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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Natural killer (NK) cells have long been known to aid in the control of viral infections by killing virus-infected cells, including those infected with human immunodeficiency virus (HIV). Among the possible NK-susceptible target cells in an infected individual, the monocyte/macrophages are of special significance since they may serve as both a reservoir of HIV and aid in dissemination of the virus throughout the body. A new technique for the enrichment and cultivation of large numbers of recombinant interleukin 2 (rIL-2)-stimulated NK cells has been developed which provides cells with high cytotoxic activity. These IL-2-activated NK cells, adherent lymphokine-activated killer cells (A-LAK), can kill monocytes infected with HIV for 24 h to 7 days, with optimal target sensitivity between 3 and 7 days. Recognition and killing of the infected monocytes did not appear to be restricted by the major histocompatibility complex (MHC) antigens and could be cold-target inhibited by tumor cell lines. A-LAK cells may be useful in newer therapeutic approaches to treatment of HIV infection.
AIDS Res Hum Retroviruses 1990 Aug
PMID:Cytotoxic activity against HIV-infected monocytes by recombinant interleukin 2-activated natural killer cells. 222 37

In HIV-infected patients major histocompatibility complex (MHC) class I and II (= HLA-A, B, C, DR) association has been controversial. Of the MHC class III coded complement components C2, BF, C4A/C4B especially C4 allotypes appear of major immunogenetic relevance for their potential differences in virus neutralizing potency and immune complex formation. In the present study 29 patients with AIDS-related complex and Walter-Reed 5 ARC/WR5), 35 patients with disseminated Kaposi's sarcoma (KS), and 160 HIV-negative control individuals were compared for MHC class I to III allotypes. Diagnosis of ARC and KS (WR criteria) was done by clinical and laboratory parameters, MHC testing, by standard procedures. An increase in frequency (p less than or equal to 0.05) was observed between ARC/WR5 patients and controls for HLA-B35/CW4, DRW14, a decrease for B16, CW6/DR7. However, values were not significant if corrected for the number of tested antigens. No significant differences were seen between KS and ARC patients or controls for class III allotypes, nor for previously reported associations, e.g. for B8, DR2, DR3, and especially DR5, including the DR5 splits DRW11, 12. The results indicate the lack of a strong MHC association with the investigated antigens in West German Caucasoids, and support the hypothesis of ethnic dependence of HIV-related diseases. The HLA-B35/CW4 increase, also associated with the duplicated C4 A*3 A*2 and the silent C4B*Q0, was more pronounced in ARC patients with progression to AIDS-OI. The increased frequency of C4B*Q0 alleles in these patients was thought to be secondary to a hypothetical increase in 'converted' and dysregulated C4 genes not seen to be associated in this study.
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PMID:Major histocompatibility complex class I to III allotypes in patients with AIDS-related complex/Walter-Reed 5, disseminated Kaposi's sarcoma and in normal controls. The ARC-IVIG Study Group. 223 73

A hypothesis is presented in which HIV infection leads to immunodeficiency through indirect subversion of critical T cell regulatory mechanisms. Acting at the T cell receptor complex (TCR), viral components (gp120) mimic the natural ligands of CD4, molecules of the major histocompatibility complex (MHC), and deliver physiologically active, inappropriate signals resulting in generalized, uncontrolled lymphocyte activation, or "panergy." Clinical manifestations of panergy include autoimmune phenomena, lymphadenopathy, hyperglobulinemia, and symptoms mediated by lymphokines. Immunologic unresponsiveness occurs early in HIV infection prior to T cell depletion because activated cells do not respond to further stimulation. Ultimately, activation disrupts T cell homeostasis by interference with the generation of memory cells ("imnesia") and leads to net T cell loss, clonal deletion, and the development of AIDS. The clinical and immunologic features of HIV disease and AIDS are reviewed from this perspective. This hypothesis is consistent with the paucity of infected T cells, the clinical findings of both AIDS-related complex (ARC) and frank AIDS, the prolonged "incubation period," and a role for antigen-specific cofactors. Based on this view of HIV pathophysiology, therapeutic modalities should avoid immune stimulation and seek to block aberrant gp120 signals at CD4 and eliminate HIV-infected cells.
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PMID:AIDS as immune system activation. II. The panergic imnesia hypothesis. 240

