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1.
J Immunol ; 166(5): 3580-8, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11207319

ABSTRACT

Induction of T cell help is critical in HIV-1 control and potentially in prevention by immunization. A practical approach is needed to identify HIV-1-specific helper activities in vivo. We explored the feasibility of measuring delayed-type hypersensitivity (DTH) following intradermal injection of recombinant soluble HIV-1(MN) glycoprotein 120 in HIV-1-infected, vaccinated, and exposed individuals. DTH reactions were elicited within 48 h in 16 of 29 untreated, infected patients and in 24 of 30 uninfected vaccinees. Concomitant envelope-specific lymphoproliferation in vitro was undetectable among 9 infected patients tested with positive envelope-specific DTH. By contrast, no 48-h DTH reactions occurred among 25 high risk and 32 low risk, uninfected volunteers. However, 7--12 days after injection, 10 (40%) high risk and 11 (34%) low risk individuals developed induration resembling DTH, and the cellular infiltrates contained monocytes and T cells. Five of 18 examined also developed anti-gp120 Abs. The very delayed time course and lack of correlation with previous Ag exposure clearly distinguish this reaction from DTH. Thus, HIV-1 skin testing can identify persons with HIV-specific recall responses resulting from infection, in the absence of in vitro lymphoproliferation, and from vaccination. In contrast, very late reactivities may signify chemotactic properties of the envelope protein and/or herald the induction of primary HIV-specific Th1-type immunity.


Subject(s)
HIV Envelope Protein gp120/immunology , HIV-1/immunology , Hypersensitivity, Delayed/immunology , Immunologic Memory , Recombinant Proteins/immunology , AIDS Vaccines/administration & dosage , AIDS Vaccines/immunology , Animals , Antigens, Fungal/immunology , CHO Cells , Candida/immunology , Cell Movement/immunology , Cells, Cultured , Cricetinae , HIV Antibodies/biosynthesis , HIV Antibodies/blood , HIV Envelope Protein gp120/administration & dosage , HIV Envelope Protein gp120/genetics , HIV Infections/immunology , Humans , Hypersensitivity, Delayed/microbiology , Hypersensitivity, Delayed/pathology , Hypersensitivity, Delayed/virology , Immunization Schedule , Immunologic Memory/immunology , Inflammation/immunology , Inflammation/microbiology , Inflammation/pathology , Injections, Intradermal , Lymphocyte Activation/immunology , Pilot Projects , Protein Sorting Signals/genetics , Recombinant Proteins/administration & dosage , Simplexvirus/genetics , Simplexvirus/immunology , Skin Tests
2.
J Virol ; 73(7): 5833-42, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10364335

ABSTRACT

Worldwide, human immunodeficiency virus (HIV) is transmitted predominantly by heterosexual contact. Here, we investigate for the first time, by examining mononuclear cells obtained from cervicovaginal tissue, the mechanisms whereby HIV type 1 (HIV-1) directly targets cells from the human genital tract. In contrast to earlier findings in mucosal models such as human skin, we demonstrate that the majority of T cells and macrophages but none or few dendritic cells (DC) express the HIV-1 coreceptor CCR5 in normal human cervicovaginal mucosa, whereas all three cell types express the coreceptor CXCR4. To understand the role of coreceptor expression on infectivity, mucosal mononuclear cells were infected with various HIV-1 isolates, using either CCR5 or CXCR4. Unstimulated T cells become rapidly, albeit nonproductively, infected with R5- and X4-tropic variants. However, DC and T cells form stable conjugates which permit productive infection by viruses of both coreceptor specificities. These results indicate that HIV-1 can exploit T-cell-DC synergism in the human genital tract to overcome potential coreceptor restrictions on DC and postentry blocks of viral replication in unactivated T cells. Thus, mononuclear cells infiltrating the genital mucosa are permissive for transmission of both R5- and X4-tropic HIV-1 variants, and selection of virus variants does not occur by differential expression of HIV-1 coreceptors on genital mononuclear cells.


