Progress of HIV infection and changes in the lipid membrane structure of CD4+ cells.
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CD4-Positive T-Lymphocytes↗
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Proliferative lymphocyte responses to foot-and-mouth disease virus and three FMDV peptides after vaccination or immunization with these peptides in cattle.
We studied proliferative responses of bovine T lymphocytes to foot-and-mouth disease virus (FMDV) serotypes A, O and C as well as to three peptides including the two major B-cell epitopes of FMDV (VP1[141-156] and VP1[200-213]). Peripheral blood mononuclear cells (PBMC) from cattle previously vaccinated with monovalent vaccine responded to both homotypic and heterotypic virus strains. Of 14 FMDV-specific bovine T-cell clones, which were prepared from PBMC of an animal vaccinated with the trivalent vaccine, 11 reacted to each of the three serotypes A, O and C. This indicates that several T-cell epitopes might be conserved among these serotypes. PBMC from one of two cattle immunized with VP1[141-156]KLH, one of two cattle immunized with VP1[200-213]KLH and two of three cattle immunized with CC-VP1[200-213]-PPS-VP1[141-156]-PCG responded to the homotypic virus strain. After immunizations with VP1[200-213]KLH also heterotypic responses were found. Thus, it appears that these two B-cell sites include T-cell determinants that are recognized by some cattle. However, when proliferative responses of PBMC from an animal vaccinated with the trivalent vaccine were tested, no responses were found to VP1[141-156] and VP1[200-213], whereas the response was very poor to CC-VP1[200-213]-PPS-VP1[141-156]-PCG. These results suggest that these sequences do not represent dominant T-cell epitopes and/or that T-cell reactivity towards these synthetic peptides does not completely cover the T-cell reactivity towards the fragments present after processing of the whole virus.
Animals↗
Cytotoxic T lymphocyte response against multiple simian immunodeficiency virusA (SIV) proteins in SIV-infected macaques.
To identify the target proteins of CD8+ T lymphocytes we have explored the cytolytic immune responses of 12 rhesus macaques experimentally infected with the simian immunodeficiency virus (SIVmac). Target cells were autologous B cell lines presenting SIVmac proteins after infection with recombinant vaccinia viruses. The eight following proteins were studied: ENV, POL, GAG, NEF, VIF, REV, TAT, and VPX. Macaque PBMC stimulated with Con A and expanded in T cell growth factor-containing medium produced cell lines with cytolytic activity in the majority of infected animals (9/12). The structural proteins ENV, POL, and GAG were recognized by cell lines derived from nine, eight, and six macaques, respectively. The small regulatory proteins also represented efficient CTL targets, a specific activity being detected against NEF (8/12), REV (7/12), VPX (7/12), TAT (6/12), and VIF (5/12). Most cytotoxic responses (except those directed against ENV) were mediated by CD8 cells and were MHC class I restricted. Limiting dilution analysis allowed us to quantify the frequency of CTL precursors and confirmed the high immunogenicity of multiple SIV proteins. Three different patterns of response could be defined: six animals were able to recognize at least six of the eight tested target proteins, two of them reacting with all eight target proteins. The other three responder macaques reacted only against a few SIV proteins, whereas no cytotoxic activity was detected in the three remaining infected macaques and in the nine negative controls. The six animals responding against multiple proteins were still healthy 12 to 22 mo after infection with two of them presenting a decrease in circulating CD4 cells concurrently to the disappearance of the CTL response. Conversely, three nonresponder or low responder macaques developed an overt disease after 4 to 12 mo, and two other presented a very low level of CD4 cells, suggesting that the pattern of response may be of prognostic value.
Animals↗
CD4-CD8+ T lymphocytes mediate AKR/gross murine leukemia virus nonresponsiveness in moderately aged AKR.H-2b:Fv-1b mice.