Characterization of the host immune response to human immunodeficiency virus type 1 (HIV-1) is critical to the rational design of an effective AIDS vaccine. In this study, cytotoxic T lymphocytes (CTL) specific for HIV-1 reverse transcriptase (RNA-dependent DNA polymerase) were found in blood samples from HIV-1-infected individuals. CTL targets were prepared by immortalizing B cells from ten seropositive and six seronegative individuals, and then infecting these cells with recombinant vaccinia viruses containing HIV-1 genes. CTL directed against autologous B lymphoblasts expressing HIV-1 reverse transcriptase were detected in fresh blood samples from eight HIV-1 seropositive subjects, but in no seronegative controls. The effector cells were identified as major histocompatibility complex-restricted CD3+CD8+ lymphocytes. Because the HIV-1 pol gene is highly conserved among different isolates and generates both humoral and cellular immune responses, it bears consideration for inclusion in a candidate AIDS vaccine.
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PMID:HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals. 245 Dec 88

Because cytotoxic T lymphocytes (CTL) may be important for preventing direct cell-to-cell transmission of human immunodeficiency virus (HIV), the agent responsible for acquired immunodeficiency syndrome, we have begun to investigate the epitope specificity and immune response (Ir) gene control of anti-HIV CTL responses in experimental animals. Mice were infected with a recombinant vaccinia virus expressing the HIV gp160 envelope gene, and the primed lymphocytes were restimulated in vitro with a transfected histocompatible cell line expressing the same gene. Our results show that H-2d mice are CTL high responders and H-2k mice are low responders to the HIV gp160 envelope protein under these conditions. Moreover, the H-2d mice respond predominantly to a single immunodominant site represented by a 15-residue synthetic peptide conforming to the amphipathic alpha-helix model of T-cell epitopes and seen by CD4- CD8+ CTL in association with the Dd class I major histocompatibility complex (MHC) molecules. The facts that CTL responses were detected in the context of only one of four class I MHC molecules tested and that the response was limited predominantly to a single epitope indicate that the CTL repertoire elicited by the HIV envelope protein in association with murine class I MHC molecules may be very limited. In addition, this epitope occurs in a highly variable segment of the envelope protein. This puts constraints on the use of a single peptide sequence from this region in a vaccine, as such a vaccine would have to be polyvalent. Nevertheless, this same variability suggests that this region may be under selective pressure from human CTL, and therefore that this site may be immunodominant in humans as well as mice and so of clinical importance in vaccine development.
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PMID:An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. 245 43

T lymphocytes, in contrast to antibodies, appear to recognize primarily a limited number of antigenic sites on any given antigenic protein. We find that a single site can so dominate the T-cell repertoire that the presence or absence of a response to one immunodominant site can make the difference between a high responder and a low responder, even though low responders respond to other sites almost as well as high responders. Besides interaction with major histocompatibility complex (MHC) molecules, the mode by which the antigen is processed into fragments for T-cell recognition also determines which sites are seen. The products of natural processing of the protein appear to be larger than the synthetic peptides and contain structures which hinder binding to certain MHC molecules or to the T-cell receptor. A third factor in immunodominance is the intrinsic structure of the antigenic site. We have shown that amphipathic helices have a higher than random chance of being immunodominant, and have developed a computer program to locate such structures in protein amino acid sequences. We prospectively predicted sites in the malaria circumsporozoite protein and found that the four most widely recognized sites in an endemic area of West Africa were all predicted. Similarly, we identified two helper T-cell sites from the HIV (AIDS virus) envelope, and have now shown that immunization with these elicits enhanced antibody responses to the whole envelope when injected into monkeys. These sites are also recognized by human T cells from volunteers who had been immunized with a recombinant vaccinia virus expressing the HIV envelope. Also, because cytotoxic T lymphocytes (CTLS) may play a critical role in defence against AIDS, we have used a recombinant vaccinia virus and transfectants expressing the HIV envelope gene to induce specific CTLS against the HIV envelope. Using synthetic peptides, we were able to identify the first CTL recognition site in the AIDS virus. These results may contribute to the rational design of vaccines.
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PMID:Structural features of T-cell recognition: applications to vaccine design. 247 71

Immunodominant T-cell antigenic sites can so dominate a response that their presence leads to high responsiveness and their absence to low responsiveness. Therefore, it is important to locate such sites for vaccine development. Factors that lead to immunodominance include features extrinsic to the structure of the site itself, such as the major histocompatibility complex (MHC) molecules of the host and the types of fragments produced by processing of the protein antigen before the T cell sees it. They also include factors intrinsic to the structure of the T-cell site, that determine a repertoire of potential immunodominant sites from which the extrinsic factors select a subset that will be immunodominant in a given individual. We have focused on one of these intrinsic factors, helical amphipathicity, that we have found to be a common feature among both helper and cytotoxic T-cell antigenic sites, suggesting that the same physical principles apply to sites seen in association with class I and class II MHC molecules. We have used this feature to locate immunodominant epitopes on the circumsporozoite protein of the Plasmodium falciparum malaria parasite and the envelope protein of the AIDS virus. Both helper and cytotoxic T-cell epitopes were identified. At least in the case of the helper T-cell sites, it was striking that the same sites in both the malaria and AIDS proteins studied that were immunodominant in the mouse were also immunodominant in the human, an indication that the same principles apply across species, and that the animal model will be useful for identifying sites to be used in vaccines for humans. These sites have been coupled with neutralizing antibody sites to produce artificial constructs that can elicit antibodies. It is hoped that the rational design of more complex versions of these artificial constructs will produce vaccines that are more effective than the natural pathogen proteins used in subunit vaccines, since such pathogen protein antigens have been selected through evolution to evade the immune system, not to optimize immunogenicity.
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PMID:Mechanisms of immunodominance in T-cell recognition, with applications to vaccine design. 247 31

