UV light exposure and HIV replication.
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
Biomedical subjects
G M Shearer
Publications and source records attributed to G M Shearer.
Changes in T-helper cell function in human immunodeficiency virus-infected children during didanosine therapy as a measure of antiretroviral activity.
Didanosine has shown activity against the human immunodeficiency virus (HIV) in both children and adults. We prospectively assessed T-helper cell (Th) function as determined by in vitro interleukin-2 (IL-2) production in response to a panel of T-cell stimuli in 22 HIV-infected children before and during didanosine therapy and we correlated the incidence of opportunistic and recurrent bacterial infections with changes in p24 antigen and CD4 counts. Didanosine (270, 360, or 540 mg/m2/d) was administered orally for periods ranging from 8 to 40 weeks (mean, 24 weeks). Five of six asymptomatic patients (Centers for Disease Control P-1) compared with 6 of 16 symptomatic (P-2) patients exhibited improved Th function (greater than threefold increase in IL-2 production to at least 2 of the 4 stimuli) during therapy. Of 12 patients without infections during therapy, 9 (75%) showed improvement in Th function, compared with only 2 of 10 patients with infections (P = .03). Notably, the incidence of infections was not correlated with improvements in CD4 count or decreases in p24 antigen. Improvement in Th function during didanosine therapy is correlated with decreased incidence of infections. Assessment of Th function may provide an additional measurement of immunologic response to antiretroviral therapy.
Adolescent↗
A factor from CD8 cells of human immunodeficiency virus-infected patients suppresses HLA self-restricted T helper cell responses.
Defective in vitro T helper cell (Th) function can occur in asymptomatic human immunodeficiency virus (HIV)-seropositive (HIV+) individuals. A characteristic, early finding is the loss of an in vitro response to recall antigens, such as influenza A virus (FLU), despite an intact Th response to alloantigen (ALLO). To determine whether suppressor cells and/or inhibitory factors could contribute to this HIV-associated Th immunodeficiency, coculture studies were performed using peripheral blood leukocytes (PBLs) from monozygotic twins, one of whom was HIV-infected (HIV+) and one of whom was uninfected (HIV-seronegative, HIV-). In vitro Th function was measured as interleukin 2 production or proliferation to FLU and ALLO. Two pairs of twins were repetitively studied. A single HIV+ individual with multiple samples of cryopreserved PBLs over 6 years (including a HIV- specimen) was also studied. PBLs from the HIV+, but not from the HIV-, individuals demonstrated defective in vitro Th function in response to FLU but not to ALLO. PBLs from HIV+ individuals could induce a similar defect in the Th function of syngeneic or autologous HIV- PBLs. This suppression was generated by CD4-depleted, but not by CD8-depleted, PBLs. A suppressive factor from CD8+ cells of HIV+ donors was generated by 24-hr unstimulated cultures of HIV+ PBLs. This factor inhibited FLU but not ALLO responses of autologous, syngeneic, or allogeneic HIV- PBLs. This suppressive effect could not be explained by HIV infection or replication during the culture period. These results demonstrate that selective abrogation of Th function to recall antigens in HIV+ individuals is associated with an inhibitory factor produced by CD8+ T cells.
CD8 Antigens↗
HIV-1 from a seronegative transplant donor.
Explore the source record for details and available documents.
AIDS Serodiagnosis↗
Regulation of graft-versus-host-reaction by Mlsa-reactive donor T cells.
Injection of A/J splenocytes (H-2Dd, Mlsc) into unirradiated (A/J x CBA)F1 (BAF1) host mice (H-2Dd/k, Mlsd) results in an acute suppressive graft-vs.-host reaction (GVHR), characterized by immune dysfunction and appreciable donor cell engraftment; injection of the CBA/J parent (H-2Dk, Mlsd), which recognizes no Mls disparity in the host, results in little or no GVHR. Furthermore, the Mlsa-reactive V beta 6 and V beta 8.1 T cell subsets in A/J T cells expand significantly in the GVHR host. Finally, depletion of V beta 6+ and V beta 8.1+ from the A/J population abrogates the proliferative response to BAF1 in vitro and the development of GVHR in vivo. Thus, the response to Mls determinants can contribute to the generation of a GVHR.
