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Biomedical subjects

G Pantaleo

Publications and source records attributed to G Pantaleo.

At least 55 records · Page 3Linked to original sources
PubMed1997

Studies on lymphoid tissue from HIV-infected individuals: implications for the design of therapeutic strategies.

Lymphoid tissue is a major reservoir of human immunodeficiency virus (HIV) infection in vivo. In addition, the lymphoid microenvironment provides a replicative advantage to the virus in that it provides a milieu of activated target cells that allows for efficient virus spread. The process of mobilization and activation of immune competent cells directed against the virus paradoxically contributes to the propagation of virus replication. Disruption of the lymphoid microenvironment during the progression of HIV disease is a poorly understood process, which may be of considerable importance pathogenically. Studies of lymph node biopsy samples taken 8 weeks apart from individuals who did not undergo any change in their therapeutic regimen (i.e., patients who either remained untreated or remained on their ongoing nucleoside analogue reverse transcriptase inhibitor monotherapy regimen) revealed little change in histopathology or viral load over the 8-week period. These results with successive lymph node biopsy samples taken from different sites indicate that an isolated lymph node biopsy accurately reflects the pathologic process associated with HIV infection and that this process diffusely involves the lymphoid system. Treatment with reverse transcriptase inhibitor monotherapy of patients in relatively early stage HIV disease had no detectable impact on the viral load in lymphoid tissue, suggesting the need to investigate more potent antiretroviral regimens during this stage of disease. Among patients with moderately advanced HIV disease, switching to combination therapy from a monotherapy regimen resulted in decreased viral replication in lymph nodes; this effect was associated with decreases in plasma viremia. Despite the fact that measures of viral replication decreased significantly, the net frequency of HIV-infected cells in peripheral blood and lymph nodes remained unchanged. Potent antiretroviral drug combinations may be capable of profound and long-term downregulation of plasma viremia. It will be essential to monitor the status of viral trapping, viral burden, and viral replication within lymphoid tissue during treatment with such drugs to determine accurately their true potential for impact on these key features of HIV pathogenesis.

Anti-HIV Agents↗
PubMed1997

Activated cytotoxic lymphocytes in lymph nodes from human immunodeficiency virus (HIV) 1-infected patients: a light and electronmicroscopic study.

Persistent generalized lymphadenopathy often develops during HIV-infection. It is characterized by follicular hyperplasia which progresses over time to follicular involution and finally lymphocyte depletion. To determine whether activated cytotoxic T cells (CD8+) are present in the hyperplastic germinal centres, light and electronmicroscopic immunogold labelling with monoclonal antibodies were used to localize two cytotoxic molecules, perforin and TIA-1. Perforin and TIA-1-positive cells were detected in the follicles and paracortex of lymph nodes from HIV-infected patients, whereas labelling was seen only in cells of the paracortex in the hyperplastic lymph nodes from HIV-negative patients. Cytotoxic granules, staining positive for perforin and TIA-1, were identified by transmission electronmicroscopy, often in proximity to follicular dendritic cells within the hyperplastic germinal centres of only HIV-positive patients. These cytotoxic cells may play a role in the follicular dendritic cell loss and concomitant follicular involution that occur during the evolution of HIV disease.

Adult↗
PubMed1997

Cyclosporin A modulation of early virologic and immunologic events during primary simian immunodeficiency virus infection in rhesus monkeys.

Virologic and immunologic effects of immunomodulation during primary simian immunodeficiency virus (SIV) infection were examined in monkeys treated with cyclosporin or vehicle for 32 days beginning 5 days before SIV inoculation. Duration of antigenemia decreased in 5 of 7 treated monkeys, 2 having delayed onset and peak of antigenemia. Although proviral DNA levels in blood and lymph nodes and infected cell numbers in lymph nodes were transiently decreased, levels were similar to those in controls by day 14. The CD4:CD8 ratio and percentage of CD4+ CD29+ cells decreased in controls 14 days after inoculation, but this decrease was delayed in treated monkeys. Two treated monkeys demonstrated rapid disease, with progressive antigenemia preceding early deaths 90-96 days after inoculation. Nevertheless, immunomodulation influenced the kinetics of primary SIV infection in some monkeys, supporting the rationale of careful exploration of the strategy of interference with the heightened state of cellular activation together with direct antiretroviral therapy in human immunodeficiency virus infection.

