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Biomedical subjects

J Margolick

Publications and source records attributed to J Margolick.

At least 19 recordsLinked to original sources
PubMed2003

Effects of asthma on cell components in peripheral blood among smokers and non-smokers.

BACKGROUND: Eosinophils play a central role in asthma, but the interplay of the effects of smoking, eosinophils and asthma remains unclear. OBJECTIVE: The primary objective of our study was to investigate the extent to which smoking modifies the effect of asthma on circulating eosinophils, CD4+ and CD8+ T cell counts. METHODS: Data were collected semiannually between 1987 and 1994 from HIV-negative participants in the Multicenter AIDS Cohort Study. Asthma was defined by a questionnaire at baseline as a self-report of diagnosed asthma. A total of 1420 blood samples from 197 asthmatics and 15 822 from 1997 non-asthmatics were collected. RESULTS: Eosinophil levels were higher in asthmatics (28% of asthmatics had eosinophils >/=4% and 16% of non-asthmatics) regardless of smoking history, but smoking modified the association between eosinophils and asthma. Namely, the odds ratios for eosinophils being >/=4% in asthmatics to non-asthmatics decreased from 2.7 (95% CI: 2.0, 3.6) in never, to 2.1 (1.4, 3.1) in former, and to 1.5 (0.9, 2.3) in current smokers. Cross-sectional and longitudinal analyses coherently showed that smoking increased eosinophils in non-asthmatics, but the converse was true for asthmatics. In contrast, no differences in peripheral blood T cell counts between asthmatics and non-asthmatics were observed. CONCLUSION: Under the established link between increased eosinophils and asthma, these data indicate that smoking modified this relationship. This finding suggests that smoking plays a different immunological role in asthmatics and non-asthmatics.

Adult↗
PubMed2001

Thrush and fever as markers of immune competence in the era of highly active antiretroviral therapy.

The presence of clinical manifestations of HIV-1 infection is one measure of immune function failure. We examined the occurrence of clinical manifestations of HIV-1 infection, in particular fever and oral thrush, before and after the initiation of highly active antiretroviral therapy (HAART). Using data collected from 645 participants in the Multicenter AIDS Cohort Study (MACS) who used HAART, 7517 person-visits from January 1992 through March 2000 were stratified by time relative to HAART initiation (> or =1 year preinitiation, <1 year preinitiation, >1 year postinitiation, and > or =1 year postinitiation) and CD4+ T cell count (< or =100, 101-200, 201-350, and >350 cells/microl). Multivariate logistic regression was used to assess the relationship between HAART, CD4+ T cell count, and each self-reported symptom (oral hairy leukoplakia, diarrhea, fever, and oral thrush). After initiation of HAART, clinical manifestations of HIV-1 infection continued to occur and, similar to patterns seen before HAART, were more likely at lower CD4+ T cell counts than at higher (p < 0.001). Except for diarrhea, symptoms did not occur more frequently after HAART. Rather, beyond 1 year after initiation of HAART, there was less oral thrush even at the same CD4+ T cell count. These results provide evidence that increases in CD4+ T cell count due to HAART represent a reconstitution of immune function.

AIDS-Related Opportunistic Infections↗
PubMed2001

Effectiveness of potent antiretroviral therapies on the incidence of opportunistic infections before and after AIDS diagnosis.

OBJECTIVES: To determine the effectiveness of potent antiretroviral therapy in reducing opportunistic infections (OI) as both a presenting event and subsequent to an AIDS-defining event. DESIGN AND METHODS: A total of 543 seroconverters and 1470 men with AIDS were compared for the time to development of OI as the presenting AIDS event and as a subsequent event in the 1984-1989, 1990-1992, 1993-1995, and 1996-1998 periods, when the major treatments were no therapy, monotherapy, combination therapy, and potent antiretroviral therapy, respectively. RESULTS: The seroconverters suffered 132 OI and the participants with AIDS had 717 OI. The relative hazard (RH) of OI as the presenting AIDS event declined by 81% in the calendar period when potent antiretroviral therapy was available compared with the monotherapy period. Declines were observed for Mycobacterium avium complex, cytomegalovirus disease, and esophageal candidiasis, but were statistically significant only for Pneumocystis carinii pneumonia. The RH of OI as a secondary infection dropped by 77% in the last calendar period compared with the monotherapy period. A significant decline was observed for all four OI. Prophylactic drug use did not increase in the era of potent antiretroviral therapy. CONCLUSION: The hazard of OI in the era of potent antiretroviral therapy has declined dramatically compared with the era of monotherapy, despite the concurrent decrease in the use of prophylactic drugs. Physicians should consider whether it is necessary to include prophylactic drugs as part of the complex drug regimen for patients on potent antiretroviral therapy.

