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Biomedical subjects

M M Lederman

Publications and source records attributed to M M Lederman.

At least 55 records · Page 3Linked to original sources
PubMed1999

Characterization of viral dynamics in human immunodeficiency virus type 1-infected patients treated with combination antiretroviral therapy: relationships to host factors, cellular restoration, and virologic end points.

Biphasic plasma viral decays were modeled in 48 patients treated with ritonavir, zidovudine, and lamivudine. Estimated first- and second-phase decay rates were d1 as 0.47/day and d2 as 0.04/day. Interpatient differences in both decay rates were significant. The d1 was directly correlated with baseline CD4+, CD4+CD28+, and CD8+CD28+ T lymphocyte counts (P<.05) and inversely correlated with baseline virus load (P=.044) and the magnitude of CD4+ and CD8+ T lymphocyte recovery (P<.01). The d2 was directly correlated with baseline percentage of CD8+ T lymphocytes (P=.023), the CD8+CD38+ cell number (P=.024), and the level of IgG that binds to human immunodeficiency virus (HIV) type 1 gp120 (P=.02). Viral decay rates were not predictive of treatment failure or durability of viral suppression. These exploratory findings are consistent with a model in which immunologic factors contribute to elimination of HIV-infected cells and suggest a dynamic interplay between regulation of HIV expression and lymphocyte activation and recovery.

ADP-ribosyl Cyclase↗
PubMed1999

Stability of plasma levels of cytokines and soluble activation markers in patients with human immunodeficiency virus infection.

Cytokine and immune activation marker levels in plasma are valuable measurements of immune status and treatment effects in human immunodeficiency virus (HIV) infection and AIDS. Five populations representing various stages of disease were studied: controls, 2 AIDS groups with <50/mm3 CD4 cells, and 2 groups of HIV-positive subjects-1 with stable CD4 T cells (median, 545/mm3) and 1 with >100/mm3 CD4 cell decline in 1 year. Relatively stable levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor (R)II, soluble interleukin-2R, neopterin, and beta2-microglobulin (beta2M) were documented over 5-8 weeks in patients with AIDS and for 1-4 years in the other groups. beta2M was generally the most stable marker. Interferon-gamma levels, however, fluctuated substantially. Individuals, whether normal or HIV-positive, maintain characteristic plasma levels of cytokines and immune activation markers. Thus, documented changes, in excess of the variability observed in this study, are likely to be significant indicators of change in disease status or effects of therapy.

Adult↗
PubMed1999

Levels of proinflammatory cytokines in plasma after pneumoccoccal immunization in human immunodeficiency virus type 1-infected patients.

To ascertain if immunization with pneumococcal polysaccharide vaccine is associated with rises in the levels of proinflammatory cytokines in the plasma of human immunodeficiency virus type 1 (HIV-1)-infected patients, the levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) were measured serially after immunization. IL-6 levels rose an average of 2.2- and 2.1-fold 6 and 8 h after immunization, respectively, but TNF-alpha levels remained unchanged. The levels of these cytokines were stable in unimmunized controls. Immunization with pneumococcal polysaccharide vaccine induces increases in the levels of IL-6 in the plasma of persons with HIV-1 infection.

Bacterial Vaccines↗
PubMed1998

Hepatitis G virus RNA is common in AIDS patients' plasma but is not associated with abnormal liver function tests or other clinical syndromes.

Hepatitis G virus (HGV) is a new virus found in 1% to 4% of blood from all donors but is more prevalent in some immunocompromised groups, with unclear clinical significance. Frozen plasma samples from 192 AIDS patients were tested for HGV RNA; 44 (23%) were positive. Positive patients did not differ from negative patients in age, gender, race, HIV infection risk factors, nor blood transfusion exposure. Hepatitis BsAg was associated with HGV infection (odds ratio [OR] = 7.7; 95% confidence interval [CI], 2.4-25.0) but hepatitis C antibody was not. Mean values for liver function tests and hematologic values did not differ significantly between the groups nor did the occurrence of certain recognized AIDS-related complications. Mean CD4+ cell counts and HIV-1 plasma RNA levels were comparable in the two groups, but the mean circulating CD8+ cell count in the HGV-positive group (853+/-458 cells/microL) was higher than in the negative group (682+/-457 cells/microL; p = .03). Hepatitis G virus, although common in AIDS patients, does not appear to alter the course of AIDS nor appear as a distinct hepatitis syndrome.