Animals↗
PubMed1997

Neutralizing antibody responses to human immunodeficiency virus type 1 in primary infection and long-term-nonprogressive infection.

The role of neutralizing antibodies in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood and was assessed by evaluating responses at different stages of infection. Undiluted sera from long-term nonprogressors (LTNP) had broad neutralizing antibodies against heterologous primary isolates and were more likely to neutralize the contemporaneous autologous isolate than were sera from short-term nonprogressors and progressors. In primary infection, envelope-specific IgG was detected before the initial decline in plasma viremia, but neutralizing antibodies developed more slowly. Here, neutralizing antibodies against strains SF-2 and MN were sometimes the first to be detected, but titers were low for at least 17 weeks from onset of symptoms. Neutralizing antibodies against the early autologous isolate were detected for 4 patients by 5-40 weeks but were undetectable in 2 additional patients for 27-45 weeks. The results indicate that neutralizing antibody responses are slow to develop during primary infection and are uniquely broad in LTNP.

CD4 Lymphocyte Count↗
PubMed1997

gp120 is present on the plasma membrane of apoptotic CD4 cells prepared from lymph nodes of HIV-1-infected individuals: an immunoelectron microscopic study.

OBJECTIVE: To study whether free gp120 can be detected on the plasma membranes of apoptotic CD4+ T lymphocytes in lymph nodes from HIV-positive patients. METHODS: Lymph-node cell suspensions prepared from three HIV-positive patients were studied by pre-embedding, double-immunogold-labeling to identify cell type, determine cell morphology, and detect the presence of bound gp120 molecules. Cells were classified by their surface antigens as helper/inducer T lymphocytes (CD4+), cytotoxic/suppressor T lymphocytes (CD8+), B cells (CD20+), and total lymphocytes [CD45+, leukocyte common antigen (LCA)+]. RESULTS: gp120 colabelled with both apoptotic and normal CD4+ T lymphocytes and LCA+ cells, but not with either apoptotic or normal CD8+ T lymphocytes or B cells. gp120 was more often identified on apoptotic than on normal CD4+ T lymphocytes. The gp120 and CD45 label were often colocalized. HIV particles were not identified to be associated with or budding from either normal or apoptotic lymphocytes. CONCLUSIONS: Free gp120 is found bound to CD4+ T cells in lymph nodes of HIV-infected individuals and potentially mark them for premature death by apoptosis.

Apoptosis↗
PubMed1996

Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations.

A small percentage of human T lymphocytes, predominantly CD8+ T cells, express receptors for HLA class 1 molecules of natural killer type (NK-R) that are inhibitory for T-cell antigen receptor (TCR)-mediated functions. In the present study, it is demonstrated that the various NK-R molecules typically expressed by NK cells are also expressed on periheral blood T lymphocytes. These CD3+ NK-R+ cells have a cell surface phenotype typical of memory cells as indicated by the expression of CD45RO and CD29 and by the lack of CD28 and CD45RA. Furthermore, by the combined use of anti-TCR V beta-specific antibodies and a semiquantitative polymerase chain reaction assay, the TCR repertoire in this CD3+ NK-R+ cell subset was found to be skewed; in fact, one or two V beta families were largely represented, and most of the other V beta s were barely detected. In addition, analysis of recombinant clones of the largely represented V beta families demonstrated that these V beta s were oligoclonally or monoclonally expanded.

CD3 Complex↗
PubMed1996

Kinetics of cytokine expression during primary human immunodeficiency virus type 1 infection.

