HLA-DR + CD38 + CD4 + T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo

Amie L. Meditz, Michelle K. Haas, Joy M. Folkvord, Kelsey Melander, Russ Young, Martin McCarter, Samantha MaWhinney, Thomas B. Campbell, Yolanda Lie, Eoin Coakley, David Levy, Elizabeth Connick

Research output: Contribution to journalArticle

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/105 cells was higher for DR + 38 + cells (1.8 × 106) than for DR - 38 - (0.007 × 106), DR - 38 + (0.064 × 106), and DR + 38 - (0.18 × 106) 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/105 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.

Original languageEnglish (US)
Pages (from-to)10189-10200
Number of pages12
JournalJournal of Virology
Volume85
Issue number19
DOIs
StatePublished - Oct 2011

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HLA-DR Antigens
Human immunodeficiency virus 1
HIV-1
tropics
T-lymphocytes
RNA
T-Lymphocytes
cells
lymph nodes
Lymph Nodes
mononuclear leukocytes
Blood Cells
Viruses
viruses
biological resistance
phytohemagglutinin
Viral RNA
T-Lymphocyte Subsets
Phytohemagglutinins
Green Fluorescent Proteins

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Meditz, A. L., Haas, M. K., Folkvord, J. M., Melander, K., Young, R., McCarter, M., ... Connick, E. (2011). HLA-DR + CD38 + CD4 + T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo. Journal of Virology, 85(19), 10189-10200. https://doi.org/10.1128/JVI.02529-10

HLA-DR + CD38 + CD4 + T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo. / Meditz, Amie L.; Haas, Michelle K.; Folkvord, Joy M.; Melander, Kelsey; Young, Russ; McCarter, Martin; MaWhinney, Samantha; Campbell, Thomas B.; Lie, Yolanda; Coakley, Eoin; Levy, David; Connick, Elizabeth.

In: Journal of Virology, Vol. 85, No. 19, 10.2011, p. 10189-10200.

Research output: Contribution to journalArticle

Meditz, AL, Haas, MK, Folkvord, JM, Melander, K, Young, R, McCarter, M, MaWhinney, S, Campbell, TB, Lie, Y, Coakley, E, Levy, D & Connick, E 2011, 'HLA-DR + CD38 + CD4 + T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo', Journal of Virology, vol. 85, no. 19, pp. 10189-10200. https://doi.org/10.1128/JVI.02529-10
Meditz, Amie L. ; Haas, Michelle K. ; Folkvord, Joy M. ; Melander, Kelsey ; Young, Russ ; McCarter, Martin ; MaWhinney, Samantha ; Campbell, Thomas B. ; Lie, Yolanda ; Coakley, Eoin ; Levy, David ; Connick, Elizabeth. / HLA-DR + CD38 + CD4 + T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo. In: Journal of Virology. 2011 ; Vol. 85, No. 19. pp. 10189-10200.
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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/105 cells was higher for DR + 38 + cells (1.8 × 106) than for DR - 38 - (0.007 × 106), DR - 38 + (0.064 × 106), and DR + 38 - (0.18 × 106) 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/105 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.",
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T1 - HLA-DR + CD38 + CD4 + T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo

AU - Meditz, Amie L.

AU - Haas, Michelle K.

AU - Folkvord, Joy M.

AU - Melander, Kelsey

AU - Young, Russ

AU - McCarter, Martin

AU - MaWhinney, Samantha

AU - Campbell, Thomas B.

AU - Lie, Yolanda

AU - Coakley, Eoin

AU - Levy, David

AU - Connick, Elizabeth

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N2 - 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/105 cells was higher for DR + 38 + cells (1.8 × 106) than for DR - 38 - (0.007 × 106), DR - 38 + (0.064 × 106), and DR + 38 - (0.18 × 106) 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/105 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.

AB - 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/105 cells was higher for DR + 38 + cells (1.8 × 106) than for DR - 38 - (0.007 × 106), DR - 38 + (0.064 × 106), and DR + 38 - (0.18 × 106) 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/105 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.

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