Biomedical subjects

Margaret A Johnson

Publications and source records attributed to Margaret A Johnson.

At least 19 recordsLinked to original sources

PubMed2007

Prevalence and predictors of antiretroviral drug resistance in newly diagnosed HIV-1 infection.

OBJECTIVES: To determine prevalence and predictors of antiretroviral drug resistance in newly diagnosed individuals with HIV-1 infection, using a systematic approach to avoid selection bias. METHODS: Plasma samples from all persons diagnosed HIV-1 seropositive at a large London centre between April 2004 and February 2006 underwent sequencing of HIV-1 reverse transcriptase (RT) and protease genes. Subtype was assigned by phylogenetic analysis. Resistance was scored according to the IAS-USA list (2005) modified to include T215revertants and exclude isolated E44D or V118I and minor protease mutations. Recent seroconversion was identified by HIV antibody avidity testing. RESULTS: The cohort of 239 included 169 (70.7%) males, 126 (52.7%) homosexuals, 118 (49.5%) persons of white ethnicity and 144 (60.0%) persons born outside the UK. Subtypes included B 134 (56.1%), C 46 (19.2%), A 17 (7.1%), other non-B 42 (17.6%). The prevalence of resistance mutations was 17/239 (7.1%; 95% confidence interval 4.5-11.1%), comprising 10/239 (4.2%) nucleoside/nucleotide RT inhibitor (NRTI); 4/239 (1.7%) non-nucleoside RT inhibitor (NNRTI) and 4/239 (1.7%) protease inhibitor (PI) associated mutations. Dual-class (NRTI + PI) resistance mutations were detected in 1/239 (0.4%) person. The prevalence of resistance mutations was 7/85 (8.2%) and 10/154 (6.5%) in persons with recent and established infection, respectively. In multivariate analysis, having been born in the UK and high CD4 count, but not gender, age, risk group, ethnicity or subtype, were independent predictors of resistance. CONCLUSIONS: In an unselected UK cohort, subtypes other than B accounted for 43.9% of new HIV-1 diagnoses. The prevalence of resistance mutations was 7.1% and highest in those born in the UK.

Acquired Immunodeficiency Syndrome↗

PubMed2007

Novel beta-barrel fold in the nuclear magnetic resonance structure of the replicase nonstructural protein 1 from the severe acute respiratory syndrome coronavirus.

The nonstructural protein 1 (nsp1) of the severe acute respiratory syndrome coronavirus has 179 residues and is the N-terminal cleavage product of the viral replicase polyprotein that mediates RNA replication and processing. The specific function of nsp1 is not known. Here we report the nuclear magnetic resonance structure of the nsp1 segment from residue 13 to 128, which represents a novel alpha/beta-fold formed by a mixed parallel/antiparallel six-stranded beta-barrel, an alpha-helix covering one opening of the barrel, and a 3(10)-helix alongside the barrel. We further characterized the full-length 179-residue protein and show that the polypeptide segments of residues 1 to 12 and 129 to 179 are flexibly disordered. The structure is analyzed in a search for possible correlations with the recently reported activity of nsp1 in the degradation of mRNA.

Amino Acid Sequence↗

PubMed2006

The stability of mRNA encoding IL-4 is increased in pulmonary tuberculosis, while stability of mRNA encoding the antagonistic splice variant, IL-4delta2, is not.

The prototype Th2 cytokine IL-4, and its competitive antagonist IL-4delta2, may be important determinants of outcome in human tuberculosis (TB). However, there are no data on how gene expression of these cytokines is regulated. To evaluate this the stability of IL-4 and IL-4delta2 mRNA after the addition of actinomycin-D, was evaluated in whole blood from subjects with pulmonary TB and uninfected healthy volunteers. The Th2/Th1 (IL-4/IFN-gamma) mRNA ratio in unstimulated cells in whole blood was significantly greater in TB subjects than in controls (p<0.05). The mRNA half-life of the agonist (IL-4), but not the antagonist (IL-4delta2), was significantly prolonged in subjects with TB compared to healthy volunteers ( approximately 5-fold, p=0.0016), and the IL-4/IL-4delta2 ratio was higher in TB patients compared to controls (p<0.05). The differential stability of the Th2 agonist, IL-4, compared to the antagonist IL-4delta2, represents a hitherto undescribed post-transcriptional regulatory mechanism that may modulate the polarisation of Th1/Th2 responses in human TB.