AIDS-Related Opportunistic Infections↗
PubMed1998

Recovery of the immune system with antiretroviral therapy: the end of opportunism?

OBJECTIVE: Clinical care of people infected with human immunodeficiency virus (HIV) has been substantially affected by the introduction of potent antiretroviral therapy. Changes in the immune system after such therapy and the clinical consequences are important issues for clinicians treating patients with HIV. DATA SOURCES: A systematic review of MEDLINE, 1993 to January 1998, of peer-reviewed publications, abstracts from national and international conferences, and product registration information through January 1998. STUDY SELECTION AND DATA EXTRACTION: Criteria used to select studies include relevance to immune reconstitution with potent antiretroviral therapy and having been published in the English language. Assessment of data quality and validity included consideration of venue of the publication and relevance to practice. DATA SYNTHESIS: Suppression of viral replication after administration of potent antiretroviral therapy that includes inhibitors of the HIV-1 protease is associated with quantitative and qualitative changes in the immune system. In patients with relatively advanced disease, there is a first-phase rise (during the initial 3 months) in both naive and memory CD4+ and CD8+ T lymphocytes and B lymphocytes. This is followed by a slower second-phase increase (after 3 months) in cells primarily of the naive CD4+ and CD8+ phenotypes. These quantitative changes are associated with qualitative improvements in host immune responses, best characterized by dramatically reduced risk of opportunistic infection. Restoration of the immune system during the first year of potent antiretroviral therapy is partial at best. CONCLUSIONS: Potent antiretroviral therapy has become the standard of care for people with HIV infection, and its use has led to significant reductions in the incidence of the acquired immunodeficiency syndrome (AIDS) and in mortality from HIV infection. Although incomplete, considerable immune recovery occurs, sufficient, in most cases, to provide adequate protection against most AIDS-associated opportunistic infections.

AIDS-Related Opportunistic Infections↗
PubMed1998

In vivo analysis of Fas/FasL interactions in HIV-infected patients.

Recent insights into the pharmacological control of HIV replication and the molecular mechanisms of peripheral T cells homeostasis allowed us to investigate in vivo the mechanisms mediating T cell depletion in HIV-infected patients. Before the initiation of highly active antiretroviral therapy (HAART), a high degree of lymphoid tissue apoptosis is present, which is reduced upon HAART initiation (P < 0.001) and directly correlates with reduction of viral load and increases of peripheral T lymphocytes (P < 0.01). Because Fas/FasL interactions play a key role in peripheral T lymphocyte homeostasis, we investigated the susceptibility to Fas-mediated apoptosis in peripheral T lymphocytes and of FasL expression in lymphoid tissue before and during HAART. High levels of Fas-susceptibility found in peripheral CD4 T lymphocytes before HAART were significantly reduced after HAART, coinciding with decreases in viral load (P = 0.018) and increases in peripheral CD4 T lymphocyte counts (P < 0.01). However, the increased FasL expression in the lymphoid tissue of HIV-infected individuals was not reduced after HAART. These results demonstrate that lymphoid tissue apoptosis directly correlates with viral load and peripheral T lymphocyte numbers, and suggest that HIV-induced susceptibility to Fas-dependent apoptosis may play a key role in the regulation of T cell homeostasis in HIV-infected individuals.

Anti-HIV Agents↗
PubMed1998

LTR and tat variability of HIV-1 isolates from patients with divergent rates of disease progression.

