Background:　Previous　studies　have　examined　the　bulk　transcriptome　of　peripheral　blood　immune　cells　in　acquired　immunodeficiency　syndrome　patients　experiencing　immunological　non-responsiveness.　This　study　aimed　to　investigate　the　characteristics　of　specific　immune　cell　subtypes　in　acquired　immunodeficiency　syndrome　patients　who　exhibit　immunological　non-responsiveness.　Methods:　A　single-cell　transcriptome　sequencing　of　peripheral　blood　mononuclear　cells　obtained　from　both　immunological　responders　(IRs)　(CD4+T-cell　count　＞500)　and　immunological　non-responders　(INRs)　(CD4+T-cell　count　＜300)　was　conducted.　The　transcriptomic　profiles　were　used　to　identify　distinct　cell　subpopulations,　marker　genes,　and　differentially　expressed　genes　aiming　to　uncover　potential　genetic　factors　associated　with　immunological　non-responsiveness.　Results:　Among　the　cellular　subpopulations　analyzed,　the　ratios　of　monocytes,　CD16+monocytes,　and　exhausted　B　cells　demonstrated　the　most　substantial　differences　between　INRs　and　IRs,　with　fold　changes　of　39.79,　11.08,　and　2.71,　respectively.　In　contrast,　the　CD4+T　cell　ratio　was　significantly　decreased　(0.39-fold　change)　in　INRs　compared　with　that　in　IRs.　Similarly,　the　ratios　of　natural　killer　cells　and　terminal　effector　CD8+T　cells　were　also　lower　(0.37-fold　and　0.27-fold,　respectively)　in　the　INRs　group.　In　addition　to　several　well-characterized　immune　cell-specific　markers,　we　identified　a　set　of　181　marker　genes　that　were　enriched　in　biological　pathways　associated　with　human　immunodeficiency　virus　(HIV)　replication.　Notably,　ISG15,　IFITM3,　PLSCR1,　HLA-DQB1,　CCL3L1,　and　DDX5,　which　have　been　demonstrated　to　influence　HIV　replication　through　their　interaction　with　viral　proteins,　emerged　as　significant　monocyte　marker　genes.　Furthermore,　the　differentially　expressed　genes　in　natural　killer　cells　were　also　enriched　in　biological　pathways　associated　with　HIV　replication.　Conclusions:　We　generated　an　atlas　of　immune　cell　transcriptomes　in　HIV-infected　IRs　and　INRs.　Host　genes　associated　with　HIV　replication　were　identified　as　markers　of,　and　were　found　to　be　differentially　expressed　in,　different　types　of　immune　cells.　©　2023　Lippincott　Williams　and　Wilkins.　All　rights　reserved.