Biomedical subjects

J B Margolick

Publications and source records attributed to J B Margolick.

At least 19 recordsLinked to original sources

PubMed1997

Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection.

BACKGROUND: The rate of disease progression among persons infected with human immunodeficiency virus type 1 (HIV-1) varies widely, and the relative prognostic value of markers of disease activity has not been defined. OBJECTIVE: To compare clinical, serologic, cellular, and virologic markers for their ability to predict progression to the acquired immunodeficiency syndrome (AIDS) and death during a 10-year period. DESIGN: Prospective, multicenter cohort study. SETTING: Four university-based clinical centers participating in the Multicenter AIDS Cohort Study. PATIENTS: 1604 men infected with HIV-1. MEASUREMENTS: The markers compared were oral candidiasis (thrush) or fever; serum neopterin levels; serum beta 2-microglobulin levels; number and percentage of CD3+, CD4+, and CD8+ lymphocytes; and plasma viral load, which was measured as the concentration of HIV-1 RNA found using a sensitive branched-DNA signal-amplification assay. RESULTS: Plasma viral load was the single best predictor of progression to AIDS and death, followed (in order of predictive strength) by CD4+ lymphocyte count and serum neopterin levels, serum beta 2-microglobulin levels, and thrush or fever. Plasma viral load discriminated risk at all levels of CD4+ lymphocyte counts and predicted their subsequent rate of decline. Five risk categories were defined by plasma HIV-1 RNA concentrations: 500 copies/mL or less, 501 to 3000 copies/mL, 3001 to 10000 copies/mL, 10001 to 30000 copies/mL, and more than 30000 copies/mL. Highly significant (P < 0.001) differences in the percentages of participants who progressed to AIDS within 6 years were seen in the five risk categories: 5.4%, 16.6%, 31.7%, 55.2%, and 80.0%, respectively. Highly significant (P < 0.001) differences in the percentages of participants who died of AIDS within 6 years were also seen in the five risk categories: 0.9%, 6.3%, 18.1%, 34.9%, and 69.5%, respectively. A regression tree incorporating both HIV-1 RNA measurements and CD4+ lymphocyte counts provided better discrimination of outcome than did either marker alone; use of both variables defined categories of risk for AIDS within 6 years that ranged from less than 2% to 98%. CONCLUSIONS: Plasma viral load strongly predicts the rate of decrease in CD4+ lymphocyte count and progression to AIDS and death, but the prognosis of HIV-infected persons is more accurately defined by combined measurement of plasma HIV-1 RNA and CD4+ lymphocytes.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Effect of smoking on the clinical progression of HIV-1 infection.

Cigarette smoking as a risk factor in progression of HIV-1 disease was investigated in the Multicenter AIDS Cohort Study of homosexual men. Longitudinal data for T-cell subsets, HIV-related clinical symptoms, smoking behavior, and AIDS medication use were collected semiannually from 2,499 HIV-1-seropositive men for up to 9 years. Survival methods, including Kaplan-Meier analysis and multivariate Cox regression models, were used to assess the effect of cigarette smoking on development of Pneumocystis carinii pneumonia (PCP), AIDS, death, and self-reported oral thrush. After adjustment for CD4+ lymphocyte count and use of antiretroviral and anti-PCP medications, smoking was not significantly associated with progression to PCP, AIDS, or death in either the HIV-seroprevalent or-seroincident cohort members. Among men who had baseline CD4+ cell counts > 200/microliter, smoking was associated with a 40% increase in the hazard of oral thrush (p < or = 0.01). These data indicate that cigarette smoking does not have a major effect on the progression of HIV-1 infection to AIDS or death but may affect the incidence of oral thrush.

Candidiasis, Oral↗

PubMed1997

Detection of infection with human immunodeficiency virus type 1 before seroconversion: correlation with clinical symptoms and outcome.