Previously we reported that as AKR.H-2b:Fv-1b mice become older than 9 wk of age they begin to specifically lose the ability to generate anti-AKR/Gross murine leukemia virus (MuLV) CTL responses after immunization and in vitro restimulation with cells expressing AKR/Gross MuLV-encoded Ag. Interestingly, the frequency of virus-specific precursor cytotoxic T lymphocytes (CTL) observed in moderately-aged AKR.H-2b:Fv-1b mice was not substantially decreased from that found in their young responder counterparts. To further investigate the mechanism(s) responsible for the inability of moderately-aged AKR.H-2b:Fv-1b mice to mount AKR/Gross MuLV-specific CTL responses, adoptive transfer experiments were performed in the present study. Transferring splenocytes from moderately-aged AKR.H-2b:Fv-1b donors into young AKR.H-2b:Fv-1b recipients resulted in inhibition of AKR/Gross MuLV-specific CTL responsiveness. Anti-Thy-1.1 plus complement depletion of T cells from the donor cell population before adoptive transfer resulted in a near complete restoration of AKR/Gross MuLV responsiveness of young recipient AKR.H-2b:Fv-1b mice suggesting that the inhibition observed in moderately aged mice was mediated by T lymphocytes. Additional experiments using depletion of T subsets before cell transfer demonstrated that inhibition of AKR/Gross MuLV-specific CTL responsiveness was mediated by a CD4-CD8+ T lymphocyte.
AKR murine leukemia virus↗
Effects of disease stage and zidovudine therapy on the detection of human immunodeficiency virus type 1 in semen.
OBJECTIVE: To determine the prevalence and temporal expression of infectious human immunodeficiency virus type 1 (HIV-1) in the semen of HIV-1 seropositive men and to determine whether the detection of HIV-1 in semen is associated with disease stage, zidovudine treatment status, or other clinical factors. DESIGN: A microculture technique was used to detect infectious HIV-1 in semen from a cohort of 95 seropositive men. In addition, semen cultures were performed monthly for at least 6 months for 14 of the men. Information was obtained by interview and extracted from medical records to identify clinical variables associated with HIV-1 in semen. PATIENTS: Sixty HIV-1 seropositive homosexual men participating in clinical studies at the Fenway Community Health Center, Boston, Mass, and 35 HIV seropositive bisexual or heterosexual men participating in the California Partner Study of the University of California, San Francisco. MAIN OUTCOME MEASURES: Semen HIV-1 culture results, seminal leukocyte counts, Centers for Disease Control (CDC) disease stage, peripheral CD4+ cell counts, zidovudine therapy, HIV risk category. RESULTS: In the cross-sectional study, HIV-1 was cultured from the semen of nine (9%) of 95 men. Factors associated with detection of HIV-1 in semen were peripheral CD4+ cell counts of 0.20 x 10(9)/L (200/microL) or less (adjusted odds ratio [OR], 23.33; 95% confidence interval [Cl], 2.89 to 175.63); symptomatic (CDC class IV) disease (adjusted OR, 6.56; 95% Cl, 1.02 to 66.76); and seminal leukocytosis (greater than 1 x 10(9) white blood cells per liter of semen) (adjusted OR, 7.02; 95% Cl, 1.28 to 39.29). Zidovudine therapy was associated with decreased detection of HIV-1 in semen (adjusted OR, 0.04; 95% Cl, 0.00 to 0.63). In the longitudinal study of 14 men who had neither peripheral CD4+ cells counts of 0.20 x 10(9)/L or less nor seminal leukocytosis, seminal HIV-1 was detected in at least one sample from six men (43%). CONCLUSION: HIV-1 is more commonly found in semen from men with advanced HIV-1 infection and seminal leukocytosis but can also be cultured from semen of men with neither of these conditions. Zidovudine therapy may decrease the prevalence and/or titer of seminal HIV-1. However, all HIV-1-infected persons should continue to assume that they are potentially infectious through sexual contact.
CD4-Positive T-Lymphocytes↗
Human immunodeficiency virus (HIV-1): infectivity transmission, risk behaviours and host susceptibility.
