity in a Tat-dependent manner. Together, these results suggest that ICER is an HIV host factor that may contribute to the HIV resistance of ECs. These findings will help elucidate the mechanisms of HIV control by ECs and may yield a new approach for treatment of HIV. IMPORTANCE A small group of HIV-infected individuals, termed elite controllers (ECs), display control of HIV replication in the absence of antiretroviral therapy (ART). However, the mechanism of ECs' resistance to HIV replication is not clear. In our work, we found an increased expression of specific, small isoforms of ICER in ECs. Further experiments proved that ICER is a robust host factor to regulate viral replication. Furthermore, we found that ICER regulates HIV LTR promoter activity in a Tat-dependent manner. These findings suggest that ICER is related to spontaneous control of HIV infection in ECs. This study may help elucidate a novel target for treatment of HIV.