Early (pre-seroconversion) infection with human immunodeficiency virus type 1 (HIV-1) was identified in 50 of 267 participants in the Multicenter AIDS Cohort Study. These 50 men had a positive EIA result, which detected IgM antibody (n = 35), p24 antigen, or serum HIV RNA (n = 15) at their last "seronegative" visit. At that visit, the mean CD4 lymphocyte number (890/mm3 vs. 1038/mm3) was significantly lower than in men who subsequently seroconverted but had no evidence of early infection. The decline in CD4 cells was slower and the duration of AIDS-free time longer in the 19 men who were symptomatic in comparison to the 31 asymptomatic men with early infection, but differences were not significant.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Evaluation of integrity of gloves used in a flow cytometry laboratory.

This study was conducted to evaluate the effect of normal use on latex glove integrity in a flow cytometry laboratory. The gloves were tested using the 1,000 microL water-tight test and met industrial standards (less than 4% leakage) before, but not after use. More durable gloves, or more frequent changes of gloves, may be needed to ensure adequate barrier protection for laboratory workers during routine procedures.

Equipment Failure↗

PubMed1997

The influence of drug use patterns on the rate of CD4+ lymphocyte decline among HIV-1-infected injecting drug users.

OBJECTIVES: To assess the relationship between various injecting drug use patterns and the rate of CD4+ lymphocyte decline in HIV-1-infected injecting drug users in Baltimore, Maryland, USA. METHODS: A cohort of 605 HIV-1-infected injecting drug users was recruited between 1988 and early 1989 in East Baltimore using extensive community outreach techniques. The participants were interviewed semi-annually to collect information on drug use practices. The outcome measure of interest was the rate of CD4+ lymphocyte decline between pairs of CD4+ lymphocyte counts. A mixed model was used to evaluate the relationship between the change in CD4+ lymphocyte count per month and previous CD4+ lymphocyte count and various drug use variables. RESULTS: The 605 HIV-infected injecting drug users had a median initial CD4+ lymphocyte count of 513 cells x 10(6)/l. Using 3209 paired observations, the mean change in CD4+ lymphocyte count was -3.2 cells x 10(6)/l per month. The rate of decline was higher in those with a higher level of CD4+ lymphocytes (P < 0.01) and length of drug use (P < 0.01), but did not vary by injection frequency or injection intensity of specific drug types. Although animal studies have suggested that the pattern of drug administration (continuous versus intermittent) and episodes of withdrawal or overdose might impact the rate of CD4+ lymphocyte decline, this was not observed in the present study. CONCLUSION: Patterns of injecting drug use, based on self-report, were not associated with the rate of decline in CD4+ lymphocytes.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Viral resistance and CMV retinitis: design and methods of a prospective study. CRVR Research Groups. Cytomegalovirus Retinitis Viral Resistance Research Group.

A prospective study following a cohort of patients with newly diagnosed, previously untreated cytomegalovirus (CMV) retinitis is being conducted to study drug resistant CMV. Prior to initiation of treatment, patients undergo a baseline eye examination, fundus photography, and blood and urine culture for presence of CMV, and drug susceptibility testing against positive isolates. Patients are followed monthly with a detailed eye examination to diagnose progression of retinitis, and for fundus photography. Cultures are repeated at 1 and 3 months after enrollment, every 3 months thereafter, and at the time of treatment reinduction for the progression of retinitis. This study was designed to determine the prevalence and incidence of drug resistant CMV, as well as risk factors for the development of resistant CMV. It also will determine the correlation between clinical outcome, as measured both by eye examination and fundus photography, and viral resistance.

AIDS-Related Opportunistic Infections↗

PubMed1996

Virologic and serologic markers of rapid progression to AIDS after HIV-1 seroconversion.

