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CD1d-restricted human natural killer T cells are highly susceptible to human immunodeficiency virus 1 infection.

Motsinger A, Haas DW, Stanic AK, Van Kaer L, Joyce S, Unutmaz D - J. Exp. Med. (2002)

Bottom Line: We demonstrate that both resting and activated human Valpha24(+) T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells.In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals.Taken together, our findings indicate that CD4(+) NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA.

ABSTRACT
Human natural killer (NK) T cells are unique T lymphocytes that express an invariant T cell receptor (TCR) Valpha24-Vbeta11 and have been implicated to play a role in various diseases. A subset of NKT cells express CD4 and hence are potential targets for human immunodeficiency virus (HIV)-1 infection. We demonstrate that both resting and activated human Valpha24(+) T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells. Remarkably NKT cells activated with alpha-galactosylceramide (alpha-GalCer)-pulsed dendritic cells were profoundly more susceptible to infection with R5-tropic, but not X4-tropic, strains of HIV-1, compared with conventional CD4(+) T cells. Furthermore, resting CD4(+) NKT cells were also more susceptible to infection. After initial infection, HIV-1 rapidly replicated and depleted the CD4(+) subset of NKT cells. In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals. Although the mechanisms of this decline are not clear, low numbers or absence of NKT cells may affect the course of HIV-1 infection. Taken together, our findings indicate that CD4(+) NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.

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Analysis of NKT cells in HIV-1 infected and healthy donors. PBMCs from healthy and HIV-infected donors were isolated and stained with anti-Vβ11-FITC, CD3-PercP.Cy5.5, CD4-PE, and CD1d-tetramer-APC. Alternatively, cells were stained with anti-Vβ11-PE, Vα24-FITC, CD3-PercP.Cy5.5, and CD4-APC. Electronic gates were set on CD3+Vβ11+Vα24+ or CD3+Vβ11+CD1d-tetramer+ cells to identify the NKT cell subset. Between 3 and 5 million events were collected for each sample. Analysis was performed on CD3-gated T cells. The sensitivity for detecting NKT cells was at least 0.003%. (A) Portion of NKT cells among CD3+ T cells of 48 HIV-infected (left) and 22 HIV-negative subjects (right). (B) Relationships between NKT cell percentage, plasma HIV-1 RNA concentration, and CD4+ T cell counts in HIV-1–infected individuals. CD4+ T cells were <200 cells/mm3 (white circles), 200–500 cells/mm3 (black circles), or >500 cells/mm3 (white squares). (C) Relationship between CD4+ NKT cell percentage and plasma HIV-1 RNA concentration in HIV-1–infected subjects. The regression line is shown.
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fig7: Analysis of NKT cells in HIV-1 infected and healthy donors. PBMCs from healthy and HIV-infected donors were isolated and stained with anti-Vβ11-FITC, CD3-PercP.Cy5.5, CD4-PE, and CD1d-tetramer-APC. Alternatively, cells were stained with anti-Vβ11-PE, Vα24-FITC, CD3-PercP.Cy5.5, and CD4-APC. Electronic gates were set on CD3+Vβ11+Vα24+ or CD3+Vβ11+CD1d-tetramer+ cells to identify the NKT cell subset. Between 3 and 5 million events were collected for each sample. Analysis was performed on CD3-gated T cells. The sensitivity for detecting NKT cells was at least 0.003%. (A) Portion of NKT cells among CD3+ T cells of 48 HIV-infected (left) and 22 HIV-negative subjects (right). (B) Relationships between NKT cell percentage, plasma HIV-1 RNA concentration, and CD4+ T cell counts in HIV-1–infected individuals. CD4+ T cells were <200 cells/mm3 (white circles), 200–500 cells/mm3 (black circles), or >500 cells/mm3 (white squares). (C) Relationship between CD4+ NKT cell percentage and plasma HIV-1 RNA concentration in HIV-1–infected subjects. The regression line is shown.

Mentions: Because NKT cell lines are efficient hosts for HIV-1 in vitro and because resting NKT cells express similar levels of CCR5, we concluded that HIV-1 can infect NKT cells in vivo. To gain insight into the role of NKT cells during natural HIV-1 infection, we quantified NKT cell numbers both in HIV-1 infected and healthy individuals. PBMCs were isolated from infected or healthy donors and cells were subjected to four-color FACS® analysis using anti-Vβ11, CD3, and CD4 mAbs in conjunction with either CD1d-tetramer or Vα24-specific antibodies. CD4+ or CD4− NKT cells were identified in 48 HIV-1 infected adults. Ages ranged from 34 to 59 y, 33% were African-American, 25% were female, 83% were receiving antiretroviral therapy, and the mean CD4+ T cell counts was 402 cells/mm3 (range 8 to 1,080 cells/mm3). 10 (21%) had serologic evidence of either hepatitis B or C virus infection. None had active cytomegalovirus disease. As controls 22 uninfected healthy individuals were studied. The HIV-infected patients were slightly older than uninfected patients (mean age 40 versus 34 y; P = 0.011). The groups did not differ with regard to gender (P > 0.05). Approximately 44% of HIV-infected donors had undetectable levels of NKT cells (our detection limit was 0.003%), whereas all of the healthy donors had at least 0.01% NKT cells within their PBMCs (P < 0.001) (Fig. 7 A). In fact, 81% of healthy donors contained >0.01% NKT cells and 19% of these donors had >0.1% NKT cells (Fig. 7 A). Only ∼30% of HIV-1–infected individuals had >0.01% NKT cells and none had >0.1% (Fig. 7 A).


CD1d-restricted human natural killer T cells are highly susceptible to human immunodeficiency virus 1 infection.