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CD4-CD8 Ratio↗
Diagnostic and therapeutic technology assessment. Surrogate markers of progressive HIV disease.
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Animals↗
Lymphocytotoxic strains of feline leukemia virus induce apoptosis in feline T4-thymic lymphoma cells.
Feline leukemia retrovirus (FeLV) strains with subgroup C env genes kill feline T4 lymphoma 3201 cells by 7 to 12 days after in vitro inoculation, whereas FeLV strains with subgroup A env genes do not. Neither FeLV-A nor FeLV-C kill feline fibroblasts. FeLV-C, but not FeLV-A, is replicated to higher titer by 3201 cells and productive infection precedes death by 3 to 7 days. Transcriptional activity of the FeLV-C long terminal repeat, as assessed by chloramphenicol acetyltransferase activity, is high in feline lymphoid cells but low in feline fibroblasts. Activity of the FeLV-A long terminal repeat is moderate in both cell types. FeLV-C-infected cells form aggregates 1 to 4 days before dying; ultrastructurally, virus particles can be seen approximating the clustered cells. Dying cells demonstrate nuclear condensation, surface blebbing, and fragmentation. DNA fragmentation and laddering compatible with apoptosis occur 1 to 2 days before massive cell death. In FeLV-C-infected 3201 cells, a shift from phospholipid to neutral lipid incorporation of [14C]oleic acid, increases in palmitic acid proportions and decreases in linoleic acid proportions occur 1 to 2 days before peak killing. Exposure of 3201 cells to ultraviolet-inactivated FeLV-KT (200-800 micrograms/10(6) cells) causes cytostasis within 2 days and death within 4 days. Blebbing and nuclear condensation occur but clusters do not form. The induction of programmed cell death in feline thymic lymphoma cells by subgroup C feline retroviruses may be relevant to the pathogenesis of FeLV-induced thymic atrophy, paracortical lymphoid depletion and acquired immunodeficiency in vivo.
Animals↗
Characterization of thymic cell subpopulations involved in IL-1- or GM-CSF-induced IL-6 production.
IL-6 has been demonstrated by in vitro studies to be a cytokine involved in thymocyte activation We show herein that thymocytes cultured at high concentrations in the absence of comitogen respond to IL-1 and, to a lesser degree, to GM-CSF, by producing IL-6. This phenomenon disappears rapidly with decreasing cell densities, suggesting the involvement of a minor cellular component of the thymus which may be solely responsible for or cooperate in IL-6 production. We have analysed several thymic subpopulations for IL-6 production and show that accessory cells, and eventually their precursors, are the major if not exclusive, producers of this cytokine. Mature steroid-resistant thymocytes do not secrete IL-6. Production of IL-6 by total CD4-CD8- thymic cells is largely reduced by the depletion of mature accessory cells which express I-A and Mac-1 antigens. As shown previously, accessory cell precursors within the CD4-CD8- compartment are induced to differentiate into M phi and DC in response to IL-1 and GM-CSF. We provide evidence that this maturation is associated with IL-6 production. Thymic DC and phagocytic cells of the thymic reticulum (P-TR) in vitro produce high levels of IL-6 which are enhanced by GM-CSF or IL-1. These factors have a synergistic effect on IL-6 production by total thymocytes, and on CD4-CD8- cells that are not depleted for mature I-A+ Mac-1+ accessory cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Parallel regulation of IL-4 and IL-5 in human helminth infections.