Adult↗

PubMed2006

A once-daily lopinavir/ritonavir-based regimen provides noninferior antiviral activity compared with a twice-daily regimen.

OBJECTIVE: To evaluate the safety and noninferiority and to explore the efficacy of administration of once-daily versus twice-daily lopinavir/ritonavir (LPV/r) in antiretroviral-naive HIV-1-infected subjects. DESIGN: Randomized, open-label, multicenter, comparative study. METHODS: One hundred ninety antiretroviral-naive subjects with plasma HIV-1 RNA level >1000 copies/mL and any CD4 cell count were randomized to lopinavir/ritonavir at a dose of 800/200 mg administered once daily (n = 115) or lopinavir/ritonavir at a dose of 400/100 mg administered twice daily (n = 75). Subjects also received tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg administered once daily. RESULTS: The median baseline plasma HIV-1 RNA level and CD4 count were 4.8 log10 copies/mL and 216 cells/mm, respectively. Before week 48, 20% (once daily) and 29% (twice daily) subjects discontinued. Virologic responses of the subjects through 48 weeks were comparable; 70% (once daily) and 64% (twice daily) achieved an HIV-1 RNA level <50 copies/mL by intent-to-treat, noncompleter = failure analysis. No subject demonstrated LPV or TDF resistance, but 3 subjects (2 in the once-daily group, 1 in the twice-daily group) demonstrated FTC resistance. Mean increases in CD4 count were similar. Diarrhea (16% in the once-daily group, 5% in the twice-daily group; P = 0.036) was the most common moderate or severe study drug-related adverse event. CONCLUSIONS: Through 48 weeks, a once-daily regimen of lopinavir/ritonavir + TDF + FTC appears to have similar virologic and immunologic responses in antiretroviral-naive subjects as the same regimen with lopinavir/ritonavir administered twice daily. Both regimens were relatively well tolerated, and no LPV or TDF resistance was observed.

Adult↗

PubMed2006

Modelling cytomegalovirus replication patterns in the human host: factors important for pathogenesis.

Human cytomegalovirus can cause a diverse range of diseases in different immunocompromised hosts. The pathogenic mechanisms underlying these diseases have not been fully elucidated, though the maximal viral load during infection is strongly correlated with the disease. However, concentrating on single viral load measures during infection ignores valuable information contained during the entire replication history up to the onset of disease. We use a statistical model that allows all viral load data sampled during infection to be analysed, and have applied it to four immunocompromised groups exhibiting five distinct cytomegalovirus-related diseases. The results show that for all diseases, peaks in viral load contribute less to disease progression than phases of low virus load with equal amount of viral turnover. The model accurately predicted the time of disease onset for fever, gastrointestinal disease and pneumonitis but not for hepatitis and retinitis, implying that other factors may be involved in the pathology of these diseases.

Cytomegalovirus↗

PubMed2006

Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials.

BACKGROUND: Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. METHODS: We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log(10) copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). FINDINGS: 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65.1%) patients on tipranavir-ritonavir and 192 (26.1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33.6%] vs 113 [15.3%]; p<0.0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0.0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group. INTERPRETATION: Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment.

Adult↗

PubMed2006

Detection of mycobacterial antigen responses in lung but not blood in HIV-tuberculosis co-infected subjects.

Forty-seven HIV-infected adults had broncho-alveolar lavage stimulated with purified protein derivate of Mycobacterium tuberculosis. Eighteen of 19 (95%) with tuberculosis co-infection had interferon-gamma synthetic CD4 lymphocyte responses > 1% versus three of 28 (11%) without (P < 0.0001). Lung response was unrelated to blood CD4 cell count. BAL HIV tuberculosis responses were similar in 25 HIV-uninfected tuberculosis patients. Responses in matched blood samples were often undetectable. Therefore, immunological tuberculosis assays seem less affected by HIV co-infection when lung-based.

