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Biomedical subjects

A Venet

Publications and source records attributed to A Venet.

At least 37 records · Page 2Linked to original sources
PubMed1994

Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections.

We have proposed that inappropriate induction of programmed cell death (PCD) or apoptosis, a physiological cell-suicide process, may play a role in the pathogenesis of AIDS. This model has been supported by several reports of abnormal levels of PCD in vitro in both CD4+ and CD8+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected persons. To further assess the significance of such a process in AIDS pathogenesis, in vitro PCD was compared in HIV-1-infected persons and in various primate models that allow discrimination between pathogenic chronic lentiviral infection either in the same species, such as rhesus macaques infected with different simian immunodeficiency viruses (SIV), or in different species, such as SIV-infected African green monkeys and HIV-1-infected chimpanzees. Abnormal levels of PCD in CD4(+)-T-cell-depleted peripheral blood mononuclear cells (PBMC), containing the CD8+ T cells, were observed in both pathogenic and nonpathogenic models. However, abnormal levels of PCD in the CD8(+)-T-cell-depleted PBMC, containing the CD4+ T cells, was only observed in the two models leading to AIDS: HIV-1-infected persons and rhesus macaques infected with a pathogenic strain of SIV. This suggests that inappropriate T-cell PCD in HIV-1-infected persons involves two distinct processes: one, concerning CD4+ T cells, is closely related to AIDS pathogenesis; and the other, concerning CD8+ T cells, may be a consequence of immune stimulation with no direct link to AIDS pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Simian immunodeficiency virus as a model for vaccination against HIV. Induction in rhesus macaques of GAG- or NEF-specific cytotoxic T lymphocytes by lipopeptides.

The protection against infection by HIV probably requires the induction of both neutralizing Abs and CTL responses. Vaccination by attenuated HIV is hardly acceptable and the use of viral genes inserted in recombinant living vectors needs further development, especially with respect to safety. The peptidic vaccination is a promising approach but free peptides are usually poorly immunogenic. Because potent immune responses have been obtained in mice with modified peptides such as lipopeptides, we have designed a study to assess the immunogenicity of lipopeptides in nonhuman primates. Seven lipopeptides were synthesized, derived from known immunogenic regions of the simian immunodeficiency virus (SIV) NEF and GAG proteins. Twelve rhesus macaques, randomly chosen and not selected on their MHC basis, were immunized subcutaneously with the seven lipopeptides in IFA. An MHC class I-restricted and CD(8+)-mediated CTL response has been observed in seven macaques directed against one or two of the synthetic immunizing peptides in each case. These CTLs were able to lyse autologous target cells infected with a recombinant vaccinia virus expressing the SIV nef or gag genes, suggesting that they recognized the naturally processed peptides. These activities are detectable in peripheral blood cells for at least 10 mo after the last immunization. Abs against the immunizing peptides have also been observed in all cases. This study demonstrates that lipopeptides can generate cytotoxic and humoral immune responses in a large number of unselected animals and this approach may thus be worth considering in the vaccination against HIV.

AIDS Vaccines↗
PubMed1993

Characterization of B-cell epitopes in the envelope glycoproteins of simian immunodeficiency virus.

We identified previously a neutralizing epitope in the V2 domain of the simian immunodeficiency virus (SIVmac) external envelope protein. The present study reports identification of five additional linear epitopes of SIVmac (isolate 251) by immunological screening of a peptide library expressed in yeast, using SIVmac-infected macaque sera. Three epitopes were localized in the envelope glycoproteins and the two others in the reverse transcriptase and in the Rev regulatory protein. Antibody response against the four envelope epitopes was monitored for 2 years in 12 macaques experimentally infected by SIVmac251. These four envelope regions represent major immunodominant epitopes of the SIVmac. Two epitopes are located in the V3 domain (a.a. 311-330) of the external gp130 and near the amino terminal part (a.a. 601-619) of the transmembrane gp36, in regions similar to those identified in HIVs, demonstrating immunological similarities between the envelopes of SIVs and HIVs. SIV-specific immunodominant epitopes were also identified in the V1 (a.a. 111-130) and V2 (a.a. 171-190) domains of the external gp130. In particular, antibody response against the V2 neutralizing region seems to play some role in the control of disease progression in SIVmac-infected macaques.