Four juvenile rhesus macaques were infected with simian immunodeficiency virus (SIV)MAC-Freshly isolated peripheral blood mononuclear cells (PBMC) from these SIVMAC-infected and from uninfected control macaques were assessed for cytotoxic T-lymphocyte (CTL) activity monthly for 7 consecutive months, beginning 2 months after infection. Target cells consisted of major histocompatibility complex (MHC) haploidentical parental PBMC which were stimulated with mitogen and then pulsed with heat-killed SIVMAC. CTL activity was demonstrated on all four infected animals. The effector cells are T cells which mediate cytotoxicity against SIVMAC-pulsed target cells in an MHC-restricted manner. Furthermore, the cytotoxicity is virus specific and predominantly, if not exclusively, mediated by CD8+ T cells; it is also MHC class-I restricted. Incubation of target cells with leupeptin prior to the cytotoxic assay inhibited target cell generation, suggesting that viral antigens are processed via an endocytic pathway.
AIDS 1989 Dec
PMID:Characterization of simian immunodeficiency virus-specific T-cell-mediated cytotoxic response of infected rhesus macaques. 256 Oct 53

The pathogenesis of cellular immune deficiency following human immunodeficiency virus (HIV) infection could result from quantitative and/or qualitative dysfunction of the CD4+ lymphocyte population. To better characterize the T-cell response to soluble antigen with HIV infection, we have isolated peripheral blood lymphocytes and purified populations of CD4+ lymphocytes from healthy HIV antibody-positive subjects, patients with acquired immunodeficiency syndrome (AIDS)-related complex (ARC), and healthy HIV antibody-negative controls. T-lymphocyte function was determined by proliferative response to lectin (phytohemagglutinin), phorbol 12-myristate 13-acetate (PMA), calcium ionophore, purified recombinant HIV envelope gp120, tetanus toxoid antigen, and tetanus toxoid antigen in the presence of recombinant gp120 or purified recombinant soluble CD4. PBLs and CD4+ lymphocytes from asymptomatic HIV-infected subjects responded equally well to lectin, PMA, and/or calcium ionophore and to tetanus toxoid as cells from uninfected control subjects. The cells that proliferated in response to a soluble antigenic stimulus did not respond to gp120. Cells from subjects with ARC had a selective antigen recognition defect independent of the number of CD4+ lymphocytes. Recombinant gp120 inhibited CD4+ lymphocyte proliferation to antigenic stimulus by 30-40%. Recombinant soluble CD4, a proposed therapeutic for HIV, had no effect on T-cell response to antigen. A selective antigen recognition response was not compromised early in HIV infection but was compromised in subjects with ARC. Inhibition of proliferation to tetanus toxoid by gp120 suggests that HIV may affect major histocompatibility complex II restricted antigen recognition independent of CD4+ cell loss.
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PMID:CD4+ lymphocyte function with early human immunodeficiency virus infection. 256 77

The complex biological processes responsible for regulating the immune system are presently the subject of considerable interest and study. New insight into this process comes from a variety of observations and it is the purpose of this communication to develop the hypothesis that two seemingly quite disparate observations point to a common biological mechanism bearing on immunoregulation. The observations concern the unique immunologic relationship between mother and fetus and the immunoregulatory abnormalities encountered in HIV-induced acquired immunodeficiency syndrome (AIDS). Exposure to foreign (allo) major histocompatibility complex (MHC) antigens can potentially occur during pregnancy, the transfusion of blood or blood products, or anal insemination. The hypothesis, in its simplest form, states that such MHC alloantigenic exposure triggers a sequence of immunoregulatory mechanisms resulting in immunosuppression and that this response has evolved in placental mammals as a means of protecting the fetus from maternal immune rejection and promoting optimal fetal development.
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PMID:Does exposure to HLA alloantigens trigger immunoregulatory mechanisms operative in both pregnancy and AIDS? 268 27


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