Animals↗
How human immunodeficiency virus ravages the immune system.
The immune system of individuals infected with human immunodeficiency virus is affected in two distinct ways: by loss of CD4+ cells and by loss of T-helper-cell function. Neither of these processes is yet fully understood. Research during 1991 that investigated the interaction between human immunodeficiency virus and the immune system has raised as many questions as it answered. Nevertheless, many of the issues raised are relevant to mechanisms responsible for the ravaging of the immune system by human immunodeficiency virus.
Acquired Immunodeficiency Syndrome↗
Cell-mediated immune response to human immunodeficiency virus (HIV) type 1 in seronegative homosexual men with recent sexual exposure to HIV-1.
Although human immunodeficiency virus (HIV) type 1 infection is efficiently transmitted by sexual intercourse, some individuals whose sexual behavior places them at extremely high risk for infection have nevertheless remained HIV-1-seronegative. An investigation was undertaken to determine whether such individuals have circulating T helper cells that are sensitized to HIV-1. Five very high risk men who had recent sexual exposure to HIV-1 were studied. Peripheral blood mononuclear cells from all 5 produced interleukin (IL)-2 in culture in response to synthetic amphipathic HIV-1 envelope peptides. One of the 5 high-risk men has subsequently seroconverted, while 4 have remained seronegative. All were initially culture-negative, and those who have remained seronegative were also virus-negative by polymerase chain reaction (PCR) testing 10 months after they were first studied. These results demonstrate that a cell-mediated immune response to HIV-1 can be detected in the absence of a humoral immune response in individuals recently exposed to HIV-1. Furthermore, IL-2 production by T cells in response to synthetic peptides may be a more sensitive test for exposure to HIV-1 than antibody, lymphoproliferation, or PCR tests.
Amino Acid Sequence↗
Reconstitution of long-term T helper cell function after zidovudine therapy in human immunodeficiency virus-infected patients.
Peripheral blood mononuclear cells from 12 asymptomatic patients infected with immunodeficiency virus (HIV) and 4 patients with AIDS were analyzed before and during therapy with zidovudine for T helper cell (Th) function. Th function improved by more than fourfold to one or more of three stimuli tested in 9 (75%) of 12 asymptomatic patients on zidovudine therapy and in 3 of 4 patients with AIDS. Only 6 (7.4%) of 80 untreated HIV-infected control patients showed spontaneous improvement in Th function (P less than 10(-6)). Improved Th function was detected as early as 5 weeks into therapy in 6 patients and continued to be evident for greater than 1 year after start of therapy in 6 patients and for greater than 2 years in 2 patients. No correlation was observed between improved Th function and changes in CD4+ or CD8+ cell numbers or in levels of serum HIV p24 antigen or beta 2-microglobulin. These results suggest inclusion of in vitro Th function as a useful marker in determining the efficacy of antiretroviral drug therapy of HIV-infected patients.
Acquired Immunodeficiency Syndrome↗
T helper cell immune dysfunction in asymptomatic, HIV-1-seropositive individuals: the role of TH1-TH2 cross-regulation.
Explore the source record for details and available documents.
HIV Seropositivity↗
CD8+ T cells from mice vaccinated against Toxoplasma gondii are cytotoxic for parasite-infected or antigen-pulsed host cells.
Mice vaccinated with a live temperature sensitive mutant (TS-4) of Toxoplasma gondii develop complete resistance to subsequent challenge with a highly virulent Toxoplasma strain (RH). Because CD8+ T cells have been demonstrated to be critical to this protective immunity in vivo, the involvement of cytotoxic T lymphocytes in the killing of infected cells in vaccinated mice was investigated. After restimulation in vitro, splenic T cells from vaccinated mice of either the BALB/c or C57BL/6 strains were found to kill syngeneic bone marrow-derived macrophages infected with TS-4 tachyzoites or preincubated with soluble T. gondii Ag. Unimmunized control mice or mice vaccinated with heat-killed TS-4 tachyzoites failed to generate significant CTL activity in vitro. Moreover, the observed lytic reaction was found to be target specific, not killing uninfected or unpulsed macrophages even when included as bystanders in the assay. Target lysis did not depend on the production by the effector cells of either a cytotoxic supernatant factor or IFN-gamma. Depletion of CD8+ cells from the splenic effector cell population, however, abrogated the cytotoxic activity, whereas depletion of CD4+ cells had little effect. The MHC restriction of the Toxoplasma-specific cytolytic reaction was confirmed in studies using effector cells from BALB/c mice and targets from congenic or mutant haplotype strains. These experiments indicated that target killing is primarily restricted by genes mapping within the H-2D/Ld loci. Together, these results establish MHC-restricted cytolysis as a major parameter of CD8+ effector function against T. gondii and indicate that, in the case of this protozoan, Ag presentation to CD8+ lymphocytes can occur as a result of either processing within infected cells or exogenous uptake of parasite Ag.