Amino Acid Sequence↗
PubMed1993

Cytotoxic T-cell response and AIDS-free survival in simian immunodeficiency virus-infected macaques.

OBJECTIVES: To determine whether cytotoxic T lymphocytes have a beneficial effect during infection with the simian immunodeficiency virus (SIV) in macaques. DESIGN AND METHODS: We followed up 12 rhesus macaques experimentally infected with SIV. Cytotoxic T lymphocytes were detected in nine macaques, who were subdivided into a group of high responders (n = 6), with a sustained and polymorphic response directed against most SIV proteins, and a second group of weak responders (n = 3), in which the responses were only transient and directed against only a few proteins. A third group was characterized by the absence of any cytotoxic T-lymphocyte response (n = 3). Proliferative responses closely paralleled cytotoxic responses in intensity and evolution. RESULTS: Clinical profiles and CD4 cell counts were markedly linked to cytotoxic activity; five out of six macaques that responded to multiple proteins were still healthy 2 years after SIV infection, with two of them presenting a decrease in circulating CD4 cells concomitant with the disappearance of the cytotoxic T-lymphocyte response. Conversely, five non-responder or weak-responder macaques developed overt disease after 4-21 months. CONCLUSIONS: These data suggest that a cytotoxic response may predict a better clinical outcome.

Animals↗
PubMed1992

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↗
PubMed1992

Three epitopic peptides of the simian immunodeficiency virus Nef protein recognized by macaque cytolytic T lymphocytes.

In 8 of 12 experimentally infected macaques, the Nef SIVmac 251 protein was recognized by cytolytic T lymphocytes (CTL) and appeared strongly immunogenic. Here, we report experiments which have been performed by using synthetic peptides to precisely determine the epitopes recognized by macaque CTL. Three epitopes of the Nef protein have been defined as CTL targets in three macaques. The epitopic peptides are located in the central region of the protein, and all of them show high homology with peptides of the human immunodeficiency virus type 1 Nef protein recognized by human CTL in association with several human leukocyte antigen molecules. These results suggest that (i) the Nef protein is a good candidate for vaccination not only because of its early expression but also because of its high immunogenicity for CTL, (ii) long peptides covering the central region of this protein could be used as vaccines and could cross the major histocompatibility complex barrier in a large variety of individuals, and (iii) the rhesus macaque is a good animal model in which to test for protection by CTL.

Amino Acid Sequence↗
PubMed1991

Correlation between CD4 cell counts and cellular and plasma viral load in HIV-1-seropositive individuals.

We conducted a study of 152 HIV-1-seropositive individuals in order to evaluate the possible correlations between the isolation of HIV from peripheral blood mononuclear cells or from plasma and CD4 cell counts. HIV was isolated from only 36% of plasma samples, and the isolation rate was closely related to CD4 cell counts, increasing gradually from 0% in subjects with greater than 800 x 10(6)/l CD4 cells to 88% in those with less than 100 x 10(6)/l CD4 cells. In contrast, HIV was isolated from 92% of cell samples (99% in subjects with less than 900 x 10(6)/l CD4 cells, 46% in those with CD4 counts greater than or equal to 900 x 10(6)/l). Since most cell samples were positive, a scoring method was designed to quantify the cellular viral load. The results obtained demonstrated that the cellular viral load was closely related to CD4 counts. We also found that the cellular viral load was higher in subjects with either positive plasma isolation or positive p24 antigenaemia. The measurement of the cellular viral load by this scoring method appears to be useful for the management of HIV-seropositive individuals and for the evaluation of therapeutic trials.

CD4 Antigens↗
PubMed1991

HIV isolation from pulmonary cells derived from bronchoalveolar lavage.

In a study of 75 alveolar cell co-cultures from 55 HIV-seropositive subjects, p24 antigen production was identified by ELISA in 11 out of 26 (42%) of unseparated cell cultures, 15 out of 39 (38%) purified alveolar macrophage cultures and eight out of 10 purified alveolar lymphocyte samples. Positivity in unseparated cell cultures was associated with an alveolar lymphocytosis greater than 30%. Negative macrophage cultures were significantly more likely in the early stages of HIV infection with none positive when the subject had a peripheral CD4+ cell count greater than 300/microliters. Alveolar macrophage infection thus appears to increase with HIV disease progression.

