HLA and natural history of HIV infection.
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CD4 Lymphocyte Count↗
Biomedical subjects
M Malkovsky
Publications and source records attributed to M Malkovsky.
Mechanisms of simian gamma delta T cell cytotoxicity against tumor and immunodeficiency virus-infected cells.
The mechanisms of cytotoxic killing of various tumor cell lines and immunodeficiency virus-infected T cell lines by simian gamma delta T cells were examined. The lysis of the majority of the target cell lines by gamma delta effectors was calcium-dependent, indicating that cytotoxicity is mediated by the perforin/granzyme pathway rather than the Fas-FasL pathway, with the exception of Jurkat cells. The gamma delta T cells were able to suppress SIV replication as measured by the p27 ELISA and the suppression was contact-dependent. We further determined that the target cells were induced to undergo apoptosis by the gamma delta T cell effectors. These results contribute to our understanding of the function of simian gamma delta T cells and their similarities to human gamma delta T cells, and extend our knowledge on the cytotoxic mechanisms employed by gamma delta T cells in general.
Animals↗
Gamma delta T lymphocyte responses to HIV.
Natural immunity may be involved in controlling viral spread in hosts infected with HIV. A panel of gamma delta T cell receptor-positive lymphocyte clones was isolated from the peripheral blood of healthy HIV- donors and tested for anti-HIV cytotoxic responses. Twelve of 30 (40%) V gamma 9+/V delta 2+ T cell clones, but none of seven V delta 1+ T cell clones, displayed lytic activity against HIV-infected cells. The V gamma 9+/V delta 2+ clones cytotoxic for HIV-infected cells also lysed Daudi cells. However, not all V gamma 9+/V delta 2+ clones which lysed Daudi targets had the capacity to lyse HIV-infected cells. Some of the gamma delta T cell clones were also investigated for potential proliferative responses to HIV-infected cells. One V gamma 9+/V delta 2+ T cell clone (ME8-7) and one V delta 1+ T cell clone (ME18-2) demonstrated proliferative responses towards HIV-infected cells. Another V gamma 9+/V delta 2+ clone (VM39) proliferated in response to cell-free HIV. Taken together, these results provide direct evidence of anti-HIV gamma delta T cell responses in healthy, HIV- persons.
Clone Cells↗
Inhibition of human immunodeficiency virus replication by nonimmunosuppressive analogs of cyclosporin A.
Analogs of the immunosuppressive cyclic undecapeptide cyclosporin A (CsA) with substitutions in positions 1, 4, 6, and/or 11 were rationally designed to possess substantially diminished or no immunosuppressive activity. When these compounds were assayed for their capacity to interfere with the replication of human immunodeficiency virus, some displayed a potent antiviral activity in newly infected cells. However, only CsA could interfere with virus replication in persistently infected cells. One CsA analog with antiviral activity costimulated the phytohemagglutinin-induced production of interleukin 2 by human lymphocytes. Human immunodeficiency virus particles from drug-exposed cells showed lower infectivity than virions from untreated cells. Thus, these nonimmunosuppressive analogs of CsA constitute a promising class of lead compounds to develop drugs for effective treatment of the acquired immunodeficiency syndrome.
Antiviral Agents↗
Gamma/delta T lymphocytes in viral infections.
T lymphocyte progenitors differentiate into two distinct T cell lineages. Although the alpha beta and gamma delta T cell lineages resemble each other phenotypically and functionally, there are some striking differences. Some gamma delta T cells recognize, similarly to alpha beta T cells, peptides presented by major histocompatibility complex (MHC) proteins or MHC-like molecules. However, there are gamma delta T cells that recognize MHC molecules in a fundamentally different manner in comparison with alpha beta T cells. Also in contrast recognizing nonpeptide antigens. Most responses of gamma delta T cells appear to be directed against microbial pathogenic agents including bacteria, parasites, and viruses. In particular, the potent cytotoxic responses of gamma delta T cells against cells infected with, for example, herpesviruses or lentiviruses may be essential for the overall antiviral defense of vertebrates. The analysis of antiviral immunosurveillance by gamma delta T cells is crucial for understanding the unique biological role of this lymphocyte subset.