In the present study, we have determined the kinetics of constitutive expression of a panel of cytokines [interleukin (IL) 2, IL-4, IL-6, IL-10, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha)] in sequential peripheral blood mononuclear cell samples from nine individuals with primary human immunodeficiency virus infection. Expression of IL-2 and IL-4 was barely detected in peripheral blood mononuclear cells. However, substantial levels of IL-2 expression were found in mononuclear cells isolated from lymph node. Expression of IL-6 was detected in only three of nine patients, and IL-6 expression was observed when transition from the acute to the chronic phase had already occurred. Expression of IL-10 and TNF-alpha was consistently observed in all patients tested, and levels of both cytokines were either stable or progressively increased over time. Similar to IL-10 and TNF-alpha, IFN-gamma expression was detected in all patients; however, in five of nine patients, IFN-gamma expression peaked very early during primary infection. The early peak in IFN-gamma expression coincided with oligoclonal expansions of CD8+ T cells in five of six patients, and CD8+ T cells mostly accounted for the expression of this cytokine. These results indicate that high levels of expression of proinflammatory cytokines are associated with primary infection and that the cytokine response during this phase of infection is strongly influenced by oligoclonal expansions of CD8+ T cells.

Cells, Cultured↗
PubMed1996

Immunopathogenic mechanisms of HIV infection.

A complex array of multiphasic and multifactorial immunopathogenic mechanisms are involved in the establishment and progression of human immunodeficiency virus (HIV) disease. After primary infection, acute viremia occurs with wide dissemination of HIV. During this early viremic phase, the virus is trapped within the processes of follicular dendritic cells in the germinal centers of lymphoid tissue. Also, during this phase of primary infection, some patients show major expansions of certain subsets of CD8+ T cells that are identified by the expression of a particular variable region of the beta chain of the T-cell receptor. These expansions are manifestations of responses to HIV that may be important in controlling the progression of HIV infection. In addition, inappropriate immune activation and elevated secretion of certain proinflammatory cytokines occur during HIV infection; these cytokines play a role in the regulation of HIV expression in the tissues. Infection of progenitor cells in bone marrow and the thymus contribute to the lack of regeneration of immunocompetent cells. Dendritic cells are involved in the initiation and propagation of HIV infection in CD4+ T cells. In studies of long-term nonprogressors - persons who have stable CD4+ T-cell counts and no HIV disease progression despite years of HIV infection - preserved lymph node architecture, low viral burden, and viral expression were found.

Dendritic Cells↗
PubMed1996

Toward an understanding of the correlates of protective immunity to HIV infection.

Considerable progress has been made recently in understanding the genetic, immunologic and virologic factors in human immunodeficiency virus (HIV)-infected individuals who either rapidly progress or do not progress to acquired immunodeficiency syndrome (AIDS). In addition, detection of HIV-specific immune responses in HIV-negative individuals who have been exposed to the virus multiple times suggests that natural immune responses to HIV may be protective in rare individuals. Understanding the correlates of protective immunity to HIV infection is critical to efforts to develop preventive HIV vaccines as well as to determine the feasibility of treating HIV infection by boosting immunity to HIV.

AIDS Vaccines↗
PubMed1996

Neutralizing and infection-enhancing antibody responses to human immunodeficiency virus type 1 in long-term nonprogressors.

Serum antibodies from human immunodeficiency virus type 1 (HIV-1)-infected long-term non-progressors (LTNPs) and non-LTNPs were evaluated for virus neutralization and infection enhancement in vitro. Sera from LTNPs had higher average titers of neutralizing antibodies to HIV-1 strains IIIB and MN and more frequently neutralized primary isolates from progressors (14.9% vs. 1.3%, P = .002). Replication-competent HIV-1 was isolated from peripheral blood mononuclear cells and lymph nodes of 3 LTNPs. All viruses from LTNPs had a non-syncytium-inducing phenotype, were resistant to neutralization by autologous serum obtained at the time of virus isolation, and showed little evidence of a heightened sensitivity to neutralization by heterologous sera. Complement-mediated, antibody-dependent enhancement (C'-ADE) of HIV-1IIIB and primary isolates was equally prevalent for sera from LTNPs and non-LTNPs. Results indicate that LTNPs produce vigorous serum antibody responses and that long-term nonprogression is not associated with homologous neutralization or the absence of C'-ADE.