Bronchoalveolar Lavage Fluid↗
PubMed1990

Actuarial rate of clinical and biological progression in a cohort of 250 HIV-1-seropositive subjects. Laennec HIV Study Group.

This study was undertaken to define the risk of AIDS in a cohort of 250 HIV-seropositive patients identified by their clinical and biological status. All patients were enrolled between October 1985 and March 1988. They were classified according to clinical classes A, asymptomatic (n = 97); B, lymphadenopathic (n = 123); and C, AIDS-related complex, (n = 30). Also as CD4 cell stages 1 (CD4 greater than or equal to 600/microliters; n = 126); 2 (CD4 less than 600 and greater than or equal to 300/microliters; n = 83); and 3 (CD4 less than 300/microliters; n = 41); and serum p24 antigen positive (n = 48) or negative (n = 202). All patients were evaluated every 3-6 months, until AIDS development or April 1989: 29 cases of AIDS occurred during the follow-up period. The risk of AIDS in class C is very high (64% at 2 years) compared with the 3-year risk of classes A (13%) and B (25%). On the other hand the three CD4 stages have significantly different prognosis (stage 1 6%; stage 2 22%; and stage 3 89%; P less than 10(-2]. Antigen p24 negative and positive patients have also different prognosis (18% and 53%; P less than 10(-4]. Interestingly, p24 antigen conserved its prognostic value in stage 2 (positive 37%, negative 16%) while stages 1 are at low risk of AIDS and stages 3 at high risk whatever their p24 antigen status. We have also identified the risk of becoming stage 3 and/or p24 antigen positive in p24 antigen negative patients at stages 1 and 2 (respectively, 18% and 47%). This classification should serve to design randomized trials better with experimental drugs with earlier end-points than AIDS onset.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Autoreactive cytotoxicity in HIV-infected individuals.

A possible role for autoimmunity in the pathogenesis of HIV infection has been suggested, based upon the certain degree of homology shared by HIV gp41 and MHC class II molecules. A number of humoral markers of autoimmunity have since been found in seropositive subjects. We have evaluated the cellular autoreactive response in HIV-infected individuals. Our study demonstrates the existence of a cytolytic activity, present in seropositive but not in seronegative subjects. This activity is mediated by CD3+ T cells, which only occasionally express the CD8 or the CD4 surface markers. Effector cells do not appear to exert their activity in a MHC-restricted fashion, since allogeneic target cells could also be killed, recovered from allogeneic seropositive as well as from seronegative subjects. Several types of target cells were lysed: T cell blasts and Epstein-Barr virus (EBV) transformed B cells, suggesting that the target antigen is common to at least these two cell types. The fact that cells from seronegative individuals were lysed argues against the recognition of an HIV-specific antigen. The nature of the target determinants and the identity of the effector cells are discussed.

Antigens, CD↗
PubMed1988

Bronchoalveolar lymphocytosis in patients with tropical spastic paraparesis associated with human T-cell lymphotropic virus type 1 (HTLV-1). Clinical, immunologic, and cytologic studies.

STUDY OBJECTIVE: To determine the features of pulmonary involvement in patients with tropical spastic paraparesis associated with human T-cell lymphotropic virus type 1. DESIGN: Nonrandomized prospective case series. SETTING: Tertiary care units in two university medical centers. PATIENTS: Consecutive sample of 21 patients with tropical spastic paraparesis associated with human T-cell lymphotropic virus type 1 infection. INTERVENTIONS: Chest roentgenogram and bronchoalveolar lavage were done in all patients. Fifteen patients had pulmonary function tests. Alveolar T-lymphocyte subsets were analysed in 10 patients and thoracic computed tomographic scans were done in 10 patients. MEASUREMENTS AND MAIN RESULTS: All patients were free of clinical pulmonary symptoms and had normal chest roentgenograms. Thoracic computed tomographic scans were normal in 9 of 10 patients and showed mild interstitial pneumonitis in 1. Pulmonary function tests were within the normal range in 13 patients and showed a mild restrictive syndrome in 2. Eighteen patients had increased absolute numbers of alveolar lymphocytes (mean, 77 +/- 39 X 10(3) lymphocytes/mL; range, 13.5 X 10(3) to 259 X 10(3) lymphocytes/mL). Sixteen patients had percentages of alveolar lymphocytes higher than 20% of all alveolar cells (mean, 33.5 +/- 12.7; range, 9 to 69). In all 10 patients tested, 64.2% +/- 13.2% of alveolar lymphocytes were CD8+ cells. CONCLUSIONS: Excessive absolute numbers and percentages of alveolar lymphocytes were observed in 18 and 16 patients, respectively. Most alveolar lymphocytes were CD8+ cells.

