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Biomedical subjects

G Gras

Publications and source records attributed to G Gras.

At least 19 recordsLinked to original sources
PubMed1998

B cell-driven HIV type 1 expression in T cells: an essential role of CD86 costimulatory molecule.

During HIV-1 infection, HIV-1 is sequestered and actively replicates within lymphoid organs, mainly in areas essential for antigen-specific T-B interactions. We investigated whether cognate T-B interactions not only drive humoral response to HIV-1 but also enhance viral replication. Costimulation of in vitro HIV-1-infected tonsillar T cells with autologous or allogeneic activated B cells increased both viral replication and T cell proliferation. Addition of CD86 MAb to cocultures inhibited most p24 (84 +/- 12%, n = 13) and IL-2 (99 +/- 2%, n = 6) production, decreased T cell proliferation by 46 +/- 15% (n = 13), and decreased TNF-alpha and IFN-gamma production by 67 +/- 17% (n = 6) and 53 +/- 6% (n = 6), respectively. In contrast, CD80 MAb, which strongly inhibited IL-2 production (77 +/- 10%, n = 6), moderately downregulated p24 and TNF-alpha production (29 +/- 21%, n = 13 and 34 +/- 10%, n = 6, respectively) and did not decrease T cell proliferation (8 +/- 10%, n = 13) or IFN-gamma production (14 +/- 13%, n = 6). We thus showed that B cells deliver a potent CD86/CD28 costimulatory signal that induces T cell proliferation and simultaneously enhances HIV-1 replication. CD86+ B cells, mainly localized within the light zone of germinal centers, might thus favor active in situ replication of HIV-1 in response to each new challenge by T-dependent antigens.

Antigens, CD↗
PubMed1998

CD80 expression is decreased in hyperplastic lymph nodes of HIV+ patients.

A centrofollicular hyperplasia is present within secondary lymphoid organs during all the asymptomatic phase of the HIV disease. Although this hyperplasia has been well characterized by histological studies, the nature of the phenotypic alterations in B cell populations occurring within HIV+ lymphoid organs remains to be established. By immunohistochemistry, we thus investigated whether a particular germinal center (GC) B cell population was increased during HIV-induced hyperplasia and whether any phenotypic change was specific to HIV-1 infection. As compared to normal tonsils (three cases) and HIV- hyperplastic lymph nodes (eight patients), we observed a loss of GC polarization in all HIV+ sections (11 patients), with no more delineation between dark and light zones, as shown by Ki67, CD10, CD77, CD95 and CD86 staining. In contrast to CD86 expression which remained as intensive in HIV+ as in HIV- lymph nodes, CD80 staining was strongly decreased in GC of HIV+ lymph nodes but not in their extrafollicular zones. The loss of CD80 expression from CD19+ B cells was also observed by cytometric analysis of cell suspensions of three HIV+ patients. Although we found no evidence of an increase in a particular GC B cell subset in HIV-1-induced hyperplasia, the strong GC disorganization observed may induce impaired cell-cell interactions and thus participate in the loss of CD80 antigen. In contrast to HIV- situations where CD80 and CD86 was similarly expressed on B cells, the lower level of CD80 expression in HIV+ GC may favor Th2 T cell responses through CD86-CD28 interactions.

Adult↗
PubMed1998

Neutralizing antibodies and complement-mediated, antibody-dependent enhancement (C'-ADE) of human immunodeficiency virus infection in its vertical transmission.

PROBLEM: Mother-to-child transmission is a major route for the spread of human immunodeficiency virus (HIV) worldwide. Our understanding of its mechanisms and parameters is still limited. Among the factors possibly involved in virus passage determination are the level and quality of antiviral humoral response. METHOD OF STUDY: Anti-HIV-1/Lai neutralizing activity in sera from 35 mother-infant pairs (in which 13 transmission cases occurred) was investigated, as was the complement-mediated antibody-dependent enhancement capacity of the same sera. RESULTS: Neutralization titers of 640 or more were found only in four mothers of uninfected children, but this result was not significant. No significant link was obtained with the occurrence of complement-mediated, antibody-dependent enhancement. CONCLUSIONS: As suggested by a synthesis of the literature, vertical transmission of HIV is probably the result of multiple active and/or stochastic parameters in the mother, the fetal structures, and the viral population. The precise definition of cellular mechanisms involved in in utero infection would help to better define which immune activity in the mother should be more carefully considered.

Cohort Studies↗
PubMed1997

Consequences of gamma-irradiation on inflammatory cytokine regulation in human monocytes/macrophages.