The association between early virologic and immunologic events after human immunodeficiency virus type 1 (HIV-1) infection and progression of HIV-1 infection to acquired immunodeficiency syndrome (AIDS) was studied among 59 homosexual men with documented time of seroconversion. Epidemiologic factors, such as number of lifetime sexual partners, history of sexually transmitted diseases, and other factors, also were studied. All 17 seroconverters in the cohort who developed AIDS within 3 years (rapid progressors = RPs) were compared with 42 men without AIDS for at least 6 years seroconversion (nonrapid progressors = non-RPs). Plasma levels of HIV-1 RNA, p24 antigen, antibodies to HIV-1 structural genes, beta-2 microglobulin, neopterin, and interferon-alpha were measured at four time points: (a) the last seronegative visit, (b) the first seropositive visit, (c) the visit closest to AIDS (or the corresponding visit for the non-RPs) and (d) 6 years after seroconversion (for non-RPs). Up to seroconversion, the RPs had a significantly higher number of lifetime sexual partners than non-RPs (503 versus 171, respectively). At the first seropositive visit, RPs had significantly higher concentrations of plasma HIV-1 RNA (p < 0.01) and prevalence of p24 antigenemia (p < 0.001) and significantly lower levels of antibodies to the HIV-1 gag proteins p17 and p24 (p < 0.01-0.001) compared with non-RPs. These differences increased during follow-up visits. Antibodies to p66 and gp120 were significantly different only at the visit closet to AIDS (p < 0.001), as were beta-2 microglobulin and interferon alpha. These findings suggest that early virologic-immunologic events after HIV-1 infection may determine the rate of progression to AIDS. Anti-gag immune response may prevent rapid progression of HIV-1 disease and should be considered for future vaccine studies.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Discriminant quantitation of posttransplant hepatic reticuloendothelial function. The impact of ischemic preservation.

This study focuses upon two discrete components of posttransplant hepatic reticuloendothelial system (RES) function-phagocytosis and killing of bacteria-under various conditions of ischemic preservation. We had previously reported that, following intravenous injection of rats with 51Cr and 125I double-labeled Escherichia coli, hepatic 51Cr levels can be used to reliably quantify hepatic phagocytic clearance of the bacteria from the blood (HPC), while the subsequent release of 125I from the liver accurately parallels hepatic bacterial killing. Here, Wistar rats were transplanted with syngeneic livers perfused with either normal saline (NS) or University of Wisconsin solution (UW) and stored at 4 degrees C for 1, 2, or 3 hr prior to implantation. Control rats underwent laparotomy and hepatic artery ligation. Using the double-labeled E coli assay, HPC was decreased in all transplanted animals when compared with controls, reaching a nadir on the third postoperative day (P < 0.05). In rats transplanted with livers preserved in NS, the fraction of phagocytosed organisms that were subsequently killed (hepatic killing efficiency=HKE) was increased to 142%, 129%, or 112% of normal following 1, 2, or 3 hr of cold ischemia, respectively; P < 0.05). Conversely, preservation of donor allografts in UW was associated with marked depression of HKE. Moreover, rats receiving NS- or UW-preserved livers tolerated an intravenous challenge with Streptococcus pneumoniae poorly (50% mortality) compared with hepatic artery ligated controls (12% mortality) at 7 days. Ischemic preservation of rat livers in NS resulted in a dose (of ischemia)-dependent reduction of hepatic phagocytosis coupled with a potentiation of HKE. Preservation in UW, however, produced a striking suppression of both components of hepatic RES function. Following a septic challenge survival was reduced in both groups of transplanted rats.

Adenosine↗

PubMed1996

Existence and failure of T-cell homeostasis prior to AIDS onset in HIV-infected injection drug users.

Prior studies, based on populations of homosexual men, have shown that during HIV infection, levels of total circulating T-cells (CD3+ lymphocytes) remain constant for long periods of time after seroconversion. This suggested homeostatic phenomenon was observed to break down about 18 months prior to AIDS diagnosis with a quick loss of T-cells. The objective of this study was to determine whether (a) total T-cells are maintained at a constant level for long periods of time among HIV-infected injection drug users (IDUs) and (b) total T-cells decline before AIDS onset in this risk group and, if so, by how long. The design and setting was prospective follow-up, with semiannual clinic visits, of 646 HIV-infected IDUs who participate in the ALIVE study (Baltimore, MD). Among AIDS cases, T-cell levels remained quite stable at about 1500 cells/microl up to approximately 24 months prior to AIDS. However, a steep decline in CD3+ cell levels began approximately 24 months prior to AIDS diagnosis and was -17.5% per 6 months in the last 18 months before AIDS. Among seropositive IDUs without AIDS, a gradual decline of less than -4% per 6 months was observed. These trends remained virtually unchanged after accounting for current injection drug use, smoking, and HIV-related medications. IDUs, like homosexual men, exhibited T-cell homeostasis following HIV infection, as well as failure of this homeostasis about 2 years before AIDS. Although the mechanisms for the maintenance and later failure of the homeostasis of T-lymphocytes are not well understood, the observation has a potentially important prognostic value as well as biological interest.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Relationship between infectious cell-associated human immunodeficiency virus type 1 load, T lymphocyte subsets, and stage of infection in homosexual men.