Animals↗
Persistent non-B cell lymphocytosis in HIV-infected individuals.
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Adult↗
Gamma delta T cells in rhesus monkeys and their response to simian immunodeficiency virus (SIV) infection.
Recent reports of the increase in peripheral blood gamma delta T cells in HIV+ patients prompted us to examine the gamma delta T cell system in rhesus monkeys (Macaca mulatta) and the responses of these cells to SIV infection. Our results reveal differences in the gamma delta T cell subset composition and their expression of CD8 in the peripheral blood of monkeys and humans. The outgrowth of simian gamma delta T cells in response to Daudi cells is similar to that in humans, but the exposure to IL-2 stimulates preferentially the simian V delta 1 subset rather than the V gamma 9/V delta 2 subset as found in humans. Upon SIV infection of the monkeys, we observed a transient increase of the percentage of total gamma delta T cell and the V gamma 9 subset. gamma delta T cells from infected animals also express more activation markers such as CD69, CD44 and the memory marker CD45RO. However, they respond to a lesser degree to Daudi or IL-2 stimulation in the outgrowth experiments compared with uninfected animals, although the subset composition of total gamma delta T cells is similar in infected and uninfected animals. The results clearly indicate that gamma delta T cells in rhesus monkeys are influenced by SIV infection. The detailed analysis of the gamma delta T cell response to SIV infection can serve as a model for understanding human gamma delta T cell responses to HIV infections.
Animals↗
Stress responses to viral infection.
Virus infection leads to an increased production of stress proteins in the host. These appear to have two important roles: (1) facilitation of virus replication and assembly and (2) recognition by the immune system when expressed on virus-infected cells and consequent elimination of the infected cells.
Heat-Shock Proteins↗
SIV transmission across the mucosal barrier.
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Age Factors↗
CD4-binding compounds: an assay to detect new classes of immunopharmacological agents.
The interaction of antibodies with protein antigens is accepted as a paradigm of protein-protein interactions. In searching for a new generation of immunomodulatory compounds based on the interaction of the T-cell surface glycoprotein CD4 with MHC class II antigens, a model assay has been developed in which MHC molecules have been substituted by a monoclonal antibody (anti-Leu3a) to the CD4 amino-terminal domain-specific epitope, Leu3a. This assay can detect diverse classes of molecules including proteins such as HIV envelope glycoprotein gp120 and low molecular weight compounds such as aurin tricarboxylic acid, dextran sulphate and Evans blue. The interaction of these molecules with CD4 in the assay appears to be identical to their interaction with native CD4 on intact cells. Other protein-antibody pairs could be substituted for CD4-anti-Leu3a enabling this assay format to be used for the detection of proteins or small organic compounds which interfere with a wide range of therapeutically-relevant macromolecular interactions.
Adjuvants, Immunologic↗
New hydroxyethylamine HIV protease inhibitors that suppress viral replication.