Animals↗
Repopulation of host lymphohematopoietic systems by donor cells during graft-versus-host reaction in unirradiated adult F1 mice injected with parental lymphocytes.
The graft-vs-host reaction (GVHR) generated by the injection of parental lymphocytes into unirradiated immune-competent F1 hosts is characterized by an acute loss of immune functions, an attack on host tissues, and a gradual recovery of function. Flow cytometric analysis of the donor- and host-derived splenic populations during the course of acute dysfunction and gradual recovery revealed a complex pattern of changes in lymphoid and myeloid populations that resulted in the repopulation of the host with donor-derived cells. Initially, donor-derived T cell populations expanded, particularly CD8+ T cells. Next, host T cell and B cell populations disappeared. Finally, donor-derived cells repopulated the lymphohematopoietic system in the sequence myeloid populations, B cells, and, after a protracted period, T cells. The recovery of immune functions following GVHR-induced immune deficiency was associated with this repopulation of the spleen by donor-derived cells. Donor repopulation of the host lymphohematopoietic system required the presence of both CD4 and CD8 cells in the original donor inoculum. Depletion of donor CD4 populations precluded development of GVHR or any donor engraftment; depletion of CD8 cells resulted in engraftment solely of donor CD4 populations.
Animals↗
Multiple patterns of alloantigen presenting/stimulating cell dysfunction in patients with AIDS.
The APC/stimulating cell (APC/SC) potential of PBMC from Walter Reed stage 1 and 2 patients and patients with AIDS was tested by using these PBMC as stimulators in an allogeneic MLR. The responding cells were PBMC from unrelated, HIV- donors that were either unfractionated or depleted of APC by plastic and nylon wool adherence. Using this approach, we observed no defect in the APC/SC potential of PBMC from Walter Reed stage 1 and 2 patients. However, PBMC from AIDS patients used as allogeneic stimulators exhibited three different patterns of APC/SC function: 1) no defect in alloantigen (ALLO) APC/SC potential; 2) a defect in ALLO APC/SC function that was detected only if the responder cells were depleted of APC (presenting cell defect); and 3) a defect in ALLO APC/SC function, irrespective of whether the responder cells were depleted of APC (stimulating cell defect). These results indicate that in addition to Th cell defects associated with AIDS, the PBMC from AIDS patients can also exhibit a defect in APC/SC function. This study provides an approach that permits the testing of Ag-presenting function in all AIDS patients, and is therefore not limited to testing patients for whom HIV-, HLA-identical T cells and APC are available.
Acquired Immunodeficiency Syndrome↗
Detection of cytotoxic T lymphocytes specific for synthetic peptides of gp160 in HIV-seropositive individuals.
Four synthetic peptides corresponding to the IIIB sequence of gp160 of HIV were recently reported to stimulate Th cell function by PBL from HIV-infected, asymptomatic patients. In the present report, we used these same peptides to demonstrate CTL activity in a similar patient population. EBV-transformed B-cell lines from asymptomatic, HIV seropositive and seronegative control donors were pre-incubated with the peptides. Fresh PBL from 19 (76%) of 25 HIV seropositive donors lysed autologous targets pulsed with at least one of the four peptides. Autologous targets pulsed with two non-immunogenic peptides were not lysed. PBL from none of the eight HIV seronegative controls lysed peptide-preincubated autologous targets. The CTL activity was mediated by T cells, was predominantly MHC class I restricted, and was increased by in vitro restimulation of PBL with the peptides. HLA A-2 was identified as a restricting element for all four peptides in different patients, and for three of the peptides in the same donor. HLA-A1 or -B8 may also present some of the peptides. Thus, the same peptides can be recognized by human Th cells and class I MHC-restricted CTL.