To investigate the relationship between cytokine production and the increased levels of serum IgE and peripheral eosinophilia commonly accompanying human helminth infections, we studied the ability of PBMC of normal (N1) (n = 18) and eosinophilic individuals with helminth infections (H1) (n = 9) to produce IL-3, IL-4, IL-5, granulocyte-macrophage-CSF, and IFN-gamma in vitro after stimulation with PMA (50 ng/ml) and ionomycin (1 microgram/ml). The two groups differed in both the levels of serum IgE and eosinophilia. For mitogen-induced production of granulocyte-macrophage-CSF and IFN-gamma, there was no difference in cytokine production between the two groups. In marked contrast, supernatants from PBMC of infected individuals had significantly higher levels of IL-4 (mean = 213 pg/ml for N1 and 944 pg/ml for H1, p less than 0.02), IL-5 (mean = 180 pg/ml for N1 and 1118 pg/ml for HL, p less than 0.001), and IL-3 (mean = 13900 pg/ml for N1, 28029 pg/ml for H1, p less than 0.05). In addition, helminth-infected patients had approximately 5-fold greater numbers of T cells capable of producing IL-5 and 2.5-fold greater frequency of IL-4-secreting cells than did normal individuals; GM-CSF- and IFN-gamma-producing T cell numbers were not significantly different in the two groups. IL-3-producing cell frequencies could not be evaluated by this method. There was a direct correlation between IL-4 production and IL-5 production at the level of both protein production and frequency of T cells capable of producing these cytokines. These data indicate that individuals with reactive eosinophilia and elevated serum IgE have an expanded population of lymphocytes producing IL-4 and IL-5 and the association of the two suggests that the regulation of IL-4 and IL-5 may be linked.
CD4-Positive T-Lymphocytes↗
Fibroblast stimulation in schistosomiasis. XII. Identification of CD4+ lymphocytes within schistosomal egg granulomas as a source of an apparently novel fibroblast growth factor (FsF-1).
Granulomas that form around Schistosoma mansoni eggs deposited in the liver secrete a variety of fibrogenic factors that may provide a molecular link between chronic inflammation and hepatic fibrogenesis in schistosomiasis. We recently isolated from conditioned medium of egg granuloma cultures a approximately equal to 60-kDa heparin-binding growth factor for fibroblasts. Because this protein is distinct from other defined heparin-binding growth factors, we designated it "fibroblast stimulating factor-1" (FsF-1). We now report that FsF-1 is a lymphokine. We prepared IgG antibody against purified FsF-1 and determined that it did not cross-react with a variety of growth factors or recombinant interleukins. Using two-color flow cytometry of dissociated granuloma cell suspensions, we observed that approximately 20% to 25% of granuloma CD4+ lymphocytes express surface FsF-1. We isolated CD4+ granuloma lymphocytes by FACS and observed that these cells spontaneously secrete into culture supernatant a fibroblast mitogen that is neutralized by anti-FsF-1 antibody. Furthermore, anti-FsF-1 can specifically immunoprecipitate a metabolically labeled protein produced by the granuloma CD4+ lymphocytes. The labeled protein has the same apparent molecular mass (approximately equal to 60 kDa) as FsF-1 purified from granuloma culture supernatants. These findings define CD4+ lymphocytes as a source of FsF-1. Because FsF-1 has biologic and chemical features distinct from most other defined lymphokines and from other heparin-binding growth factors, FsF-1 appears to be a novel lymphokine.
Animals↗
Guidelines for the performance of CD4+ T-cell determinations in persons with human immunodeficiency virus infection.
This document has been developed by CDC to give guidance to laboratories performing lymphocyte immunophenotyping assays in human immunodeficiency virus-infected persons. The recommendations in this document reflect current technology in a field that is rapidly changing. The recommendations apply to laboratory safety, specimen collection, specimen transport, maintenance of specimen integrity, specimen processing, flow cytometer quality control, sample analyses, data analysis, data storage, data reporting, and quality assurance.
CD4-Positive T-Lymphocytes↗
Helper T cell memory: more questions than answers.
The critical participation of helper T cells in immunologic memory of animals is clear. Features of antigen-specific CD4 memory cells in primed animals that distinguish them from naive cells are their increased frequency, their ability to secrete lymphokines in addition to IL-2 and their expression of distinct arrays of surface molecules. The latter include increased CD44, CD45RO, LFA-3 and VLA-4 and decreased CD45RA,B and Mel-14. These differences in surface markers may contribute to increased interaction potential for APC, and to distinct patterns of recirculation, but direct demonstrations of the former have yet to be provided. Other possible distinctions that are also largely hypothetical, include distinct requirements for activation and the ability to respond more rapidly to stimulation. The factors that regulate the development of memory helper T cells are also unknown.