Adult↗
PubMed1988

Effects of cyclosporin on T-cell subsets in human immunodeficiency virus disease.

Cyclosporin (7.5 mg/kg daily) was given to 8 AIDS patients for 17-66 days and to 25 HIV-seropositive non-AIDS patients, 15 with stage II (T4 cells/microliter greater than or equal to 300, less than 600) and 10 with stage III (T4/microliter less than 300), for 3-6 months with the hypothesis that the drug could inhibit both HIV replication and the potential autoimmune component of HIV disease. A sustained increase over 600 T4/microliter occurred in 7 patients with stage II and 1 with stage III. T8 cells significantly decreased in most patients and lymphadenopathy disappeared in 14/16. After cyclosporin withdrawal T4 and T8 cells as well as lymphadenopathy returned to pretreatment status. Cyclosporin side effects (hypertension, creatinine increase, and anemia) were moderate and reversible. These results might stimulate biological research as well as clinical trials with cyclosporin in selected groups of HIV-seropositive subjects with the aim of delaying or preventing AIDS occurrence.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Serum suppressive activity of HIV seropositive patients.

The mechanisms by which HIV induces immunosuppression are still poorly understood so far. Several pathways of CD4 cell destruction are known, including cytolysis with or without syncitium formation and killing by cytotoxic effectors of HIV infected or non-infected CD4 cells. However, a discrepancy exists between the small number of actually infected cells in vivo and the extent of HIV-related immunodeficiency. Among other possible immunosuppressive factors, serum blocking factors have been reported, but only in AIDS-related opportunistic infections (OI), i.e. in a quite specific type of full-blown HIV disease. The purpose of this work was to determine whether serum blocking activity was unique to this group of patients, or if it was also expressed in other clinical presentations and, moreover, at earlier stages of the disease. We also attempted to delineate the nature of these seric factors. In order to do so, we assessed serum suppressive activity of 50 HIV seropositive patients, seven with OI, eight with Kaposi's sarcoma (KS), and 35 with no clinical AIDS. Our results confirm the existence of serum inhibiting factors in AIDS, and demonstrate their presence at earlier stages of the disease. They also highlight the fact that the level of serum suppression does not correlate with patients clinical status, but increases with the severity of the disease. The lower the CD4 count, the higher the suppression exerted. Furthermore, we showed that the suppression was at least partly mediated by small size molecules, which are not complement-mediated or directly lymphocytotoxic. On the other hand, this activity does not correlate with the serum level of p24 HIV core protein. The possible relation with other viral components is discussed. The relevance of these data to prognosis and pathogenesis of HIV disease deserves further investigation.

Acquired Immunodeficiency Syndrome↗
PubMed1988

[Broncho-alveolar lavage in pulmonary involvement in rheumatoid arthritis].

This study was designed to investigate by bronchoalveolar lavage (BAL) the characteristics of lung involvement in rheumatoid arthritis (RA). Twenty six patients with RA were included; ten were active smokers. Chest X Ray, pulmonary function tests and BAL were performed in all patients. Bronchiolitis was found in 7% of cases, pleurisy in 30% of cases. 83% of patients were found to have diffuse alveolar and/or interstitial disease, 17% rheumatoid nodules. Functional evaluation showed a restrictive pattern and a significant reduction in the carbon monoxyde diffusing capacity. Smokers had elevated BAL macrophages and decreased lymphocytes compared with non-smokers: respectively 89% vs 62.9% and 7.3% vs 18.9%. Patients with bronchiolitis had lower FVC than others: 38 +/- 14% vs 61 +/- 3%, and their BAL neutrophils were increased: 71 +/- 23% vs 7.5 +/- 2%. There was an inverse correlation between neutrophil counts and FVC in non-smokers, and diffusing capacity. We conclude that BAL inflammatory cells profiles are abnormal in RA and modified by a smoking history and the existence of a bronchiolitis.

Arthritis, Rheumatoid↗