AIDS-Related Opportunistic Infections↗
PubMed2001

TAPI polymorphisms in several human ethnic groups: characteristics, evolution, and genotyping strategies.

Genetic variations in the locus encoding the transporter associated with antigen processing, subunit 1 (TAP1), were systematically studied using samples from Caucasians, Africans, Brazilians, and compared with data from chimpanzees. PCR-amplified genomic sequences corresponding to the 11 exons were analyzed by single-strand conformation polymorphism (SSCP) and sequencing. Six nonsynonymous and 2 synonymous single nucleotide polymorphisms (SNPs) were found to be common in one ethnic group or another, and they involved codons 254 (Gly-GGC/Gly-GGT) in exon 3, 333 (Ile-ATC/Val-GTC) in exon 4, 370 (Ala-GCT/Val-GTT) in exon 5, 458 (Val-GTG/Leu-TTG) in exon 6, 518 (Val-GTC/Ile-ATC) in exon 7, 637 (Asp-GAC/Gly-GGC), 648 (Arg-CGA/Gln-CAA) and 661 (Pro-CCG/Pro-CCA) in exon 10. At each SNP site the sequence listed first was predominant in all ethnic groups. Several SNPs segregated on the same chromosome regardless of populations and species. Together, the SNPs produced 5 major human TAP1 alleles, 4 of which matched the officially recognized alleles *0101, *02011, *0301, and *0401; the 5th allele differed from each of those by at least 4 SNPs. Overall, TAP1*0101 was the predominant allele in all ethnic groups, with frequencies ranging from 0.667 in Zambians to 0.808 in US Caucasians. The TAP1*0401 frequency showed the greatest difference between Africans (0.221-0.254) and Caucasians (0.033), with Brazilians (0.058) fitting in the middle. Consistent with earlier work based on Caucasians and gorillas, *0101 appeared to be the newest human TAP1 allele, suggesting a dramatic spread of *0101 into all human populations examined. Characterization of TAP1 polymorphisms allowed the design of a PCR-based genotyping scheme that targeted 7 SNP sites and required 2 separate genotyping techniques.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Causal pathways for CCR5 genotype and HIV progression.

A homozygous 32-bp deletion in the gene encoding CCR5, a major coreceptor for HIV-1, leads to resistance to infection with HIV-1, and heterozygosity for the deletion is associated with delayed disease progression in persons infected with HIV-1. We investigated the effect of CCR5 heterozygosity on disease progression as measured by both CD4+ T-cell count decline and the occurrence of clinical AIDS symptoms. Using a unified statistical model for CD4 count progression and AIDS development, we examined whether the effect of CCR5 heterozygosity on clinical AIDS is direct or indirect through its effect on CD4 counts. Based on data from the Multicenter AIDS Cohort Study, we noted a protective effect of CCR5 heterozygosity on both CD4 cell count progression and on AIDS occurrence. Furthermore, we found that this protective effect on the occurrence of AIDS was completely mediated through an effect on the CD4 marker. Additional adjustment for the effect of an initial viral load measurement indicate that CCR5 heterozygosity did not have predictive value for either CD4 progression or the development of AIDS beyond its association with early viral load.

Adult↗
PubMed1999

High rates of transmission of subtype E human immunodeficiency virus type 1 among heterosexual couples in Northern Thailand: role of sexually transmitted diseases and immune compromise.

The heterosexual transmission of subtype E human immunodeficiency virus type 1 (HIV-1) infection was evaluated in 467 couples in Thailand in whom the man was HIV-1 positive and the woman had no risk factors for HIV other than sex with her infected partner. At baseline, 216 (46.3%) of the 467 women were positive for HIV-1; prevalence of HIV among women was 52.2% when their male partners had CD4+ lymphocyte counts of <200 cells/microL, 45.9% in women whose partners had counts of 200-499 micro/L, and 39.2% in women whose partners had counts of >/=500/microL. Women were twice as likely to be HIV positive if their partners had a history of a sexually transmitted disease (STD); however, their HIV prevalence was 29% among couples who had no STD history. It appears that female partners of men infected with subtype E HIV-1 are at high risk of infection even when the man's CD4+ cell count is relatively high. A high rate of STDs may contribute significantly to this risk [corrected].