Motsinger A, Haas DW, Stanic AK, Van Kaer L, Joyce S, Unutmaz D - J. Exp. Med. (2002)

Analysis of NKT cells in HIV-1 infected and healthy donors. PBMCs from healthy and HIV-infected donors were isolated and stained with anti-Vβ11-FITC, CD3-PercP.Cy5.5, CD4-PE, and CD1d-tetramer-APC. Alternatively, cells were stained with anti-Vβ11-PE, Vα24-FITC, CD3-PercP.Cy5.5, and CD4-APC. Electronic gates were set on CD3+Vβ11+Vα24+ or CD3+Vβ11+CD1d-tetramer+ cells to identify the NKT cell subset. Between 3 and 5 million events were collected for each sample. Analysis was performed on CD3-gated T cells. The sensitivity for detecting NKT cells was at least 0.003%. (A) Portion of NKT cells among CD3+ T cells of 48 HIV-infected (left) and 22 HIV-negative subjects (right). (B) Relationships between NKT cell percentage, plasma HIV-1 RNA concentration, and CD4+ T cell counts in HIV-1–infected individuals. CD4+ T cells were <200 cells/mm3 (white circles), 200–500 cells/mm3 (black circles), or >500 cells/mm3 (white squares). (C) Relationship between CD4+ NKT cell percentage and plasma HIV-1 RNA concentration in HIV-1–infected subjects. The regression line is shown.
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fig7: Analysis of NKT cells in HIV-1 infected and healthy donors. PBMCs from healthy and HIV-infected donors were isolated and stained with anti-Vβ11-FITC, CD3-PercP.Cy5.5, CD4-PE, and CD1d-tetramer-APC. Alternatively, cells were stained with anti-Vβ11-PE, Vα24-FITC, CD3-PercP.Cy5.5, and CD4-APC. Electronic gates were set on CD3+Vβ11+Vα24+ or CD3+Vβ11+CD1d-tetramer+ cells to identify the NKT cell subset. Between 3 and 5 million events were collected for each sample. Analysis was performed on CD3-gated T cells. The sensitivity for detecting NKT cells was at least 0.003%. (A) Portion of NKT cells among CD3+ T cells of 48 HIV-infected (left) and 22 HIV-negative subjects (right). (B) Relationships between NKT cell percentage, plasma HIV-1 RNA concentration, and CD4+ T cell counts in HIV-1–infected individuals. CD4+ T cells were <200 cells/mm3 (white circles), 200–500 cells/mm3 (black circles), or >500 cells/mm3 (white squares). (C) Relationship between CD4+ NKT cell percentage and plasma HIV-1 RNA concentration in HIV-1–infected subjects. The regression line is shown.
Mentions: Because NKT cell lines are efficient hosts for HIV-1 in vitro and because resting NKT cells express similar levels of CCR5, we concluded that HIV-1 can infect NKT cells in vivo. To gain insight into the role of NKT cells during natural HIV-1 infection, we quantified NKT cell numbers both in HIV-1 infected and healthy individuals. PBMCs were isolated from infected or healthy donors and cells were subjected to four-color FACS® analysis using anti-Vβ11, CD3, and CD4 mAbs in conjunction with either CD1d-tetramer or Vα24-specific antibodies. CD4+ or CD4− NKT cells were identified in 48 HIV-1 infected adults. Ages ranged from 34 to 59 y, 33% were African-American, 25% were female, 83% were receiving antiretroviral therapy, and the mean CD4+ T cell counts was 402 cells/mm3 (range 8 to 1,080 cells/mm3). 10 (21%) had serologic evidence of either hepatitis B or C virus infection. None had active cytomegalovirus disease. As controls 22 uninfected healthy individuals were studied. The HIV-infected patients were slightly older than uninfected patients (mean age 40 versus 34 y; P = 0.011). The groups did not differ with regard to gender (P > 0.05). Approximately 44% of HIV-infected donors had undetectable levels of NKT cells (our detection limit was 0.003%), whereas all of the healthy donors had at least 0.01% NKT cells within their PBMCs (P < 0.001) (Fig. 7 A). In fact, 81% of healthy donors contained >0.01% NKT cells and 19% of these donors had >0.1% NKT cells (Fig. 7 A). Only ∼30% of HIV-1–infected individuals had >0.01% NKT cells and none had >0.1% (Fig. 7 A).

Bottom Line: We demonstrate that both resting and activated human Valpha24(+) T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells.In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals.Taken together, our findings indicate that CD4(+) NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232, USA.

ABSTRACT
Human natural killer (NK) T cells are unique T lymphocytes that express an invariant T cell receptor (TCR) Valpha24-Vbeta11 and have been implicated to play a role in various diseases. A subset of NKT cells express CD4 and hence are potential targets for human immunodeficiency virus (HIV)-1 infection. We demonstrate that both resting and activated human Valpha24(+) T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells. Remarkably NKT cells activated with alpha-galactosylceramide (alpha-GalCer)-pulsed dendritic cells were profoundly more susceptible to infection with R5-tropic, but not X4-tropic, strains of HIV-1, compared with conventional CD4(+) T cells. Furthermore, resting CD4(+) NKT cells were also more susceptible to infection. After initial infection, HIV-1 rapidly replicated and depleted the CD4(+) subset of NKT cells. In addition, peripheral blood NKT cells were markedly and selectively depleted in HIV-1 infected individuals. Although the mechanisms of this decline are not clear, low numbers or absence of NKT cells may affect the course of HIV-1 infection. Taken together, our findings indicate that CD4(+) NKT cells are directly targeted by HIV-1 and may have a potential role during viral transmission and spread in vivo.

Show MeSH
Related in: MedlinePlus