The relationship between cell-associated infectious human immunodeficiency virus type 1 (HIV) load (infectious units/10(6) peripheral blood mononuclear cells [IUPM]) and phenotypes of CD4+ and CD8+ lymphocytes was studied. IUPM were measured in 242 HIV-infected homosexual men by quantitative microculture and T cell subsets by two-color flow cytometry. In multivariate analysis, IUPM correlated negatively with CD4+ lymphocyte level and with a diagnosis of AIDS and positively with the proportion of CD8+ lymphocytes expressing the activation marker CD38. After adjusting for level of CD4+ lymphocytes, men with AIDS had significantly lower IUPM than those without AIDS. The correlation between IUPM and CD4+ lymphocyte level was largely explained by correlation with level of CD4+ lymphocytes with resting phenotypes (HLA-DR-, CD38-) rather than with those expressing HLA-DR and CD38. Thus, subsets of CD4+ lymphocytes may vary in cell-associated infectious HIV content at different stages of HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed1996

The effect of influenza vaccination on human immunodeficiency virus type 1 load: a randomized, double-blind, placebo-controlled study.

To determine if vaccination induces replication of human immunodeficiency virus type 1 (HIV-1), 42 HIV-1-infected subjects with CD4 cell counts of 200-500 cells/microL were randomized to receive influenza vaccine or saline placebo. Infectious cell-associated and plasma HIV-1 RNA virus load were measured twice at baseline and then at 7, 10, 14, and 30 days after injection by quantitative microculture and branched DNA amplification. The ratios of the geometric mean plasma HIV-1 load of the four follow-up visits compared with baseline in vaccine (n = 28) and placebo (n = 14) recipients were similar (1.05 [95% confidence interval, 0.80-1.37] for vaccine; 0.96 [95% confidence interval, 0.68-1.33] for placebo; P = .90). The geometric mean ratios of plasma virus load at each follow-up visit to baseline did not differ significantly from 1.0 for each group. Infectious cell-associated virus load measures yielded similar results. CD4 cell counts declined similarly in both groups at 6 months. Influenza vaccination did not increase HIV-1 load in this controlled clinical trial.

Adult↗

PubMed1996

Selective transmission of human immunodeficiency virus type 1 variants to SCID mice reconstituted with human peripheral blood monoclonal cells.

The relative infectiousness of laboratory and primary human immunodeficiency virus type 1 (HIV-1) variants was evaluated in in vitro cell cultures of peripheral blood mononuclear cells or MT-2 cells and in Hu-PBL-SCID mice. HIV(MN) and syncytium-inducing primary isolates were preferentially transmitted to cells in tissue culture. HIV(Ba-L) and non-syncytium-inducing (NSI) primary isolates were more infectious in Hu-PBL-SCID mice. Phylogenetic analysis of env sequences derived from the primary isolates, from the cell cultures, and from five Hu-PBL-SCID mice was performed by using methods designed for resolving differences among closely related sequence pairs. This analysis demonstrated preferential transmission of an evolutionarily related subset of NSI variants to Hu-PBL-SCID mice. The pattern of selective transmission of a restricted range of NSI variants that is observed in the clinical setting is maintained in Hu-PBL-SCID mice and not in tissue culture systems. The Hu-PBL-SCID mouse model system, when used with appropriate phylogenetic analysis methodologies, will be useful for identifying and characterizing the more infectious HIV-1 variants that should be targeted for vaccine development.