Blood Donors↗
PubMed1998

Genetic acceleration of AIDS progression by a promoter variant of CCR5.

The CCR5 gene encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for macrophage-tropic (R5) strains of human immunodeficiency virus-type 1 (HIV-1). Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of genotypes bearing CCR5P1, CCR5-Delta32, CCR2-64I, and SDF1-3'A affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection do so because they are homozygous for CCR5P1/P1, and 7 to 13 percent of all people carry this susceptible genotype. The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors limiting AIDS disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Patterns of HIV-1 evolution in individuals with differing rates of CD4 T cell decline.

Evolution of HIV-1 env sequences was studied in 15 seroconverting injection drug users selected for differences in the extent of CD4 T cell decline. The rates of increase of either sequence diversity at a given visit or divergence from the first seropositive visit were both higher in progressors than in nonprogressors. Viral evolution in individuals with rapid or moderate disease progression showed selection favoring nonsynonymous mutations, while nonprogressors with low viral loads selected against the nonsynonymous mutations that might have resulted in viruses with higher levels of replication. For 10 of the 15 subjects no single variant predominated over time. Evolution away from a dominant variant was followed frequently at a later time point by return to dominance of strains closely related to that variant. The observed evolutionary pattern is consistent with either selection against only the predominant virus or independent evolution occurring in different environments within the host. Differences in the level to which CD4 T cells fall in a given time period reflect not only quantitative differences in accumulation of mutations, but differences in the types of mutations that provide the best adaptation to the host environment.

Base Sequence↗
PubMed1997

Cultured blood dendritic cells retain HIV-1 antigen-presenting capacity for memory CTL during progressive HIV-1 infection.

Dendritic cells (DC) are potent APC that may be involved in the pathogenesis of HIV-1 infection. We studied the APC function of DC from HIV-1-infected subjects that were derived from monocyte-depleted PBMC by culture in human IL-4 and human granulocyte-macrophage CSF. The cultured cells from the HIV-1-infected subjects had similar morphology and phenotype of mature DC (CD80 = 41 +/- 8%, CD86 = 77 +/- 5%, CD40 = 87 +/- 6%, CD1a = 1 +/- 1%) to DC cultured from seronegative subjects. The yield of these DC was lower than from HIV-1-seronegative subjects (4 +/- 0% vs 11 +/- 2%, p < 0.01), and the lower DC yields correlated with lower numbers of blood CD4+ T cells (r = 0.60, p < 0.01) and higher plasma viral load (r = -0.49, p < 0.01). DC from HIV-1-infected subjects were infected with recombinant vaccinia virus vectors expressing Gag, Pol, and Env and were able to stimulate equal or higher levels of MHC class I-restricted, anti-HIV-1 memory CTL (CTLm) than were similarly treated, autologous B lymphocyte cell lines. DC pulsed with peptides representing HIV-1 CTL epitopes stimulated higher levels of anti-HIV-1 CTLm responses than did DC infected with the vaccinia virus-HIV-1 constructs. Allogeneic, MHC class I-matched DC also stimulated anti-HIV-1 CTLm activity in cells from HIV-1-infected subjects. DC from early and late stages of HIV-1 infection had a similar ability to activate CTLm specific for targets expressing either HIV-1 genes via vaccinia virus vectors or HIV-1 immunodominant synthetic peptides. However, DC from either early or late stages of HIV-1 infection could not overcome the defect in anti-HIV-1 CTLm response in advanced infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.

Anti-HIV Agents↗
PubMed1997

Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection.

The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus and viral RNA in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. We show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<10(7) cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.

Anti-HIV Agents↗
PubMed1997

Differential susceptibility of naive and memory CD4+ T cells to the cytopathic effects of infection with human immunodeficiency virus type 1 strain LAI.

