TY - JOUR
T1 - Differential Expression of CREM/ICER Isoforms Is Associated with the Spontaneous Control of HIV Infection
AU - Luo, Zhenwu
AU - Li, Min
AU - Li, Tai Wei
AU - Lv, Zongyang
AU - Ye, Zhiwei
AU - Cisneros, William J.
AU - Zhang, Jie
AU - Yuan, Lingmin
AU - Hultquist, Judd F.
AU - Migueles, Stephen A.
AU - Huang, Lei
AU - Zhu, Jian
AU - Jiang, Wei
N1 - Funding Information:
We received support from the National Institute of Allergy and Infectious Diseases (grants AI128864 to W.J., R01DE025447 to J.Z., R01AI150448 to J.Z., and R56AI15787 to J.Z.), as well as the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001450 (the pilot grant, W.J.). The Medical Research Service at the Ralph H. Johnson VA Medical Center provided merit grant VA CSRD MERIT CX-002422 (W.J.). The Gilead Sciences Research Scholars Program in HIV provided funds to J.F.H. The NIH provided the following support: grant K22 AI136691 (J.F.H.), grant R01 AI150998 (J.F.H.), Third Coast CFAR (NIH-supported) grant P30 AI117943 (J.F.H.), and HARC Center (NIH-sponsored) grant P50 GM082250 (J.F.H.).
Publisher Copyright:
© 2022 American Society for Microbiology. All rights reserved.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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 CD41 T cell line and primary CD41 T cells. Overexpression of ICER isoforms decreased HIV infection in primary CD41 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.
AB - 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 CD41 T cell line and primary CD41 T cells. Overexpression of ICER isoforms decreased HIV infection in primary CD41 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.
KW - CREM/ICER gene
KW - Elite controllers
KW - HIV
KW - Host factor
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U2 - 10.1128/MBIO.01979-21
DO - 10.1128/MBIO.01979-21
M3 - Article
C2 - 35041523
AN - SCOPUS:85125932045
VL - 13
JO - mBio
JF - mBio
SN - 2161-2129
IS - 1
M1 - e01979
ER -