Adult↗
PubMed1996

Antiretroviral monotherapy in early stage human immunodeficiency virus disease has no detectable effect on virus load in peripheral blood and lymph nodes.

Initiation of antiretroviral monotherapy early in the course of infection with human immunodeficiency virus may result in a temporary slowing in the rate of disease progression; however, little is known about the virologic effects of early therapy. Virus load was measured in peripheral blood and lymph nodes from 16 antiretroviral-naive patients with a mean CD4 T lymphocyte count of 659 cells/microliter at baseline and after 8 weeks of either no treatment or zidovudine therapy. CD4 T lymphocyte counts and all virologic parameters examined remained unchanged regardless of zidovudine treatment status. Histopathology and virus distribution within lymph nodes remained constant between baseline and week 8 in each patient, indicating that the virologic and histologic parameters examined in a single lymph node are representative of a systemic process. Early antiretroviral monotherapy with zidovudine had no effect on virologic parameters in this group of patients with relatively high CD4 T lymphocyte counts and low measures of virus load at baseline.

Adult↗
PubMed1996

Immunopathogenesis of HIV infection.

The rate of progression of HIV disease may be substantially different among HIV-infected individuals. Following infection of the host with any virus, the delicate balance between virus replication and the immune response to the virus determines both the outcome of the infection, i.e. the persistence versus elimination of the virus, and the different rates of progression. During primary HIV infection, a burst of viremia occurs that disseminates virus to the lymphoid organs. A potent immune response ensues that substantially, but usually not completely, curtails virus replication. This inability of the immune system to completely eliminate the virus leads to establishment of chronic, persistent infection that over time leads to profound immunosuppression. The potential mechanisms of virus escape from an otherwise effective immune response have been investigated. Clonal deletion of HIV-specific cytotoxic T-cell clones and sequestration of virus-specific cytotoxic cells away from the major site of virus replication represent important mechanisms of virus escape from the immune response that favor persistence of HIV. Qualitative differences in the primary immune response to HIV (i.e. mobilization of a restricted versus broader T-cell receptor repertoire) are associated with different rates of disease progression. Therefore, the initial interaction between the virus and immune system of the host is critical for the subsequent clinical outcome.

Clonal Deletion↗
PubMed1995

Decreased human immunodeficiency virus type 1 plasma viremia during antiretroviral therapy reflects downregulation of viral replication in lymphoid tissue.

Although several immunologic and virologic markers measured in peripheral blood are useful for predicting accelerated progression of human immunodeficiency virus (HIV) disease, their validity for evaluating the response to antiretroviral therapy and their ability to accurately reflect changes in lymphoid organs remain unclear. In the present study, changes in certain virologic markers have been analyzed in peripheral blood and lymphoid tissue during antiretroviral therapy. Sixteen HIV-infected individuals who were receiving antiretroviral therapy with zidovudine for > or = 6 months were randomly assigned either to continue on zidovudine alone or to add didanosine for 8 weeks. Lymph node biopsies were performed at baseline and after 8 weeks. Viral burden (i.e., HIV DNA copies per 10(6) mononuclear cells) and virus replication in mononuclear cells isolated from peripheral blood and lymph node and plasma viremia were determined by semiquantitative polymerase chain reaction assays. Virologic and immunologic markers remained unchanged in peripheral blood and lymph node of patients who continued on zidovudine alone. In contrast, a decrease in virus replication in lymph nodes was observed in four of six patients who added didanosine to their regimen, and this was associated with a decrease in plasma viremia. These results indicate that decreases in plasma viremia detected during antiretroviral therapy reflect downregulation of virus replication in lymphoid tissue.

Adult↗
PubMed1995

Analysis of apoptosis in lymph nodes of HIV-infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden.