The synthesis of analogues of AcSerLeuAsn[Phe-HEA-Pro]IleValOMe (1, JG-365; where HEA stands for the hydroxyethylamine unit 2), a tight-binding inhibitor of HIVP, are reported. Systematic modification of the P3 and P3' regions of the inhibitors has led to smaller HIVP inhibitors that inhibit viral replication in HIV-infected and SIV-infected cell cultures. Six aliphatic and/or aromatic derivatives were prepared by replacing residues in the P3 regions of BocLeuAsn[Phe-HEA-Pro]IleValOMe. Aromatic side chains at P3 gave better inhibitors than aliphatic side chains. The better inhibitors in this series contained a beta-naphthylalanine or a biphenyl unit at P3. A second series of HIVP inhibitors were obtained by converting the P3 group into acyl groups. CbzAsn[Phe-HEA-Pro]IlePheOMe and Qua-Asn-[Phe-HEA-Pro]-Ile-Phe-OMe (where Qua = quinolin-2-ylcarbonyl) are potent HIVP inhibitors with Ki values equal to 1.0 and 0.1 nM, respectively. The inhibition constants were determined by using the continuous fluorometric assay developed by Toth and Marshall. The activities of the protease inhibitors for inhibition of SIV replication were determined in vitro using CEM x 174 cells. Inhibition of HIV infection was determined essentially as reported by Pauwels and co-workers. The anti-HIV assay was carried out in culture using CEM cells (a CD4+ lymphocyte line) infected with virus strain HTLV-IIIb with a multiplicity of infection of 0.1. Several analogues inhibited the cytopathic effect at concentrations of 0.1-0.8 microgram/mL. These results establish that good inhibitors of HIV protease that inhibit viral replication in infected lymphocytes in in vitro cell assays can be obtained from JG-365 when the AcSerLeu unit is replaced by aromatic acyl derivatives.
Amino Acid Sequence↗
MHC-unrestricted cytotoxic and proliferative responses of two distinct human gamma/delta T cell subsets to Daudi cells.
Human V gamma 9/V delta 2 T cells, the major subset of gamma/delta T cells in peripheral blood of adults, mediate proliferative and cytotoxic responses to Daudi Burkitt's lymphoma cells without previous in vitro exposure to Daudi. Our experiments show that some gamma/delta T cells coexpressing V gamma 9 and V delta 1 genes also react to Daudi cells in cytotoxic and proliferative assays. Expression of V gamma 9 is not sufficient for the recognition of Daudi cells because most gamma/delta T cells expressing V delta 1 paired with V gamma 9 or other V gamma genes neither kill Daudi cells nor proliferate to Daudi. V gamma 9/V delta 2 T cells do not proliferate to other cell lines such as K562 or Molt4 that are sensitive to MHC-unrestricted cytolysis by NK cells and by most IL-2-activated gamma/delta T cell clones. Cold target inhibition assays demonstrate that Daudi cells are stronger inhibitors than K562 and Molt4 of MHC-unrestricted lysis by V gamma 9/V delta 2 clones. However, cold Daudi cells are relatively weaker inhibitors of MHC-unrestricted lysis by NK cell clones, most gamma/delta T cell clones expressing V delta 1 and alpha/beta T cell clones. Thus, recognition by V gamma 9/V delta 2 T cells and certain V gamma 9/V delta 1 T cells of Daudi appears to involve a specific triggering pathway that is distinct from recognition by these gamma/delta T cells of Molt4, K562, and other target cells. NK cell clones and most other gamma/delta and alpha/beta T cell clones derived from the same normal volunteer blood donors do not show this specific interaction with Daudi cells. These data show that distinct subsets of human gamma/delta T cells recognize Daudi cells and support the idea that the gamma/delta TCR may be directly involved.
Antigens, Bacterial↗
Subset heterogeneity among gamma delta T cells found in peripheral blood during Plasmodium falciparum malaria.
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Adult↗
Polyclonal origin of rheumatoid synovial T-lymphocytes.
Nineteen T-cell clones from seven patients with RA were obtained by cloning infiltrating lymphocytes from needle synovial biopsies. Southern blot analysis of the T-cell receptor (TCR) beta-chain genes in these clones revealed that there were no T-cell clones with an identical rearrangement of the TCR beta gene. These results do not support the idea that the infiltrating T-lymphocytes in RA are of monoclonal or oligoclonal origin.
Arthritis, Rheumatoid↗
The influence of adjuvants on the generation of autoantibody and specific suppression in rat erythrocyte-immunized mice.
A number of adjuvants were investigated for their ability to modulate either the autoimmune response induced in mice by immunization with rat erythrocytes (RRBC) or the ability of RRBC-primed spleen cells to suppress the induction of anti-red cell autoimmunity in recipient mice. The inability of the agents used to do so is discussed on the background of models used to explain the generation of suppression in this system.