Inflammation is a frequent result of radiation damage, especially after therapeutic irradiation. Monocytes and macrophages play an important role in inflammatory cytokine secretion. However, knowledge of monocyte/ macrophage involvement in the pathogenesis of inflammation is still incomplete. In this study, we investigated the inflammatory cytokine regulation after in vitro gamma-irradiation of monocytes/macrophages. Semiquantitative RT-PCR after irradiation revealed no significant induction of interleukin 1 beta or tumour necrosis factor-alpha mRNA expression. When induction was observed, for only two donors out of seven, only interleukin 6 gene expression was affected by irradiation, with a 5-14-fold increase in level according to the donor, 2h after irradiation compared with sham-irradiated cells. For only one of seven donors tested, monocytes/macrophages responded to 10-Gy gamma-rays by releasing inflammatory cytokines.

Cell Separation↗
PubMed1997

Modulations of cytokine expression in pregnant women.

PROBLEM: Although the overall anti-infectious and anti-parasitic immunity of parous women appears normal, several aspects of maternal cell-mediated and humoral immunity are altered during pregnancy. This has been suggested to occur via preferential local and systemic secretion of Th-2 type cytokines, which down-regulate or prevent secretion/action of Th-1 type cytokines, in animals as well as in humans. METHOD: To evaluate the influence of gestation on the maternal immune system, we have measured, in pregnant women, the mRNAs coding for several cytokines (TNF alpha, IFN gamma, GM-CSF, IL-1 beta, IL-2, IL-4, IL-6, and IL-10) in peripheral blood mononuclear cells, by use of semi-quantitative RT-PCR. RESULTS: Our results show significant modulations of IFN gamma, IL-1 beta, IL-4, and IL-6 genes expression especially during the third trimester and near parturition. CONCLUSION: Cytokine expression is thus finely tuned in peripheral blood during pregnancy, in a previously unexpected complex pattern, related to gestational stage.

Cohort Studies↗
PubMed1997

Immune suppression and Th1/Th2 balance in pregnancy revisited: a (very) personal tribute to Tom Wegmann.

PROBLEM: The paradigm of local suppression necessary to understand the survival of the fetal allograft is often compared with the host-tumor relationship. METHODS: We investigated two components of local immune suppression: placenta-induced immunosuppression, which is mediated at least in part by a soluble factor of low molecular weight that can induce anergy in lymphocytes, and interleukin-10 (IL-10). RESULTS: We show that enhancement of IL-10 production in the decidua and placenta after alloimmunization requires the presence of Asialo GM1+ cells. Placenta-induced immunosuppression is linked with defects in phosphorylation of some components of the T cell receptor. CONCLUSION: NK cells could be in fact regulatory cells pushing maternal immune response toward a Th2 profile, beneficial for fetal survival, or toward a Th1 type of immune response, which acts in synergy. Modulation of TcR may represent a new mechanism for maternal-fetal tolerance.

Animals↗
PubMed1996

CD40/CD40L interactions and cytokines regulate HIV replication in B cells in vitro.

Using our in vitro model of normal B cell infection, we investigated whether cellular interactions and/or cytokines directing the B cell response also regulate HIV replication. Phorbol esters and CD40 Ab plus IL4, added prior to infection, substantially increased subsequent viral replication. Postinfection, IL2 with or without IL4 and, to a lesser extent, CD40/CD40L interactions enhanced viral replication. In contrast, IL10 down-regulated HIV replication induced by cytokines, without affecting spontaneous or CD40 Ab-induced replication. Both enhancing and inhibitory effects of cytokines on viral replication were independent of their ability to modulate B cell proliferation. Thus, these two phenomena seem to be independently regulated in human B cells.

Animals↗
PubMed1996

Mechanisms of opsonized HIV entry in normal B lymphocytes.

Using our in vitro model of normal B cell infection that functions with low doses of HIV but requires virus opsonization by seropositive patient serum, and complement, we analyzed what receptors allowed virus entry. Here, we show that HIV infection of B cells occurs through 2 major receptors: the CD4 antigen and the CR1/CR2 complex. These 2 pathways work independently since a complete inhibition of virus entry requires both CD4 and CD21/CD35 blockade on CD4dim tonsillar B cells whereas only the latter is critical on CD4-negative B cells.

Antibodies, Monoclonal↗
PubMed1996

Anti-HIV potential of a new interferon, interferon-tau (trophoblastin).