Subject(s)
Dendritic Cells/metabolism , Genitalia, Female/virology , HIV-1/physiology , Receptors, CCR5/biosynthesis , Receptors, CXCR4/biosynthesis , T-Lymphocytes/metabolism , Cervix Uteri/cytology , Cervix Uteri/virology , Dendritic Cells/virology , Female , Genitalia, Female/cytology , HIV-1/metabolism , Humans , Leukocytes, Mononuclear/cytology , Mucous Membrane/cytology , Phenotype , T-Lymphocytes/virology , Vagina/cytology , Vagina/virology , Virus Replication
3.
J Infect Dis ; 179(3): 548-57, 1999 Mar.
Article in English | MEDLINE | ID: mdl-9952360

ABSTRACT

It has been hypothesized that protection against human immunodeficiency virus (HIV)-1 infection may result from either acquired host immunity, inheritance of a dysfunctional CCR5 HIV-1 coreceptor, or a low or attenuated virus inoculum. Thirty-seven HIV-1-uninfected persons engaging in repeated high-risk sexual activity with an HIV-1-infected partner were prospectively studied to determine the contribution of these factors in protecting against HIV-1 transmission. More than one-third (13/36) demonstrated HIV-1-specific cytotoxicity, and this activity significantly correlated with the wild type CCR5 genotype (P=.03). Only 1 subject (3%) demonstrated the homozygous CCR5 32-bp deletion (Delta32/Delta32). Median plasma HIV-1 RNA levels from 18 HIV-1-infected sex partners were not statistically different from those of matched infected control patients. These results indicate that inheritance of the Delta32 CCR5 mutation does not account for the majority of persistently HIV-1-resistant cases, and the presence of cellular immunity in these persons suggests either undetected infection or protective immunity.


Subject(s)
Acquired Immunodeficiency Syndrome/immunology , HIV Seronegativity/genetics , HIV Seronegativity/immunology , HIV-1/immunology , Receptors, CCR5/genetics , T-Lymphocytes/immunology , Adult , Female , HIV Antigens/immunology , Heterosexuality , Homosexuality, Male , Humans , Immunity, Cellular , Immunity, Innate , Lymphocyte Activation , Male , Middle Aged , RNA, Viral/blood , Receptors, CCR5/physiology , Risk-Taking , Sequence Deletion , T-Lymphocytes, Cytotoxic/immunology
4.
J Immunol ; 158(2): 807-15, 1997 Jan 15.
Article in English | MEDLINE | ID: mdl-8992998

ABSTRACT

Prior immunity to HIV-1 elicited by vaccination may modify subsequent responses upon exposure to infectious HIV-1. An HIV-1-uninfected person entered in a vaccine trial that included immunizations to HIV-1(LAI) envelope with a recombinant vaccinia vector and recombinant protein developed envelope-specific CD4+ T cell responses, including proliferative and cytolytic responses, but was not protected from a high risk HIV-1 exposure. CD4+ T cell clones derived from blood at the peak of vaccine-induced immunity recognized and lysed autologous target cells expressing four distinct regions within the HIV-1(LAI) envelope region; three of these CTL clones also recognized targets expressing envelope from a similar viral subtype, HIV-1(MN). The epitope specificity of CD4+ clone 9G8, recognizing both HIV-1(LAI) and HIV-1(MN) envelope, was within the 571-590 amino acid envelope region. Sequence analysis of the first infectious autologous strain revealed two amino acid mutations within this region. The 9G8 CTL clone induced by immunization failed to recognize targets expressing the corresponding CTL epitope from the infecting virus. Moreover, a peptide based on the epitope sequence of the infecting isolate antagonized the vaccine-induced CTL clone such that the CTL clone was no longer able to recognize the vaccine strain or HIV-1(MN) epitope. These findings suggest a potentially novel mechanism associated with vaccine failure whereby the infecting virus may not only escape from CTL activity, but also alter the ability of CTL to recognize other variants in an individual.


Subject(s)
AIDS Vaccines/antagonists & inhibitors , CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV-1/immunology , HIV-1/pathogenicity , CD4-Positive T-Lymphocytes/virology , Clone Cells , Epitope Mapping/methods , HIV Envelope Protein gp120/immunology , HIV Envelope Protein gp41/immunology , HIV-1/classification , Humans , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology
5.
J Infect Dis ; 173(3): 559-64, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8627017