CD4+ T lymphocytes of individuals infected with human immunodeficiency virus type 1 (HIV-1) exhibit a qualitative defect in their ability to mount memory responses to previously encountered antigens although their responses to mitogens remain normal. T cells responsible for memory responses can be distinguished from naive T cells based on differential expression of isoforms of the tyrosine phosphatase CD45. It has been suggested that memory CD4+ T cells from infected individuals have a greater virus burden than naive CD4+ T cells and that this accounts for the loss of recall responses in infected individuals. However, it has been unclear whether naive and memory T cells are equally susceptible to infection and to the cytopathic effects of the virus. We therefore infected highly purified resting naive and memory CD4+ T cells from HIV-1-seronegative individuals with HIV-1(LAI). Infected cells were then stimulated with phytohemagglutinin to render them permissive for viral replication. Cell viability and growth rate were monitored for 8 to 10 days as indicators of cytopathic effects induced by HIV-1(LAI). Our results indicated that naive and memory CD4+ T cells display marked differences in susceptibility to the cytopathic effects induced by HIV-1(LAI), infection. The cytopathic effects induced by HIV-1(LAI) were much more severe in memory CD4+ T cells than in naive CD4+ T cells. Differential cytopathic effects in naive and memory T cells were not due to differences in virus entry into and replication in these cell populations. Rather, memory cells were more susceptible to cytopathic effects. Pronounced cytopathic effects in memory cells were clearly detectable at 7 day postinfection. Cell death occurred at the single-cell level and was not accompanied by syncytium formation. The growth rate of infected memory CD4+ T cells was also severely compromised compared to that of naive CD4+ T cells, whereas the growth rates of both uninfected naive and memory CD4+ T cells were approximately the same. At least a portion of the dying cells exhibited biochemical changes characteristic of apoptosis. These results suggest that the selective functional defects present in the memory CD4+ T-cell subset of HIV-1-infected individuals may in part be the result of the greater susceptibility of memory T cells to cytopathic effects induced by HIV-1.

Apoptosis↗
PubMed1996

Longitudinal relation between smoking and white blood cells.

Higher white blood cell counts in smokers compared with nonsmokers have been well documented, but the longitudinal relation between changes in smoking and changes in white blood cells has not been well described. Since 1984, data have been collected semiannually by the Multicenter AIDS Cohort Study (MACS), a four-center prospective cohort study of acquired immunodeficiency syndrome (AIDS) in homosexual men. The study population includes 2,435 participants who were human immunodeficiency virus (HIV) seronegative as of September 1994 and who contributed 20,918 person-visits for this analysis. For individuals who modified their smoking behavior, changes in white blood cell counts occurred primarily during the first 6 months following changes in the amount of cigarettes smoked. Among former smokers who resumed smoking, the extent of the increase in white blood cell count depended on the number of cigarettes smoked. Specifically, increases of 241, 340, and 740 cells/microliter were observed for smokers who resumed smoking < 1, 1 to < 2, and > or = 2 packs/day, respectively. Conversely, smokers who quit smoking had a decrease of white blood cell count: -32, -629, and -1,122 cells/microliter for men who previously smoked < 1, 1 to < 2, and > or = 2 packs/day, respectively. Long-term ex-smokers, however, still had higher white blood cell counts than did never smokers. There was a high within-individual correlation of white blood cell count in persons who reported a consistent level of smoking (i.e., average correlations between two white blood cell counts 6 years apart were 0.51 for never smokers, 0.48 for ex-smokers, 0.56 for men who smoked < 1 pack/day, and 0.43 for men who smoked > or = 1 pack/day). These analyses indicate an acute effect of changes in smoking on changes in white blood cell count, a residual effect of having been a smoker, and high long-term tracking for white blood cell count.

Adult↗
PubMed1996

HIV-1 gp120-specific antibody-dependent cell-mediated cytotoxicity correlates with rate of disease progression.

The Ab-dependent cell-mediated cytotoxicity (ADCC) activity of anti-gp120 Abs in serum from four groups of HIV-1-positive individuals in the Multicenter AIDS Cohort Study was evaluated at several time points over a 10-yr period. HIV-1-positive individuals who progressed to AIDS within 3 yr of seroconversion (rapid progressors) were compared with seroconverters who did not progress to AIDS within 6 yr (nonrapid progressors) and individuals who were seropositive when they entered the study and did not progress to AIDS within 9-10 yr (nonprogressors). At the visit closest to AIDS, rapid progressors had significantly lower titers of Abs that mediate ADCC against HIV-1 gp120 than those of nonrapid progressors at corresponding visits or those of nonprogressors at any visit. Nonprogressors generally had high titers of ADCC Abs at all visits. Differences between ADCC titers of rapid progressors and nonrapid progressors or nonprogressors remained when longitudinal changes within individuals were compared. Among seroconverters who were nonrapid progressors, those with low or declining ADCC titers lost significantly more CD4+ cells during the study than those whose ADCC titers were stable or increasing, even though both groups had similar serum virion RNA levels. This demonstrates that high titers of Abs that mediate ADCC correlate with a successful host defense against AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Cyclosporin A attenuates genetic airway hyperresponsiveness in mice but not through inhibition of CD4+ or CD8+ T cells.

