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HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women.

Musey L, Hu Y, Eckert L, Christensen M, Karchmer T, McElrath MJ - J. Exp. Med. (1997)

Bottom Line: Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1.Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids.Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The University of Washington School of Medicine, Seattle 98195, USA.

ABSTRACT
Although T lymphocytes are present in the genital mucosa, their function in sexually transmitted diseases is unproven. To determine if cervical T cells mediate HIV-specific cytolysis, mononuclear cells in cytobrush specimens from HIV-1-infected women were stimulated in vitro with antigen. Resultant cell lines lysed autologous targets expressing HIV-1 proteins in 12/19 (63%) subjects, and these responses were detected intermittently on repeated visits. All 8 subjects with blood CD4+ counts > or =500 cells/microl had HIV-1-specific cervical CTL, whereas only 4/11 with counts <500 cells/microl had detectable responses (P = 0.008). Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1. Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids. Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood. These studies provide the first definitive evidence for an MHC-restricted effector function in human cervical lymphocytes.

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Cervical CTL are detected intermittently in HIV-infected  females. The graphs depict responses in six HIV-1-infected adult females  (donor number at upper right) tested at 4–8 weekly intervals. Percent specific lysis directed against autologous B-LCL expressing either Env (vPE-16)  (open bar), Gag (vDK-1) (black bar), or Pol (vRT) (lined bar) is represented  at an E/T ranging from 1:1 to 5:1. Lysis of the control target cells infected  with vaccinia alone was <5% in each experiment and is not shown.
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Figure 2: Cervical CTL are detected intermittently in HIV-infected females. The graphs depict responses in six HIV-1-infected adult females (donor number at upper right) tested at 4–8 weekly intervals. Percent specific lysis directed against autologous B-LCL expressing either Env (vPE-16) (open bar), Gag (vDK-1) (black bar), or Pol (vRT) (lined bar) is represented at an E/T ranging from 1:1 to 5:1. Lysis of the control target cells infected with vaccinia alone was <5% in each experiment and is not shown.

Mentions: Although freshly activated HIV-1-specific CTL can be found in peripheral blood of seropositive individuals, with so few T cells present in the cervical specimens we opted to test only antigen-stimulated cervical T cells for their ability to recognize and lyse autologous target cells expressing HIV-1 gene products. Experiments in 6 donors are represented in Fig. 2 and in the aforementioned 19 donors are summarized in Table 1. HIV-specific cytolytic T cells were detected at E/T of 1:1 to 5:1 in nearly two-thirds (12/19, 63%) of patients with at least one evaluable specimen, and in over one-third (25/64, 39%) of the evaluable specimens (Table 1). In decreasing order of frequency, lytic activity was directed against autologous target cells expressing HIV-1 Env (9/19, 47%), Gag (6/19, 32%), and Pol (4/19, 21%). In five patients, CTL responses were detected against more than one gene product. In addition to HIV-1-specific lytic activity, 17/62 cervical specimens (10 of the 19 donors) contained NK cytolytic responses against the target cell line, K562, with specific lysis ranging from 0–71% at an E/T of 4:1. By contrast we tested similarly 5 HIV-1-uninfected women for the presence of cervical HIV-1 CTL, and lysis of autologous B-LCL infected with rVV (vPE-16, vDK-1, or vRT) by the antigen-stimulated cell lines was <5%. These results indicated that the in vitro stimulation method is unlikely to prime de novo cytolytic responses.


HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women.

Musey L, Hu Y, Eckert L, Christensen M, Karchmer T, McElrath MJ - J. Exp. Med. (1997)

Cervical CTL are detected intermittently in HIV-infected  females. The graphs depict responses in six HIV-1-infected adult females  (donor number at upper right) tested at 4–8 weekly intervals. Percent specific lysis directed against autologous B-LCL expressing either Env (vPE-16)  (open bar), Gag (vDK-1) (black bar), or Pol (vRT) (lined bar) is represented  at an E/T ranging from 1:1 to 5:1. Lysis of the control target cells infected  with vaccinia alone was <5% in each experiment and is not shown.
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Related In: Results  -  Collection

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Figure 2: Cervical CTL are detected intermittently in HIV-infected females. The graphs depict responses in six HIV-1-infected adult females (donor number at upper right) tested at 4–8 weekly intervals. Percent specific lysis directed against autologous B-LCL expressing either Env (vPE-16) (open bar), Gag (vDK-1) (black bar), or Pol (vRT) (lined bar) is represented at an E/T ranging from 1:1 to 5:1. Lysis of the control target cells infected with vaccinia alone was <5% in each experiment and is not shown.
Mentions: Although freshly activated HIV-1-specific CTL can be found in peripheral blood of seropositive individuals, with so few T cells present in the cervical specimens we opted to test only antigen-stimulated cervical T cells for their ability to recognize and lyse autologous target cells expressing HIV-1 gene products. Experiments in 6 donors are represented in Fig. 2 and in the aforementioned 19 donors are summarized in Table 1. HIV-specific cytolytic T cells were detected at E/T of 1:1 to 5:1 in nearly two-thirds (12/19, 63%) of patients with at least one evaluable specimen, and in over one-third (25/64, 39%) of the evaluable specimens (Table 1). In decreasing order of frequency, lytic activity was directed against autologous target cells expressing HIV-1 Env (9/19, 47%), Gag (6/19, 32%), and Pol (4/19, 21%). In five patients, CTL responses were detected against more than one gene product. In addition to HIV-1-specific lytic activity, 17/62 cervical specimens (10 of the 19 donors) contained NK cytolytic responses against the target cell line, K562, with specific lysis ranging from 0–71% at an E/T of 4:1. By contrast we tested similarly 5 HIV-1-uninfected women for the presence of cervical HIV-1 CTL, and lysis of autologous B-LCL infected with rVV (vPE-16, vDK-1, or vRT) by the antigen-stimulated cell lines was <5%. These results indicated that the in vitro stimulation method is unlikely to prime de novo cytolytic responses.

Bottom Line: Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1.Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids.Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The University of Washington School of Medicine, Seattle 98195, USA.

ABSTRACT
Although T lymphocytes are present in the genital mucosa, their function in sexually transmitted diseases is unproven. To determine if cervical T cells mediate HIV-specific cytolysis, mononuclear cells in cytobrush specimens from HIV-1-infected women were stimulated in vitro with antigen. Resultant cell lines lysed autologous targets expressing HIV-1 proteins in 12/19 (63%) subjects, and these responses were detected intermittently on repeated visits. All 8 subjects with blood CD4+ counts > or =500 cells/microl had HIV-1-specific cervical CTL, whereas only 4/11 with counts <500 cells/microl had detectable responses (P = 0.008). Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1. Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids. Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood. These studies provide the first definitive evidence for an MHC-restricted effector function in human cervical lymphocytes.

Show MeSH
Related in: MedlinePlus