ABSTRACT

In vitro interactions between interleukin (IL)-12, interferon (IFN)-gamma, and human immunodeficiency virus (HIV) type 1 infection in human macrophages were examined. Macrophages were infected with HIV-1 and cocultured with autologous monocyte-depleted peripheral blood mononuclear cells (PBMC). The addition of autologous PBMC to HIV-1-infected macrophages resulted in an expansive increase in reverse transcriptase (RT) activity; however, when both autologous PBMC and IL-12 were added, RT activity decreased (75%-90%) and high levels of IFN-gamma (9-16 ng/mL) were detected. The addition of anti-IFN-gamma antibodies blocked the IL-12-induced decrease in RT activity. Surprisingly, exogenous IL-12 added to HIV-infected macrophage cultures without autologous lymphocytes resulted in a 50%-60% reduction in RT activity and no detectable increase in IFN-gamma. The addition of anti-IFN-gamma did not inhibit this IL-12-mediated effect. These results suggest that IL-12 is capable of indirectly down-regulating HIV proliferation in macrophage cultures reconstituted with autologous PBMC and of directly suppressing HIV replication in purified macrophage cultures.


Subject(s)
HIV-1/drug effects , HIV-1/physiology , Interleukin-12/pharmacology , Virus Replication/drug effects , Cell Communication , Cells, Cultured , Down-Regulation , HIV Infections/immunology , HIV Infections/virology , HIV Reverse Transcriptase , HIV-1/immunology , Humans , In Vitro Techniques , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/metabolism , Leukocytes, Mononuclear/immunology , Macrophages/drug effects , Macrophages/immunology , Macrophages/virology , RNA-Directed DNA Polymerase/metabolism , Virus Replication/immunology , Virus Replication/physiology
6.
J Immunol ; 153(12): 5782-9, 1994 Dec 15.
Article in English | MEDLINE | ID: mdl-7527449

ABSTRACT

IL-10 has been shown to be capable of down-regulating several aspects of macrophage function. This study was undertaken to define the association between IL-10 and HIV-1 infection in human macrophages. Infection of macrophages with a monocytotropic strain of the human immunodeficiency virus, HIV-BaL, resulted in expression of IL-10 mRNA within 3 to 12 h after infection, as determined by the reverse transcriptase PCR. Biologically active IL-10 was detected in supernatants from HIV-1-infected macrophages as early as 12 h post-infection. The addition of human rIL-10 to HIV-1-infected macrophage cultures resulted in a significant decrease in the viral replication. In addition, exogenous IL-10 blocked the ability of TNF-alpha to elevate viral replication. To determine whether IL-10 was associated with in vivo infection, lymph nodes from AIDS patients were examined for the presence of IL-10 mRNA by using PCR. IL-10 mRNA was evident in all lymph node tissue examined, but was absent in normal lymph node biopsies. These in vitro and in vivo findings demonstrate a strong and heterogeneous association between HIV-1 infection and IL-10.


Subject(s)
HIV Infections/immunology , HIV-1/immunology , Interleukin-10/physiology , Macrophages/virology , Virus Replication/immunology , Acquired Immunodeficiency Syndrome/immunology , Adult , HIV-1/physiology , Humans , Interleukin-10/biosynthesis , Middle Aged , RNA, Messenger/biosynthesis , RNA-Directed DNA Polymerase/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors
7.
Am J Trop Med Hyg ; 47(3): 383-9, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1524152

ABSTRACT

The influence of various dietary zinc levels on the fibrotic aspects of granuloma formation and on the humoral response to schistosome egg antigens was investigated in C57Bl/6 mice by feeding groups of animals zinc-deficient diets. At six weeks of age, control and zinc-deficient mice were exposed individually to 50-60 cercariae of the Brazilian LE strain of Schistosoma mansoni. The animals were maintained on their respective diets for eight weeks postinfection, then all animals were killed and analyzed for body weight, spleen weight, collagen content of the liver, in vivo granulomatous histopathology, and antibody responses to soluble egg antigens. Zinc-deficient mice experienced stunted growth and reduced weight gain. Granulomatous hypersensitivity to schistosome eggs in the liver was measured in liver histopathologic sections using morphometric analysis and was found to be depressed in infected mice fed the moderately and the severely zinc-deficient diets. The low level of zinc in the diet also affected the humoral immune response of the host to schistosome egg antigens.


Subject(s)
Antibodies, Helminth/biosynthesis , Granuloma/etiology , Helminth Proteins , Liver Cirrhosis/etiology , Schistosomiasis mansoni/complications , Zinc/deficiency , Animals , Antigens, Helminth/immunology , Collagen/analysis , Hydroxyproline/analysis , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Liver/chemistry , Mice , Mice, Inbred C57BL , Schistosoma mansoni/immunology , Schistosomiasis mansoni/immunology , Zinc/blood
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