title: HLA-DR+ CD38+ CD4+ T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo.
abstract: Percentages of activated T cells correlate with HIV-1 disease progression, but the underlying mechanisms are not fully understood. We hypothesized that HLA-DR(+) CD38(+) (DR(+) 38(+)) CD4(+) T cells produce the majority of HIV-1 due to elevated expression of CCR5 and CXCR4. In phytohemagglutinin (PHA)-stimulated CD8-depleted peripheral blood mononuclear cells (PBMC) infected with HIV-1 green fluorescent protein (GFP) reporter viruses, DR(-) 38(+) T cells constituted the majority of CCR5 (R5)-tropic (median, 62%) and CXCR4 (X4)-tropic HIV-1-producing cells (median, 61%), although cell surface CCR5 and CXCR4 were not elevated in this subset of cells. In lymph nodes from untreated individuals infected with R5-tropic HIV-1, percentages of CCR5(+) cells were elevated in DR(+) 38(+) CD4(+) T cells (median, 36.4%) compared to other CD4(+) T-cell subsets (median values of 5.7% for DR(-) 38(-) cells, 19.4% for DR(+) 38(-) cells, and 7.6% for DR(-) 38(+) cells; n = 18; P < 0.001). In sorted CD8(-) lymph node T cells, median HIV-1 RNA copies/10(5) cells was higher for DR(+) 38(+) cells (1.8 × 10(6)) than for DR(-) 38(-) (0.007 × 10(6)), DR(-) 38(+) (0.064 × 10(6)), and DR(+) 38(-) (0.18 × 10(6)) subsets (n = 8; P < 0.001 for all). After adjusting for percentages of subsets, a median of 87% of viral RNA was harbored by DR(+) 38(+) cells. Percentages of CCR5(+) CD4(+) T cells and concentrations of CCR5 molecules among subsets predicted HIV-1 RNA levels among CD8(-) DR/38 subsets (P < 0.001 for both). Median HIV-1 DNA copies/10(5) cells was higher in DR(+) 38(+) cells (5,360) than in the DR(-) 38(-) (906), DR(-) 38(+) (814), and DR(+) 38(-) (1,984) subsets (n = 7; P ≤ 0.031). Thus, DR(+) 38(+) CD4(+) T cells in lymph nodes have elevated CCR5 expression, are highly susceptible to infection with R5-tropic virus, and produce the majority of R5-tropic HIV-1. PBMC assays failed to recapitulate in vivo findings, suggesting limited utility. Strategies to reduce numbers of DR(+) 38(+) CD4(+) T cells may substantially inhibit HIV-1 replication.
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Amie L
authors.initials: AL
authors.lastname: Meditz
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Haas
authors.forename: Joy M
authors.initials: JM
authors.lastname: Folkvord
authors.forename: Kelsey
authors.initials: K
authors.lastname: Melander
authors.forename: Russ
authors.initials: R
authors.lastname: Young
authors.forename: Martin
authors.initials: M
authors.lastname: McCarter
authors.forename: Samantha
authors.initials: S
authors.lastname: Mawhinney
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Campbell
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Lie
authors.forename: Eoin
authors.initials: E
authors.lastname: Coakley
authors.forename: David N
authors.initials: DN
authors.lastname: Levy
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Connick
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis*; D000328:Adult; D015704:CD4 Antigens / Q000032:analysis*; D005260:Female; D015497:HIV-1 / Q000254:growth & development*; D006684:HLA-DR Antigens / Q000032:analysis*; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D008875:Middle Aged; D012367:RNA, Viral / Q000096:biosynthesis*; D019713:Receptors, CCR5 / Q000096:biosynthesis*; D015728:Receptors, HIV / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000821:virology*
chemical_list: D015704:CD4 Antigens; D006684:HLA-DR Antigens; D008562:Membrane Glycoproteins; D012367:RNA, Viral; D019713:Receptors, CCR5; D015728:Receptors, HIV; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1