Cytotoxicity, Immunologic↗
Effect of cyclosporin A on lymphopoiesis. III. Augmentation of the generation of natural killer cells in bone marrow transplanted mice treated with cyclosporin A.
The effects of cyclosporin A (CsA) on the generation of NK cells were studied using syngeneic bone marrow transplanted mice subsequently treated with CsA (BMT/CsA mice). In contrast to a severe reduction in T cells that was reported previously, these mice exhibited a marked enhancement of splenic NK activity. The enhanced NK activity was mediated by NK1.1+, Thy-1- cells as assessed by antibody plus complement treatment, and was concomitant with an absolute increase in the numbers of NK1.1+ cells as assessed by flow cytometry. Because the depletion of host-derived, mature NK cells by injection of anti-asialo GM1 antibody before bone marrow reconstitution did not affect the enhancement of NK activity, CsA appeared to augment the generation of NK cells from bone marrow precursors. To investigate a possible relationship between the enhancement of NK activity and the maturational arrest of T cells in the thymus induced by CsA, mice were thymectomized, followed by irradiation, bone marrow reconstitution, and CsA treatment. These mice exhibited as strong enhancement of splenic NK activity as BMT/CsA mice, suggesting that the CsA-induced effect on NK cells is distinct from its effect on T cell development in the thymus. Taken together, these results are the first demonstration of the positive effect of CsA on NK cell generation and may be of importance in clinical bone marrow transplantation.
Animals↗
Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine.
BALB/c mice vaccinated with a temperature-sensitive mutant (TS-4) of Toxoplasma gondii develop complete resistance to lethal challenge with a highly virulent toxoplasma strain (RH). This immunity is known to be dependent on IFN-gamma synthesis. In vitro and in vivo T cell depletions were performed in order to identify the subsets responsible for both protective immunity and IFN-gamma production. When stimulated with crude tachyzoite Ag in vitro, CD4+ cells from vaccinated mice produced high levels of TH1 cytokines (IL-2 and IFN-gamma) but not TH2 cytokines (IL-4 and IL-5). CD8+ cells, in contrast, produced less IFN-gamma and no detectable IL-2. Nevertheless, they could be induced to synthesize IFN-gamma when exposed in culture to exogenous IL-2. In vivo treatment with anti-CD4 plus anti-CD8 or anti-IFN-gamma antibodies during challenge infection completely abrogated resistance to T. gondii. In contrast, treatment with anti-CD4 alone failed to reduce immunity, whereas anti-CD8 treatment partially decreased vaccine-induced resistance. These results suggest that although IFN-gamma and IL-2-producing CD4+ lymphocytes are induced by vaccination, IFN-gamma-producing CD8+ T cells are the major effectors of immunity in vivo. Nevertheless, CD4+ lymphocytes appear to play a synergistic role in vaccine-induced immunity, probably through the augmentation of IFN-gamma synthesis by the CD8+ effector cells. This hypothesis is supported by the observation that when giving during vaccination, as opposed to after challenge, anti-CD4 antibodies are capable of blocking protective immunity.
Animals↗
Functional dichotomy of CD4+ T helper lymphocytes in asymptomatic human immunodeficiency virus infection.