The occurrence of in vivo apoptosis was investigated in lymph node sections obtained from HIV-infected persons at different stages of disease. The degree of apoptosis in lymph nodes from HIV-infected individuals was compared with that observed in lymph nodes obtained from HIV-negative individuals. Apoptosis was readily detected in lymph nodes obtained from both HIV-negative and HIV-positive persons; however, the degree of apoptosis in lymph nodes obtained from HIV-positive persons was three to four times higher than that observed in the lymph nodes obtained from HIV-negative persons. In contrast to HIV-negative lymph nodes in which apoptosis was confined largely to germinal centers, in HIV-positive lymph nodes all functional compartments of the lymph node (i.e., cortex, paracortex, and sinuses) were extensively involved by this phenomenon. Furthermore, a significant correlation was observed between intensity of apoptosis and degree of activation of the lymphoid tissue associated with HIV infection. In contrast, intensity of apoptosis correlated neither with the clinical stage of HIV disease nor with the viral burden in the lymph node. Finally, apoptosis was not restricted only to CD4+ T cells; both B cells and CD8+ T cells were found to undergo apoptosis. Taken together, these results indicate that the increased intensity of the apoptotic phenomenon in HIV infection is caused by the general state of immune activation, and is independent of the progression of HIV disease and of the levels of viral load.

Acridine Orange↗
PubMed1995

Studies in subjects with long-term nonprogressive human immunodeficiency virus infection.

BACKGROUND: In a small percentage of persons infected with human immunodeficiency virus type 1 (HIV-1), there is no progression of disease and CD4+ T-cell counts remain stable for many years. Studies of the histopathological, virologic, and immunologic characteristics of these persons may provide insight into the pathogenic mechanisms that lead to HIV disease and the protective mechanisms that prevent progression to overt disease. METHODS AND RESULTS: We studied 15 subjects with long-term nonprogressive HIV infection and 18 subjects with progressive HIV disease. Nonprogressive infection was defined as seven or more years of documented HIV infection, with more than 600 CD4+ T cells per cubic millimeter, no antiretroviral therapy, and no HIV-related disease. Lymph nodes from the subjects with nonprogressive infection had significantly fewer of the hyperplastic features, and none of the involuted features, characteristic of nodes from subjects with progressive disease. Plasma levels of HIV-1 RNA and the viral burden in peripheral-blood mononuclear cells were both significantly lower in the subjects with nonprogressive infection than in those with progressive disease (P = 0.003 and P = 0.015, respectively). HIV could not be isolated from the plasma of the former, who also had significantly higher titers of neutralizing antibodies than the latter. There was viral replication, however, in the subjects with nonprogressive infection, and virus was consistently cultured from mononuclear cells from the lymph nodes. In the lymph nodes virus "trapping" varied with the degree of formation of germinal centers, and few cells expressing virus were found by in situ hybridization. HIV-specific cytotoxic activity was detected in all seven subjects with nonprogressive infection who were tested. CONCLUSIONS: In persons who remain free of disease for many years despite HIV infection the viral load is low, but viral replication persists. Lymph-node architecture and immune function appear to remain intact.

Adult↗
PubMed1995

Effect of anti-V3 antibodies on cell-free and cell-to-cell human immunodeficiency virus transmission.

The present study was undertaken to compare the effects of a type-specific (HIV-1 MN) anti-V3 antibody on in vitro human immunodeficiency virus (HIV) infection of peripheral blood mononuclear cells in systems of cell-free versus cell-to-cell transmission of virus. Anti-V3 antibody completely prevented HIV-1 infection when cell-free virus was the sole mechanism of infection. A significant reduction of the neutralizing activity of the anti-V3 antibody was observed when infectivity was dependent on both cell-free and cell-to-cell mechanisms of infection. Furthermore, when cell-to-cell transfer of virions was the primary mechanism of HIV-1 infection, inhibition of HIV-1 infection was not observed. Therefore, a potent neutralizing antibody with a single epitope specificity failed to effectively control dissemination of a persistent HIV-1 infection in a system characterized predominantly by cell-to-cell transfer of virus.

Amino Acid Sequence↗