The genetic heterogeneity and transcription activity of the human immunodeficiency virus type 1 (HIV-1) LTR region and tat gene have been examined. Comparison involved the relevant genomic regions of viruses isolated from twenty long-term survivors and from ten typical progressors. No significant differences were observed in mutation frequencies among the two groups, although there was a significant higher proportion of synonymous substitutions in the tat gene of viruses from typical progressors. Four LTR sequences showed an insertion of 20-31 residues at the junction between the LTR Nef-coding and the LTR noncoding region. Neither these insertions nor other genetic changes found in these sequences affected the LTR transcription function, as measured in transient expression assays using transfection of both established cell lines and peripheral blood lymphocytes with plasmid DNA. The results did not allow the association of structural or functional alterations in LTR or tat with a degree of disease progression. The results reinforce the concepts of complexity of HIV-1 evolution in infected individuals, and the multifactorial nature of progression to AIDS.

Adult↗
PubMed1998

Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315.

Human immunodeficiency virus (HIV)-1 infection is associated with progressive cell-mediated immune deficiency and abnormal immune activation. Although highly active antiretroviral therapy regimens can increase circulating CD4 T lymphocyte counts and decrease the risk of opportunistic complications, the effects of these treatments on immune reconstitution are not well understood. In 44 persons with moderately advanced HIV-1 infection, after 12 weeks of treatment with zidovudine, lamivudine, and ritonavir, plasma HIV-1 RNA fell a median of 2.3 logs (P < .0001). Circulating numbers of naive and memory CD4 T lymphocytes (P < .001), naive CD8 T lymphocytes (P < .004), and B lymphocytes (P < .001) increased. Improved lymphocyte proliferation to certain antigens and a tendency to improvement in delayed-type hypersensitivity also were seen. Dysregulated immune activation was partially corrected by this regimen; however, the perturbed expression of T cell receptor V regions in the CD4 and CD8 T lymphocyte populations was not significantly affected. Ongoing studies will ascertain if longer durations of virus suppression will permit more complete immune restoration.

Adult↗
PubMed1998

Proinflammatory cytokine and human immunodeficiency virus RNA levels during early Mycobacterium avium complex bacteremia in advanced AIDS.

The relationship between Mycobacterium avium complex (MAC) bacteremia and proinflammatory cytokine and human immunodeficiency virus type 1 (HIV-1) RNA levels in AIDS was investigated. During a prospective study, blood samples were drawn monthly for mycobacterial cultures. Sera were available at baseline and onset of MAC bacteremia from 20 cases and at corresponding times from 19 controls. Mean interleukin-6 (IL-6) levels were 154% greater at the time of MAC bacteremia in cases than in controls. The IL-6 levels correlated with body temperature, serum tumor necrosis factor (TNF-alpha) levels, and alkaline phosphatase levels (P < or = .004 for each). Although TNF-alpha levels tended to rise more in MAC patients than in controls, the difference was not significant. However, among both cases and controls, serum TNF-alpha levels rose significantly from baseline to the time of last sample, irrespective of MAC infection (P = .015). Bacteremia was not associated with increased serum HIV-1 RNA levels. Thus, early MAC bacteremia is associated with increases in serum IL-6 levels, while TNF-alpha levels rise over time during advanced AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1998

Measurement of induced cytokines in AIDS clinical trials using whole blood: a preliminary report. ACTG Inducible Cytokines Focus Group. AIDS Clinical Trials Group.

Measures of immune function have become increasingly important as endpoints in AIDS clinical trials, with respect to both modulation and reconstitution of immunity by experimental therapies. Measurement of immune function in this setting requires the development of robust analytic approaches suitable for the clinical laboratory. Experiments were performed to evaluate the suitability of using cultured heparinized ("whole") blood for induction of tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma), two cytokines critical in AIDS pathogenesis. TNF-alpha expression ranged from 229 to 769 pg/ml in lipopolysaccharide (LPS)-stimulated cultures and was not detected in unstimulated cultures. IFN-gamma expression ranged from 0 to 112,000 pg/ml in phytohemagglutinin A (PHA)-stimulated cultures and from 0 to 789 pg/ml in antigen-stimulated cultures. The mean coefficient of variation observed in three weekly determinations was 0.47 for TNF-alpha and ranged from 0.12 to 1.73 for IFN-gamma. These values indicate that sample sizes of 8, 24, and 29 subjects would be sufficient to detect twofold changes in LPS-induced TNF-alpha and in PHA- and antigen-induced IFN-gamma respectively, if two baseline and two treatment determinations were obtained, and if the interpatient variability of changes in true levels from baseline to follow-up is negligible compared to the variability in the three weekly measurements. Measurement of LPS-induced TNF-alpha and mitogen- or antigen-induced IFN-gamma can be performed simply and reproducibly in human immunodeficiency virus-infected persons by the whole-blood culture method. Further studies are warranted to determine the effect of overnight shipping on assay reproducibility and to determine the extent to which responses can be reliably detected in subjects with low CD4 cell numbers.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Parvovirus B19 quiescence during the course of human immunodeficiency virus infection in persons with hemophilia.