The majority of asymptomatic, human immune deficiency virus seropositive (HIV+) individuals exhibit a defect in CD4+ T helper cell (Th) function that is selective for responses to recall antigens, but not to HLA alloantigens. The CD4-dependent Th response to HLA alloantigens (Allo) can be mediated by two distinct Th pathways: self-restricted CD4+ Th that recognize allogeneic determinants processed and presented by autologous or self accessory or antigen-presenting cells (sAC); and allo-restricted, CD4+ Th that recognize allogeneic determinants directly on allogeneic accessory or antigen-presenting cells (aAC). In contrast, the Th response to recall antigens requires CD4+ Th and sAC and is therefore limited to the major histocompatibility complex (MHC) self-restricted pathway. Peripheral blood leukocytes from 56 asymptomatic HIV+ patients that exhibited a selective defect in CD4+ Th function were analyzed to determine whether the Th response to Allo was entirely functional, or whether one of the CD4-mediated components of the Allo Th response was also defective. By depletion of AC and/or CD8+ Th subsets (to analyze CD4+ Th function), we demonstrated that HIV+ patients who were selectively deficient in Th function to recall antigens were also unresponsive to Allo presented by autologous AC (HLA self-restricted Th pathway), but retained Allo Th activity presented by allogeneic AC (allo-restricted CD4+ Th pathway). These findings indicate that the CD4+ Th defect seen in the majority of asymptomatic, HIV+ individuals is not limited to recall antigens, but also extends to the component of the response to HLA alloantigens that involves the self-restricted, CD4+ Th pathway. Thus, the Th defect observed in asymptomatic, HIV+ patients does not involve a CD4+ Th defect per se, but is limited to the HLA self-restricted component of Th function.
Antigen-Presenting Cells↗
Immunization with subunit human immunodeficiency virus vaccine generates stronger T helper cell immunity than natural infection.
Healthy, human immunodeficiency virus seronegative (HIV-) volunteers were multiply immunized with a recombinant gp160 (rgp160) candidate acquired immunodeficiency syndrome (AIDS) vaccine. Peripheral blood lymphocytes from volunteers immunized with 40 micrograms or with 80 micrograms (two volunteers per group) of rgp160, as well as from control donors, were tested for T helper (Th) cell function either prior to immunization, 8 to 12 months after the third immunization, or 2 to 5 months after the fourth immunization. The Th cell functional tests included antigen-induced in vitro interleukin 2 (IL 2) production and proliferation in response to influenza A virus (FLU) and to four synthetic peptides of HIV gp120 and gp160, previously demonstrated to be recognized by T cells from HIV naturally infected patients. Our results demonstrate the following: (a) immunization of HIV- individuals with rgp160 results in IL 2 production and T cell proliferation in response to HIV determinants; (b) boosting with rgp160 enhances Th function; (c) HIV-specific Th function is up to 100-fold greater in the multiply immunized volunteers than that observed in asymptomatic, HIV-infected individuals; and (d) multiple immunization with rgp160 does not impair Th function to a non-HIV antigen such as influenza A virus. These results indicate that immunization of uninfected individuals with an HIV subunit vaccine results in much stronger Th cell immunity than does natural infection and suggests that vaccination against HIV may be possible.
Gene Products, env↗
Common sequence in HIV 1 GP41 and HLA class II beta chains can generate crossreactive autoantibodies with immunosuppressive potential early in the course of HIV 1 infection.
We have previously reported the identification of highly conserved homologous regions located in the carboxy terminus of the HIV 1 gp41 (aa 837-844), and the amino-terminal of the beta chain of all human HLA class II antigens (aa 19-25). Murine monoclonal antibodies raised against synthetic peptides from these homologous regions bound not only to the isolated peptides, but also to "native" HLA class II molecules on cells. Screening of sera from HIV 1 infected individuals revealed high frequency of sera (35%) containing anti-class II crossreactive antibodies (CRAb), not only in AIDS patients, but also in early, asymptomatic patients. The CRAb containing sera caused potent inhibition of normal CD4-bearing cells' proliferative responses to tetanus toxoid in vitro. They could also kill class II bearing cells by ADCC. The possible contribution of these antibodies to the establishment of immunodeficiency state in HIV 1 infected individuals and/or to disease progression, was examined in two clinical studies: I. Asymptomatic patients were tested in parallel for their PBL responses to flu/tetanus, HLA alloantigens, and PHA (proliferation and IL2 production), and for the presence of anti-class II CRAb. About 50% of these patients showed a selective loss of their in vitro responses to recall antigens (flu/tetanus), which depend on CD4+ cells, while still responding to PHA and ALLO. Interestingly, positive correlation was found (P less than 0.001) between patients' lack of responsiveness to flu/tetanus and the presence in their sera of anti-class II CRAb. II. Retrospective study of HIV 1-infected hemophiliacs, suggest that patients with high titers of CRAb early in the disease progressed faster to full blown disease.
Amino Acid Sequence↗