CCR5 serves as R5-tropic HIV co-receptor. Knocking out CCR5 in HIV patients, which has occurred <10 times, is believed important for cure. JAK/STAT inhibitors tofacitinib and ruxolitinib inhibit CCR5 expression in HIV ⁺ viremic patients. We investigated the association of JAK/STAT signaling pathway with CCR5/CCR2 expression in human primary CD4 ⁺ T cells and confirmed its importance. Six of nine JAK/STAT inhibitors that reduced CCR5/CCR2 expression were identified. Inhibitor-treated CD4 ⁺ T cells were relatively resistant, specifically to R5-tropic HIV infection. Furthermore, single JAK2, STAT3, STAT5A, and STAT5B knockout and different combinations of JAK/STAT knockout significantly reduced CCR2/CCR5 expression of both RNA and protein levels, indicating that CCR5/CCR2 expression was positively regulated by JAK-STAT pathway in CD4 ⁺ T cells. Serum and glucocorticoid-regulated kinase 1 (SGK1) knockout affected CCR2/CCR5 gene expression, suggesting that SGK1 is involved in CCR2/CCR5 regulation. If cell surface CCR5 levels can be specifically and markedly down-regulated without adverse effects, that may have a major impact on the HIV cure agenda.

The efforts to discover HIV therapeutics have continued since the first human immunodeficiency virus (HIV) infected patient was confirmed in the 1980s. Ten years later, the first HIV drug, zidovudine (AZT), targeting HIV reverse transcriptase, was developed. Meanwhile, scientists were enlightened to discover new drugs that target different HIV genes, like integrase, protease, and host receptors. Combination antiretroviral therapy (cART) is the most feasible medical intervention to suppress the virus in people with HIV (PWH) and control the epidemic. ART treatment has made HIV a chronic infection rather than a fatal disease, but ART does not eliminate latent reservoirs of HIV-1 from the host cells; strict and life-long adherence to ART is required for the therapy to be effective in patients. In this review, we first discussed the scientific history of conventional HIV drug discovery since scientists need to develop more and more drugs to solve drug-resistant issues and release the side effects. Then, we summarized the novel research technologies, like gene editing, applied to HIV treatment and their contributions to eliminating HIV as a complementary therapy.

C–C chemokine receptor type 5 (CCR5) is the R5-tropic human immunodeficiency virus type 1 or HIV co-receptor. Lower CCR5 levels can reduce T cell and macrophage susceptibility and suppress HIV infection. Moreover, CCR5Δ32 homozygous stem cell transplantation is central to HIV cure. Other studies have shown that CCR5 plays a vital role in cancer development and cell migration, and it was considered a potential therapeutic target for several types of malignancy. In addition to HIV and cancer, CCR5 also participates in immune response and plays a role in graft-versus-host disease in bone marrow transplant patients. It is also associated with other diseases, such as Parkinson’s disease and rheumatoid arthritis. Thus, investigating its regulatory mechanisms is critically important for understanding the progress and therapeutics of other illnesses. Transcriptional regulation of genes is a complex process that controls when, where, and how much the RNA transcript is produced. In this minireview, we discuss epigenetic regulatory mechanisms, such as DNA methylation and histone modification, transcription factors, and signal transduction pathways, involved in the regulation of CCR5 transcripts.