Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Mucosal Immunol ; 9(6): 1528-1536, 2016 11.
Article in English | MEDLINE | ID: mdl-26838048

ABSTRACT

Understanding vaginal and rectal HIV transmission and protective cellular and molecular mechanisms is critical for designing new prevention strategies, including those required for an effective vaccine. The determinants of protection against HIV infection are, however, poorly understood. Increasing evidence suggest that innate immune defenses may help protect mucosal surfaces from HIV transmission in highly exposed, uninfected subjects. More recent studies suggest that systemically administered type 1 interferon protects against simian immunodeficiency virus infection of macaques. Here we hypothesized that topically applied type 1 interferons might stimulate vaginal innate responses that could protect against HIV transmission. We therefore applied a recombinant human type 1 interferon (IFN-ß) to the vagina of rhesus macaques and vaginally challenged them with pathogenic simian/human immunodeficiency virus (SHIV). Vaginal administration of IFN-ß resulted in marked local changes in immune cell phenotype, increasing immune activation and HIV co-receptor expression, yet provided significant protection from SHIV acquisition as interferon response genes were also upregulated. These data suggest that protection from vaginal HIV acquisition may be achieved by activating innate mucosal defenses.


Subject(s)
Antiviral Agents/administration & dosage , Interferon-beta/administration & dosage , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Acquired Immunodeficiency Syndrome/transmission , Simian Immunodeficiency Virus/drug effects , Administration, Intravaginal , Administration, Topical , Animals , Biomarkers , CD4 Antigens/metabolism , Female , Gene Expression Regulation/drug effects , Lymphocyte Activation/immunology , Macaca mulatta , Macrophages/immunology , Macrophages/metabolism , Myeloid Cells/drug effects , Myeloid Cells/immunology , Myeloid Cells/metabolism , Phenotype , Receptors, CCR5/metabolism , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/immunology , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Vagina/immunology , Vagina/virology , Viral Load
2.
J Clin Invest ; 108(5): 757-64, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11544282

ABSTRACT

Failure of CD4(+) T cells to proliferate in response to antigenic stimulation is a characteristic of HIV infection. Analysis of the proliferation defect has been hampered by an inability to identify CD4(+) cells with T cell receptor specificity for antigen. To focus only on cells that had been stimulated through the T cell receptor, CD4(+) T cells were stimulated with an anti-Vbeta3 Ab that activates approximately 3-5% of peripheral blood T cells. This approach revealed proliferation defects in cells from HIV-infected patients that were not appreciated using anti-CD3 Ab stimulation and provided the capacity to examine responses on a single cell basis. After anti-Vbeta3 Ab stimulation, CD4(+)Vbeta3(+) cells from HIV-infected patients demonstrated defects in expression of cell cycle-associated proteins, D-type cyclins, and cyclin A. However, the expression of early activation markers, CD69 and CD25, was not significantly impaired in cells from most patients. Thus, CD4(+) T cell proliferation failure in HIV disease is characterized by dysregulated activation that precludes cell cycle progression. This proliferation defect was most apparent in patients with diminished CD4(+) T cell numbers and higher plasma HIV RNA levels. CD4(+) T cell proliferation failure may be a key determinant of immune impairment in HIV disease.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , HIV Infections/immunology , HIV-1 , Lymphocyte Activation , Antibodies/immunology , Antigens, CD/biosynthesis , Antigens, Differentiation, T-Lymphocyte/biosynthesis , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , Cell Cycle , Cell Division , Cells, Cultured , Cyclin D , Cyclins/biosynthesis , Flow Cytometry , HIV-1/growth & development , Humans , Immunoglobulin Variable Region/immunology , Lectins, C-Type , Receptors, Antigen, T-Cell, alpha-beta/immunology , Receptors, Interleukin-2/biosynthesis , Virus Replication
3.
J Virol ; 75(20): 9983-5, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11559831