Antiretroviral effects of a new class of interferon (IFN), IFN-tau, were compared with those of IFN-alpha in primary peripheral blood lymphocytes (PBLs) and monocyte-derived macrophages (MDMs), infected in vitro by human immunodeficiency viruses type 1, HIV-1/LAI, and HIV-1/DAS isolates, respectively. Cells were treated with recombinant IFN 24 h before or after HIV infection and then continuously exposed. Viral replication was monitored twice a week by quantifying the reverse transcriptase activity in cell culture supernatants. Integrated proviral DNA was monitored 24 h after infection in IFN-tau-pretreated MDMs, using specific gag gene amplification by the polymerase chain reaction. IFN-tau inhibited HIV-1 replication in both PBLs and MDMs as well as in peripheral blood mononuclear cells (PBMCs). IFN-tau was 35-fold more potent than IFN-alpha in PBLs and 100-fold more potent in MDMs. Differences were observed in the amount of integrated proviral DNA between untreated and 10 IU/ml IFN-tau-treated HIV-infected MDMs. IFN-tau exhibits significant anti-HIV activity in comparison to IFN-alpha, and like other IFNs, it seems to interact with several steps of HIV replication cycle.

Antiviral Agents↗
PubMed1996

Cytokine response of B lymphocytes from splenic lymphoma with villous lymphocytes: correlation with TNF-RII (p75) and CD11c expression.

We studied the immunophenotype and the functional reactivity to cytokines of blood cells from eight patients with Splenic Lymphoma with Villous Lymphocytes (SLVL). Cells from all cases exhibited moderate to high levels of membrane immunoglobulin, CD22 and CD40 antigens and light chain restriction (kappa/lambda: 1.7/1). CD44, CD54 and CD11b expression was detected in all cases whereas CD11c was expressed in only four cases (50%). CD11c+ cells lacked CD21 and CD23 expression whereas CD11c cells expressed both these antigens. Cells from most patients (7/8) responded to IL2 whereas only four responded to IL4 and three to TNF alpha. The response to TNF alpha correlated with spontaneous TNF-RII and CD11c expression. Although two days of culture induced the TNF-RII expression in CD11c cells, they remained unresponsive to TNF alpha. These two groups of SLVL patients also differed by IL10 mRNA content: the former (CD11c+, TNF-RII+) contained TNF alpha and IL10 mRNA whereas the latter (CD11c, TNF-RII) lacked IL10 mRNA, even after two days of culture. There were thus two groups of SLVL patients: CD11c+ and CD11c, exhibiting different patterns of cytokine response and production. These groups may correspond to different cell origins or different progression stages of the disease.

Aged↗
PubMed1995

Clearance of HIV infection in 12 perinatally infected children: clinical, virological and immunological data.

OBJECTIVE: A case of HIV infection clearance in a perinatally infected infant has been recently reported. We report here on the molecular, biological and clinical features of such virus clearance in 12 children. DESIGN AND METHODS: We performed a retrospective analysis of the diagnosis in our 6-year cohort of 188 children born to HIV-seropositive mothers. HIV-1 was detected by coculture of infant peripheral blood mononuclear cells (PBMC) with cord blood cells, direct culture of infant cells, and DNA polymerase chain reaction (PCR). The children were diagnosed three times during the first 3 months of life and then followed up over a postnatal period of 18-36 months. RESULTS: The 12 reverted children had at least two positive PCR in at least two amplified regions. Among them, six were tested positive in culture/coculture assay, and five were treated long-term with zidovudine. Thus, seven out of 12 reversions cannot be attributed to antiretroviral therapy. All the virological results became negative during the first year of life, and serology lowered to negative values between 9 and 23 months. We could not find any correlation between either neutralizing or antibody-dependent cellular cytotoxicity-mediating antibodies and HIV clearance. CONCLUSION: In our cohort, we showed that an unexpected number of children born to HIV-seropositive mothers (6.7%) cleared HIV infection during the first year of life, and subsequently became seronegative. Interestingly, most of these children exhibited unspecified clinical signs during the first months of life. Five of these children were tested positive only by PCR, which suggests a low virus load and could, at least partly, explain spontaneous clearance. However, 4 years later, among the seven remaining infants, two seronegative children presented recurrent hepatosplenomegaly, which may indicate the presence of hidden virus not detectable by peripheral blood testing.

CD4-CD8 Ratio↗
PubMed1994

Induction of humoral and cellular immunity to simian immunodeficiency virus: what are the requirements for protection?