Amino Acid Sequence↗

PubMed1995

Lymphopoiesis, apoptosis, and immune amnesia.

Bone marrow transplant recipients have a functional T-cell deficit long after T-cell counts have returned to normal levels. Early after BMT, T-cell phenotype is predominantly CD45RO+/CD29high/HLA-DR+/CD38high. This profile is associated with activated memory cells in healthy subjects, but also appears on the earliest mature naive T-cells in times of lymphopoietic stress. Most of these cells apoptose in short-term unstimulated culture, suggesting that they would have had a similar fate in vivo. Twelve to 24 months after BMT, CD45RA+/CD29low/HLA-DR-/CD38low T cells increase, apoptosis decreases, and T-cell function normalizes. We hypothesize that in the adult, mature memory T cells regulate their own replacement by rescuing a proportion of newly generated naive cells from apoptosis. Ablation of memory cells consequent to high dose therapy disrupts this process, resulting in a protracted period of high lymphocyte turnover with few cells surviving to make the antigen-driven transition to memory cells. Infection with HIV-1 also eventuates in immune deficiency associated with a loss in CD4+ T cells and dominance of the phenotypic/apoptotic profile which we have associated with lymphopoietic stress. Recent data independently confirm that T-cell turnover is greatly elevated in HIV infection. Catastrophic or chronic depletion of memory T cells due to marrow ablative therapy or HIV-1 infection interferes with memory replacement, substituting short-lived hypofunctional naive T cells which characterize the state of immune amnesia.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Long-term survivors with HIV-1 infection: incubation period and longitudinal patterns of CD4+ lymphocytes.

To characterize long-term survival with HIV-1, we need to estimate the proportion of seroconverters remaining free from clinical AIDS for long periods. We predict that approximately 13% of homosexual/bisexual men infected at a young age may remain so for > 20 years. Since studies have not followed individuals for such periods, long-term survivors must be characterized using stability of immunologic markers. In a cohort of 1,809 seropositive men followed since 1984-85, 15% (187/1,214) of those with at least two consecutive visits early in the study showed no decline in CD4+ cell count. From these, 67 men with long follow-up and no use of zidovudine were identified as cases to investigate correlates of protection against HIV-1-induced immunodepletion. Two matched control subgroups, one with moderate and one with rapid CD4+ lymphocyte decline, produced 56 triplets of individuals to be contrasted. Analysis of data from early in the study on demographics, sexual behavior, and sexually transmitted diseases revealed no significant differences among the three groups. Men showing no decline in CD4+ lymphocytes persistently showed a healthier profile with respect to onset of clinical AIDS, survival, and concomitant hematologic variables. Moderate decliners had rates of clinical AIDS and death significantly higher than those in the stable group but lower than the fast decliners.

CD4 Lymphocyte Count↗

PubMed1995

Assessment of aerosol containment on the ELITE flow cytometer.

Biohazardous aerosols generated during cell sorting have been of increased concern recently because of interest in sorting specimens containing human immunodeficiency virus type 1 (HIV-1). Current flow cytometers have features designed to contain such aerosols within the sorting chamber, but the efficacy of these features has not been established. Therefore, we tested aerosol containment by two ELITE flow cytometers (Coulter Cytometry, Inc., Hialeah, FL) during sorting of specimens containing high titers of bacteriophage. Agar plates confluent with susceptible Escherichia coli were used to detect infectious units released from the sorting chamber. Under recommended operating conditions very few infectious units were released from the sorting chambers. Release increased when the center stream was not optimally collected in a vacuum-exhausted tube or the chamber door was not completely closed. Failure of the negative pressure and high efficiency particle air (HEPA) filtration features had less of an effect. The data indicate that these standard safety features provide a rational expectation of safety for the flow cytometry operator.

Aerosols↗

PubMed1995

Changes in markers of disease progression in HIV-1 seroconverters: a comparison between cohorts of injecting drug users and homosexual men.