Adjuvants, Immunologic↗
Modulation of anti-tumor cytotoxicity of cultured mast cells by metabolic inhibitors.
IL-3-dependent, murine mast cell lines derived from embryonic yolk sac precursors display a tumoricidal activity that is blocked by antibodies against tumor necrosis factor-alpha, indicating that this cytokine is the major mediator involved in the cytotoxic activity of the cultured mast cell lines. Further, cholera toxin strongly inhibits the cytotoxic activity of mast cells as well as their IL-3-induced DNA synthesis response but not IgE-mediated serotonin release. Cyclosporin A diminished cytotoxicity and serotonin release, but not DNA synthesis. Actinomycin D markedly suppressed the cytotoxicity of one mast cell line but only slightly suppressed that of another, whereas the IL-3-induced proliferation of both mast cell lines was strongly inhibited. Thus, our studies indicate that the cytotoxic function of mast cells is relatively independent of their degranulation and proliferation and may utilize different signalling pathways.
Animals↗
Analysis of the basis of resistance and susceptibility of CD4+ T cells to human immunodeficiency virus (HIV)-gp120 induced anergy.
The resistance and susceptibility of T cells to human immunodeficiency virus (HIV)-gp120 induced anergy was examined. Antigen-dependent proliferation of polyclonal T cells was markedly inhibited by gp120, whereas from the analysis of monoclonal populations, T cells resistant to the effects of gp120 could be identified. Similarly, exposure of monoclonal T cells to gp120 in the absence of accessory cells, also demonstrated that some T cells could resist the induction of anergy. Loss of antigen recognition was associated with phenotypic modulation of CD3 and CD28, which was not observed in T cells resistant to functional inactivation by gp120. Modulation of CD4 was not related to induction of anergy in the monoclonal T cells examined in this study. Inhibition of T-cell responses by anti-CD4 antibodies was compared to that by gp120. Anti-CD4 antibodies, which cross-compete with gp120 for binding to CD4, inhibited the response to antigen of monoclonal T cells. In contrast, no tolerogenic signals were delivered by pretreating T cells with the anti-CD4 antibodies in the absence of accessory cells, indicating that inhibition was due to abrogation of the interaction of CD4 with major histocompatibility complex (MHC) class II molecules expressed on accessory cells. Although the free CD4-binding region peptide of gp120 could inhibit polyclonal T-cell responses, only the carrier-bound peptide was able to modulate cloned T cells, suggesting a conformational requirement for functional inactivation through engagement of CD4. The results reported here using clonal CD4+ T-cell populations demonstrate that effects of gp120 on antigen-dependent proliferation are not uniform, and that therapeutic intervention might be directed at T-cell populations identified as susceptible to HIV-gp120 induced anergy.
Antigens, CD↗
The combined treatment of human peripheral blood mononuclear cells with thymolymphotropin and interleukin 2 increases PPD-driven T-cell proliferation and IL-2 induced cellular cytotoxicity against HIV-infected cells.
Two in vitro systems (the DNA synthetic response to mycobacterial antigens and cytotoxicity against lymphoid cells) were used to analyse the effect of thymolymphotropin (TLT) on peripheral blood mononuclear cells (PBMC). Purified protein derivative of mycobacteria (PPD)-driven T-cell proliferation in low-responder donors was increased by the combined treatment with TLT and suboptimal doses of recombinant interleukin 2 (IL-2). Similarly, the activities of natural killer (NK) cells and lymphokine-activated killer (LAK) cells have been enhanced in PBMC cultures pretreated with TLT. Also, TLT showed an enhancing effect on the development of LAK cells capable of lysing Epstein-Barr virus (EBV)-transformed B-lymphocytes infected or uninfected with the human immunodeficiency virus (HIV).
Cytotoxicity, Immunologic↗