Animals↗
Progressive changes in CD45RB phenotype and lymphokine production by murine CD4+ T cells after alloantigen exposure.
Changes in CD45R expression correlate with changes in phenotype in mouse, rat and human T cells. It has been shown in mouse that CD45RB high T cells produce mostly interleukin-2 (IL-2) while CD45RB low T cells produce more IL-4 than IL-2 after mitogen stimulation in vitro. CD45RB expression also decreases when T cells are stimulated. In this study we compared responses of CD45RB high and low CD4+ T cells to alloantigens. Although a majority of unstimulated murine T cells from unimmunized mice are CD45RB high, we were able to isolate and purify sufficient numbers of T cells to study their response to alloantigens. When separated cells were stimulated in vitro with alloantigen the CD45RB high T cells became heterogeneous for their expression of CD45RB, indicating that high cells decrease their expression of CD45RB epitopes. Surprisingly, only CD45RB high T cells from unimmunized mice were alloreactive, as measured by proliferation and lymphokine secretion. In contrast, both CD45RB high and low populations from mice primed with allogeneic spleen were responsive to alloantigens. The 'primary' response of T cells from alloantigen-primed mice to third party stimulators is 10-fold greater in the CD45RB high population than in the CD45RB low, as would be predicted by our results in the primary mixed lymphocyte/leucocyte reaction (MLR). Furthermore, the response of CD45RB low T cells from unprimed mice and the response to third party alloantigen from primed mice was reconstituted by the addition of exogenous IL-2. The response of CD45RB low cells from primed mice was specific, as the third party alloresponsive cells were again primarily contained within the CD45RB high population. In the CD45RB high population in the secondary MLR we observed an increase in the production of IL-4 relative to IL-2.
Animals↗
The role of T cells in pathogenesis and protective immunity to murine malaria.
T-cell-mediated immunity to a virulent strain of Plasmodium berghei NK65 (Pb NK65) and to an attenuated derivative (Pb XAT) of the strain were examined in CBA mice by the administration of monoclonal antibodies against T-cell subsets or interferon-gamma (IFN-gamma). The injection of anti-CD8+ or anti-IFN-gamma delayed the mortality of mice infected with Pb NK65, although it did not affect the parasitaemia. In the late stage of PB NK65 infection, T cells, especially CD8+ T cells, were increased in number in the liver at the expense of splenic CD8+ T cells. These CD8+ T cells released IFN-gamma in culture without antigen stimulation and were thought to induce tumour necrosis factor-alpha (TNF-alpha) production by the cells in the liver. In mice infected with Pb XAT, or mice primed with Pb XAT and then challenged with Pb NK65, CD4+ T cells had a crucial role in preventing parasite growth and in protective immunity. IFN-gamma was again the key molecule in protective immunity. These results suggest that T cells stimulated with malaria antigen play important roles both in protective immunity and pathogenesis depending upon their subsets; CD8+ T cells in pathogenesis, and CD4+ T cells in protective immunity. These apparently contradictory responses may be mediated by the same cytokine, IFN-gamma.
Animals↗
IgG subclass responses to Theiler's murine encephalomyelitis virus infection and immunization suggest a dominant role for Th1 cells in susceptible mouse strains.