We examined the influence of T lymphocytes on genetically determined airway hyperresponsiveness to acetylcholine (ACh) in mice. A/J and C3H/HeJ mice were treated with the T-cell suppressant cyclosporin A [(CsA) 25 to 100 mg/kg, intraperitoneally (i.p.), for 5 to 10 days], whereas control animals received the vehicle or remained untreated. CsA treatment induced a dose-dependent suppression of mitogen-stimulated spleen cell proliferation which was equivalent between the two strains. A/J control animals demonstrated approximately 8-fold greater ACh-stimulated airway responsiveness, assessed by the time-integrated peak inspiratory pressure (APTI) compared with C3H/HeJ control mice. ACh-induced APTI was attenuated by CsA in a dose- and time-dependent manner in the A/J strain; no significant changes occurred in the C3H/HeJ strain. To determine whether lymphocyte subtypes mediated this response, we depleted T-cell subsets with either rat anti-mouse CD4+ (L3T4) monoclonal antibody (GK1.5, 500 micrograms, i.p.) or anti-CD8+ monoclonal antibody (J1.2, 500 micrograms; or YTS169.4, 150 micrograms, i.p.) and assessed airway responsiveness. No significant change in airway responsiveness was detected in either strain after CD4+ or CD8+ T-cell depletion. Thus, although CsA administration attenuated spleen cell activation and was associated with a marked attenuation of airway responsiveness in mice with genetically hyperresponsive airways, CD4+ and CD8+ T cells do not appear to mediate this response.

Acetylcholine↗
PubMed1995

In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency.

Although it is presumed that the integration of HIV-1 into the genome of infected CD4+ T lymphocytes allows viral persistence, there has been little direct evidence that CD4+ T cells with integrated provirus function as a latent reservoir for HIV-1 in infected individuals. Using resting CD4+ T-cell populations of extremely high purity and a novel assay that selectively and unambiguously detects integrated HIV-1, we show that resting CD4+ T cells harbouring integrated provirus are present in some infected individuals. However, these cells do not accumulate within the circulating pool of resting CD4+ T cells in the early stages of HIV-1 infection and do not accumulate even after prolonged periods in long-term survivors of HIV-1 infection. These results suggest that because of viral cytopathic effects and/or host effector mechanisms, productively infected CD4+ T cells do not generally survive for long enough to revert to a resting memory state in vivo.

Base Sequence↗
PubMed1995

Association between anti-CD4 antibodies and a decline in CD4+ lymphocytes in human immunodeficiency virus type 1 seroconverters.

Serum specimens (n = 161) from 31 persons before and after human immunodeficiency virus type 1 (HIV-1) seroconversion were tested for anti-CD4 antibodies. These antibodies were detected by both ELISA and Western blot in 55% (17/31) of subjects when HIV-1 seroconversion was detected and in 26% (8/31) from sera obtained 6-24 months earlier. A decrease in CD4+ cell number was associated more with development of anti-CD4 antibodies or peak anti-CD4 antibody activity than with development of anti-HIV-1 antibodies. Quantitative DNA polymerase chain reaction assay of peripheral blood mononuclear cells from 7 seroconverters showed evidence of HIV-1 infection in 4 of 4 specimens obtained after HIV-1 seroconversion but was nonreactive for 12 of 12 specimens obtained before HIV-1 seroconversion, including 4 specimens positive for anti-CD4 antibodies by ELISA and Western blot. Therefore, anti-CD4 antibodies are frequently present in the sera of HIV-1-infected persons before and at the time HIV-1 seroconversion is detectable and are associated with a decline in CD4+ cell counts, but they are not a marker for HIV-1 infection in seronegative persons.

Antibodies↗