In an effort to produce a strong humoral and cellular immune response that might protect against simian immunodeficiency virus (SIV) infection, groups of five rhesus macaques each were immunized intramuscularly at 0, 2 and 6 months with 100 micrograms of an inactivated preparation of SIV/Delta B670 in either an oil-in-water emulsion with Ribi Detox, containing mycobacterial cell wall skeleton and monophosphoryl lipid A (CWS/MPL) (group A) or a water-in-oil emulsion with incomplete Freund's adjuvant, containing CWS/MPL for the first two injections (group B). Animals were challenged with 10-100 monkey ID50 of monkey-cell-grown SIVmac251 3 months after the last injection, along with a group of four unvaccinated controls. Group B animals demonstrated the strongest immune responses following immunization, including neutralizing antibody titres against the challenge virus ranging from 160 to 320 and SIV-specific ELISA titres ranging from 10(5)-10(6) on the day of challenge, as well as strong in vitro lymphoproliferative and interleukin-2 (IL-2) production responses to the immunogen. Neutralizing antibody was not detectable in group A animals, ELISA titres were lower (10(2)-10(4)), no in vitro lymphoproliferative responses were observed, and in vitro IL-2 production was less pronounced. No protection against challenge was observed in either group. Moreover, group B animals exhibited a more pronounced clinical response following challenge than either group A animals or controls, consisting of hyperthermia and a greater degree of lymphadenopathy on day 7, followed by hypothermia and generally higher levels of serum viraemia on day 14.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Antibody-dependent cellular cytotoxicity and neutralization of human immunodeficiency virus type 1 by high affinity cross-linking of gp41 to human macrophage Fc IgG receptor using bispecific antibody.

Human monocytes/macrophages, which express Fc receptors for IgG are involved in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis. These receptors are known to mediate numerous immunological functions including cell-mediated killing and possibly targeting of HIV to the lysophagosome monocyte-derived macrophage (MDM) entry route for virus neutralization. To study both activities in HIV-1 infection, MDM Fc gamma RI was specifically selected using bispecific antibody (Bs-Ab) containing whole human monoclonal antibody against gp41 and the Fab' fragment of murine anti-Fc gamma RI 22.2 antibody. Bs-Ab was found to mediate potent antibody-dependent cellular cytotoxicity and virus neutralization.

Antibodies, Bispecific↗
PubMed1993

Complement and virus-specific antibody-dependent infection of normal B lymphocytes by human immunodeficiency virus type 1.

We tested the susceptibility of human purified, normal B lymphocytes to human immunodeficiency virus type 1 (HIV-1) infection, in the presence or absence of complement-sufficient serum and of virus-specific antibodies. Virus replication was detected when cells were infected in the presence of both complement and anti-HIV antibodies (C'-ADE conditions), by day 2 postinfection. Similar results were obtained when B lymphocytes were purified either from peripheral blood (three healthy donors) or from tonsils (four individuals with chronic tonsillitis). HIV infection was shown by polymerase chain reaction (PCR) detection of proviral sequences (gag and pol genes), by p24 antigen synthesis, and by cocultivation assay with MT2 cells. The higher p24 production was obtained when B cells were preactivated for 2 days by phorbol 12-myristate 13-acetate (PMA) before infection and then cultured in the presence of low-molecular weight B-cell growth factor (LMW-BCGF). Expression of virus envelope glycoprotein (gp) 120 could also be detected on a subpopulation of B cells (CD19+, CD22+) by flow cytometry. Blocking experiments with monoclonal antibodies (MoAbs) against CD4, CD21 (complement receptor 2 [CR2]), CD35 (CR1), CD19, and CD5 surface molecules indicated that infection of B cells involves CD4, CD21, and CD35 antigens. Indeed, blocking of CD4 receptor inhibited 10% of p24 production, and blocking of both CD21 and CD35 led to extinction of p24 signal. CR-dependent pathway is thus a major route for C'-ADE of HIV infection in normal B cells. Our results emphasize the importance of studying interactions between HIV and the complement system for better understanding infection mechanisms and the major dysfunctions of B cells in HIV-infected individuals.

B-Lymphocytes↗
PubMed1993

In vitro infection of human macrophages with human T-cell leukemia virus type 1.

The tropism of the human T-cell leukemia virus type 1 (HTLV-1) for the cells of monocyte-macrophage lineage was evaluated by the coculture of blood monocyte-derived macrophages, with irradiated cells of HTLV-1 producing cell lines MT2 or C91/PL. The susceptibility to HTLV-1 was assessed by the detection of viral DNA using the polymerase chain reaction method. HTLV-1 gene expression in the cells was detected using in situ hybridization and by immunofluorescent staining of viral antigen. The presence of type C virus-like particles detected by electron microscopy and the ability to infect normal cord blood lymphocytes demonstrated that the infected macrophages produced infectious virus. These results indicate that human macrophages are susceptible in vitro to productive HTLV-1 infection, and thus might be involved in the pathogenesis of HTLV-1-related diseases.

Cells, Cultured↗