Inbred mouse strains differ in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. A strong correlation between disease susceptibility and delayed-type hypersensitivity (DTH) has been previously demonstrated, but no strong correlation between disease susceptibility and total anti-TMEV ELISA titres was shown. Since both DTH and IgG2a antibody production are regulated by CD4+ Th1 cells, we investigated three strains of mice to determine whether antivirus IgG2a antibody levels, like DTH in previous studies, correlated with disease susceptibility. Susceptible SJL/J, intermediately susceptible C3H/HeJ, and resistant C57BL/6 mice were infected intracerebrally (i.c.) with the BeAn strain of TMEV and monitored for clinical signs of demyelination and for levels of TMEV-specific antibody of different IgG subclasses using a particle concentration fluorescence immunoassay (PCFIA). Resistant C57BL/6 mice were found to have significantly lower concentrations of total anti-TMEV antibody than susceptible SJL/J mice and intermediately susceptible C3H/HeJ mice show variable antibody responses. A predominance of anti-TMEV IgG2a (Th1 regulated) antibody was seen in susceptible and intermediately susceptible mice, whereas resistant mice displayed a predominant anti-TMEV IgG1 (Th2 regulated) response accompanied by a marked deficiency of IgG2a. In contrast, immunization of C57BL/6 mice with UV-inactivated TMEV in adjuvant revealed that this strain was not defective either in its ability to generate high levels of anti-TMEV antibody or in its ability to produce IgG2a antibody. These results suggest that the antivirus IgG subclass profile is dependent upon the immunization route, virus viability and/or the use of adjuvant and that the levels of antivirus subclasses may be predictive of disease susceptibility.
Animals↗
The relationship of HIV-1 viral sequences detected by the polymerase chain reaction in haemophilic patients to clinical and other markers of infection.
A nested primer polymerase chain reaction (PCR) of pol gene sequences of human immunodeficiency virus-1 (HIV-1) was applied to whole blood of 31 haemophiliacs who were, or had been, positive for HIV p24 antibody (HIVAb) by enzyme linked immunosorbent assay (ELISA) and samples from 22 persistently HIVAb negative haemophiliacs who had been at risk of contracting HIV from treatment. The results were compared with those of p24 HIV antigen determination, T4 cell counts beta 2 Microglobulin (beta 2M) levels and clinical evidence of progression of HIV disease. There was no discrepancy between the PCR results and past or present seropositivity for HIVAb. The qualitative PCR was more sensitive than the p24 antigen assay but the presence of the latter was predictive of progression of infection as determined clinically and by falling T4 cell counts and rising levels of beta 2M. The results of the PCR are reassuring for HIVAb negative haemophiliacs at risk from treatment and to HIVAb negative sexual contacts of HIVAb positive persons.
Adult↗
Herpes simplex virus-1-specific human cytotoxic T lymphocytes are induced in vitro by autologous virus-infected mononuclear cells.
A new technique for in vitro activation of cytotoxic T lymphocytes (CTLs) specific for herpes simplex virus type 1 (HSV-1) is described. Autologous phytohemagglutinin (PHA)-activated, HSV-1-infected peripheral blood mononuclear cells (PBMC) were used, after fixation with 1% paraformaldehyde, to activate virus-specific CTLs in short-term cultures. The same unfixed PBMC were used as target cells in the cytotoxicity assay. By using this technique high levels of HSV-1-specific cytotoxic activity (50.06 +/- 16.76% at 30:1 effector:target ratio) were repeatedly obtained in 24 experiments using PBMC from 16 HSV-1 antibody-positive healthy donors, while no cytotoxic activity was observed using PBMC from 3 HSV-1 antibody-negative donors. HSV-1-induced CTLs were shown to be virus-specific as they did not lyse autologous, PHA-activated PBMC infected with influenza A virus or autologous Epstein-Barr virus (EBV) lymphoblastoid cell line (LCL), while they were able to lyse both HSV-1-infected, autologous PHA-activated PBMC and EBV-LCL. HSV-1-specific cytotoxicity was mediated by T lymphocytes, since depletion of CD3-positive cells from the effector population completely removed the killing of HSV-1-infected target cells. CD8-positive CTLs were primarily involved in the killing of HSV-1-infected targets since depletion of CD8-positive cells caused a strong reduction of virus-specific cytotoxic activity while elimination of CD4-positive lymphocytes increased killing capacity. Finally, this technique has proven to be highly reproducible, easy to perform, and thus suitable for clinical investigations.
Cell Line↗