To detect and characterize parvovirus B19 infection during the course of progressive immune deficiency from human immunodeficiency virus (HIV), ten subjects enrolled in the Multicenter Hemophilia Cohort Study were followed for 6.4 to 15 years from HIV seroconversion through extreme immune deficiency. Four to five sera or plasma samples from each subject, collected at predetermined CD4+ lymphocyte levels, were tested for immunoglobulin G (IgG) and M (IgM) B19 antibodies and DNA. All 42 samples were positive for B19 IgG antibodies, and three were weakly positive for IgM antibodies. Only one sample, collected coincident with HIV seroconversion, was unequivocally positive for B19 DNA. No persistent hematologic adverse effects of B19 infection were observed. Thus, although B19 IgG antibodies are highly prevalent among HIV-infected persons with hemophilia or related disorders, B19 viremia and its hematologic consequences were not detected, even with severe depletion of CD4+ lymphocytes. If primary B19 infection occurs after immune deficiency, however, the consequences may be more adverse.

Adolescent↗
PubMed1997

The effect of tenidap on cytokines, acute-phase proteins, and virus load in human immunodeficiency virus (HIV)-infected patients: correlation between plasma HIV-1 RNA and proinflammatory cytokine levels.

Proinflammatory cytokines may be important in the pathogenesis of human immunodeficiency virus type 1 (HIV-1) disease. Tenidap decreases interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF) production by peripheral blood mononuclear cells and decreases IL-6 plasma levels in rheumatoid arthritis patients. In this randomized double-blind study, 43 HIV-1-infected patients received tenidap (120 mg) or placebo daily for 6 weeks and then crossed over to the alternative therapy for an additional 6 weeks. Mean entry CD4 cell count was 140/microL. Analyses were performed on cytokines, acute-phase proteins, virus load, and CD4 cell counts. With the exception of small differences in plasma TNF levels, tenidap had no significant effect on these indices. Significant correlations of plasma IL-6 and TNF levels with HIV-1 RNA were noted. Six patients discontinued tenidap due to rash. The effects of tenidap in HIV-1 infection contrast to results in arthritis patients, in whom tenidap decreased plasma levels of IL-6 and acute-phase proteins.

Acute-Phase Proteins↗
PubMed1997

Bacterial antigen activation of Vdelta1 and Vdelta2 gammadelta T cells of persons infected with human immunodeficiency virus type 1.

Vdelta2 gammadelta T cells are readily activated by microbial antigens. In persons infected with human immunodeficiency virus type 1 (HIV-1), the number of gammadelta T cells remains the same or increases in association with reversal of the Vdelta2/Vdelta1 ratio from > or = 1 to < 1. Vdelta2 T cell responses to microbial antigens were tested in 11 HIV-1-infected (> or = 500 CD4 cells/mm3) and 7 uninfected persons. In persons with HIV-1 infection, Mycobacterium tuberculosis expanded Vdelta2 cells in 1 person as did Salmonella typhimurium in 4; however, Candida albicans antigens did not lead to more Vdelta2 cells. Vdelta2 responses to M. tuberculosis were enhanced by interleukin (IL)-2 in HIV-1-infected persons (from 1 subject to 7; P < .01) and were associated with increased interferon-gamma production. Bacterial antigens and IL-2 increased HIV-1 replication; M. tuberculosis antigens induced the greatest increase. Thus, in HIV-1-infected persons with > or = 500 CD4 cells/mm3, Vdelta2 T cell responses to bacterial antigens remain intact.

Antigens, Bacterial↗