Comparisons of human immunodeficiency virus (HIV) disease progression between risk groups are difficult primarily because of the long incubation period of acquired immune deficiency syndrome (AIDS) and unknown times of infection. This is believed to be the first study that directly compared changes in T-lymphocyte subsets following HIV-1 seroconversion between cohorts of predominantly black injecting drug users and predominantly white homosexual men. Longitudinal trends of CD4 and CD8 percentages of total lymphocytes during 4 years were modeled as piecewise linear functions with a two-parameter correlation structure to accommodate within-person repeated observations. Prior to seroconversion the 151 injecting drug users started with similar CD4% and CD8% levels compared with the 99 homosexual men. Following seroconversion, larger changes were observed overall in the homosexual men compared with the injecting drug users for both markers (p < or = 0.001). The major discrepancies, however, were limited to the first 2 years. Subsequently, the CD4% levels of the two cohorts converged and then declined at similar rates. These comparative analyses of HIV seroconverters in homosexual men and injecting drug users suggest that risk group has only a minor effect on the initial course of HIV infection.

Adult↗

PubMed1995

Apoptosis parallels lymphopoiesis in bone marrow transplantation and HIV disease.

Apoptosis has been implicated in a variety of physiological processes ranging from tissue modeling to deletion of autoreactive T lymphocytes during thymic development. The recent finding that a large proportion of peripheral T cells from HIV-infected subjects (corrected from subjects) apoptose in culture raises an important issue: does this represent a pathologic mechanism by which the virus disrupts the immune system, or a normal physiologic response to virus-mediated T-cell loss? To study the potential relationship between apoptosis and lymphopoiesis, we compared apoptosis rates in unstimulated lymphocyte cultures from healthy subjects, HIV+ gay men, and bone marrow transplant (BMT) recipients undergoing immune reconstruction. BMT recipients were chosen because they undergo massive regeneration of lymphocytes following marrow ablation and graft infusion. The data obtained in BMT recipients suggests that elevated apoptosis accompanies, and is the consequence of, elevated lymphopoiesis. We also found a strong inverse relationship between in vitro T-cell apoptosis rates and peripheral T-cell counts. These results provide new interpretation for elevated apoptosis observed in HIV-infected individuals--that it reflects increased T-cell turnover consequent to virus-mediated destruction of CD4+ T-cells.

Apoptosis↗

PubMed1995

Reduced adenylyl cyclase activation with no decrease in beta-adrenergic receptors in basenji greyhound leukocytes: relevance to beta-adrenergic responses in airway smooth muscle.

Mononuclear leukocytes (MNLs) have been used as a model of beta-adrenergic responsiveness of airway smooth muscle, but the relevance of this model remains controversial. The basenji greyhound (BG) dog model of airway hyperresponsiveness shares some features with human asthma, and airway smooth muscle shows a selective impairment in isoproterenol-stimulated adenylyl cyclase activity. In this study, MNL membranes were obtained from these same dogs, and the beta-adrenergic receptor-adenylyl cyclase cascade function was compared with that in airway smooth muscle. beta-Adrenergic receptor numbers and affinities for iodine 125-cyanopindolol were similar in the two dog groups (receptor numbers [Bmax] = 441 +/- 101 and 447 +/- 61 fmol/mg protein and dissociation constant [Kd] = 269 +/- 44 and 312 +/- 60 pmol/L for mongrel and BG MNLs, respectively). Quantities of the Gs alpha protein were not different in the membranes as determined by immunoblotting. Stimulation of adenylyl cyclase by isoproterenol (100 mumol/L) was impaired in MNL membranes of BG membranes (22% +/- 4% increase over guanosine triphosphate [10 mumol/L]) compared with mongrel membranes (47% +/- 8.6% increase over guanosine triphosphate [10 mumol/L], p < 0.05). Stimulation of adenylyl cyclase by prostaglandin E1 (10 mumol/L), NaF (10 mmol/L), or forskolin (10 mumol/L) did not differ in membranes from the two groups. No difference was found in the lymphocyte subsets in the two groups as determined by flow cytometry. These findings are qualitatively similar to studies of trachealis muscle membranes from these same dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