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However, the genetic and epigenetic changes influencing the immune response on host infected cells remain unclear. Here, this study analyzes HIV-1-infected CD4+ T cells from peripheral blood mononuclear cells from people living with HIV-1 during early infection (&lt;6 months) using single-cell RNA and ATAC sequencing. It is observed that HIV-1 hinders the antiviral response, particularly by interfering with the interferon signaling pathway. Multimodal analysis identifies KLF2 as a key transcription factor in infected CD4+ T cells. Moreover, cells harboring HIV-1 provirus are predominantly identified as Th17 cells, which exhibit elevated KLF2 activity. This suggests an increased susceptibility to HIV-1 infection and a constrained immune response due to the quiescent characteristics of these cells. The finding provides insights into the immune mechanisms and key regulators of HIV-1 maintenance in CD4+ T cells during the early stages of infection.<\/jats:p>","DOI":"10.7554\/elife.104856","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T08:25:07Z","timestamp":1740039907000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.104856","source":"Crossref","is-referenced-by-count":2,"title":["Multi-omics single-cell analysis reveals key regulators of HIV-1 persistence and aberrant host immune responses in early infection"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8006-8704","authenticated-orcid":true,"given":"Dayeon","family":"Lee","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024kbgz78","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Sciences, Gwangju Institute of Science and Technology","place":["Gwangju, Republic of 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