ABSTRACT

Subnormal T-cell production of interleukin-2 (IL-2) in human immunodeficiency virus (HIV) disease has been described; however, it is not clear whether failure to synthesize IL-2 represents a selective or global defect in T-cell cytokine production. We evaluated the intracellular production of gamma interferon (IFN-gamma) and IL-2 in CD4(+) cells that were stimulated with staphylococcal enterotoxin B or cytomegalovirus antigen. Strikingly, IFN-gamma and IL-2 are differentially regulated in T cells of HIV-infected patients such that the numbers of CD69(+) cells or IFN-gamma-positive cells that make IL-2 are proportionally decreased in CD4(+) T cells from HIV-infected patients. These findings demonstrate a selective defect in IL-2 production and suggest that enumeration of IFN-gamma-producing cells in response to T-cell receptor stimulation, while providing some estimate of antigen-reactive cell frequency, may not reflect or predict "normal" T-cell function in HIV-infected patients.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , Interferon-gamma/biosynthesis , Interleukin-2/biosynthesis , Antigens, CD/analysis , Antigens, Differentiation, T-Lymphocyte/analysis , Antigens, Viral , Cells, Cultured , Cytomegalovirus , Enterotoxins , Gene Expression Regulation , HIV Infections/blood , Humans , Interferon-gamma/analysis , Interleukin-2/analysis , Lectins, C-Type
4.
Clin Immunol ; 97(3): 241-7, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11112363

ABSTRACT

We have studied the relationship between spontaneous apoptosis and cell cycle perturbations in circulating peripheral blood lymphocytes of HIV-1-infected patients and healthy controls. PBMC obtained from HIV-1-infected patients and healthy controls were incubated in culture medium for 48 h. Cells were separated into CD4(+) and CD8(+) populations using immunomagnetic beads. Apoptosis and cell cycle phases were measured by propidium iodide staining and bromodeoxyuridine (BrdU) incorporation followed by flow cytometric analyses. In experiments using cells obtained from HIV-1-infected patients, spontaneous apoptosis was more frequent in CD4(+) T lymphocytes than in CD8(+) T lymphocytes (17.6% vs 9.5%, P < 0.005). Among healthy controls, spontaneous apoptosis in CD4(+) and CD8(+) T lymphocytes was comparable (4.5% vs 5.1%). Lymphocytes obtained from patients were more frequently in S phase than healthy controls' cells (2.2 +/- 0.9% vs 0.5 +/- 0.2%, P < 0.002) and patients' CD4(+) cells tended to enter S phase more frequently than controls' CD4(+) cells (4.2% +/- 3.5% vs 1.8% +/- 0.5% P < 0.04), whereas the frequency of S phase CD8(+) T cells was not different among patients (2.8% +/- 2.9%) and controls (1.8% +/- 0.5%) (P > 0.4). Kinetic analyses using BrdU and PI staining revealed that S phase cells were more likely to become apoptotic than resting (G(0)-G(1)) cells (28.4% +/- 10.3% vs 11.3% +/- 9.9% in patients, P < 0.04, and 15.3% +/- 2.8% vs 1.8% +/- 0.5% in controls, P < 0.003). Lymphocytes obtained from HIV-1-infected persons are activated in vivo to enter S phase and to undergo spontaneous apoptosis after brief in vitro cultivation. The present studies indicate that most apoptotic cells in this system are CD4(+) and kinetic analyses reveal that S phase cells are more likely to undergo spontaneous apoptosis than G(0)-G(1) cells. Accelerated cell death in HIV-1 disease may contribute to the failure of lymphocyte responsiveness to appropriate T cell receptor stimulation.


Subject(s)
Apoptosis/physiology , CD4-Positive T-Lymphocytes/cytology , HIV Infections/pathology , HIV-1 , S Phase/physiology , Adult , Aged , Female , Humans , Male , Middle Aged
SELECTION OF CITATIONS
SEARCH DETAIL
...