Adult↗

PubMed2006

A randomised trial of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients: the UK-Vanguard Study.

OBJECTIVE: The objective of the trial was to evaluate in a pilot setting the safety and efficacy of interleukin-2 (IL-2) therapy when used without concomitant antiretroviral therapy as a treatment for HIV infection. DESIGN AND SETTING: This was a multicentre randomised three-arm trial conducted between September 1998 and March 2001 at three clinical centres in the United Kingdom. PARTICIPANTS: Participants were 36 antiretroviral treatment naïve HIV-1-infected patients with baseline CD4 T lymphocyte counts of at least 350 cells/mm(3). INTERVENTIONS: Participants were randomly assigned to receive IL-2 at 15 million international units (MIU) per day (12 participants) or 9 MIU/day (12 participants) or no treatment (12 participants). IL-2 was administered by twice-daily subcutaneous injections for five consecutive days every 8 wk. OUTCOME MEASURES: Primary outcome was the change from baseline CD4 T lymphocyte count at 24 wk. Safety and plasma HIV RNA levels were also monitored every 4 wk through 24 wk. The two IL-2 dose groups were combined for the primary analysis. RESULTS: Area under curve (AUC) for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm(3) for those assigned IL-2 (both dose groups combined) and 13 cells/mm(3) for control participants (95% CI for difference, 51.3-181.2 cells/mm(3); p = 0.0009). Compared to the control group, significant increases in CD4 cell count were observed for both IL-2 dose groups: 104.2/mm(3) (p = 0.008) and 128.4 cells/mm(3) (p = 0.002) for the 4.5 and 7.5 MIU dose groups, respectively. There were no significant differences between the IL-2 (0.13 log(10) copies/ml) and control (0.09 log(10) copies/ml) groups for AUC of change in plasma HIV RNA over the 24-wk period of follow-up (95% CI for difference, -0.17 to 0.26; p = 0.70). Grade 4 and dose-limiting side effects were in keeping with those previously reported for IL-2 therapy. CONCLUSIONS: In participants with HIV infection and baseline CD4 T lymphocyte counts of at least 350 cells/mm(3), intermittent subcutaneous IL-2 without concomitant antiretroviral therapy was well tolerated and produced significant increases in CD4 T lymphocyte counts and did not adversely affect plasma HIV RNA levels.

Journal Article↗

PubMed2006

Solution structure of Asl1650, an acyl carrier protein from Anabaena sp. PCC 7120 with a variant phosphopantetheinylation-site sequence.

Cyanobacteria, such as Anabaena, produce a variety of bioactive natural products via polyketide synthases (PKS), nonribosomal peptide synthetases (NRPS), and hybrid peptide/polyketide pathways. The protein Asl1650, which is a member of the acyl carrier protein family from the cyanobacterium Anabaena sp. PCC 7120, is encoded in a region of the Anabaena genome that is rich in PKS and NRPS genes. To gain new insight into the physiological role of acyl carriers in Anabaena, the solution structure of Asl1650 has been solved by NMR spectroscopy. The protein adopts a twisted antiparallel four-helix bundle fold, with a variant phosphopantetheine-attachment motif positioned at the start of the second helix. Structure comparisons with proteins from other organisms suggest a likely physiological function as a discrete peptidyl carrier protein.

Acyl Carrier Protein↗

PubMed2006

Changes over time in risk of initial virological failure of combination antiretroviral therapy: a multicohort analysis, 1996 to 2002.

BACKGROUND: Triple-combination antiretroviral therapy (CART) for human immunodeficiency virus infection has been in use for almost a decade, but the extent to which treatment success has changed is uncertain. We examined risk of initial virological failure of CART according to the year of starting therapy. METHODS: We included subjects from 5 complete clinic cohorts in Europe and Canada who started CART without previous antiretroviral therapy from 1996 to 2002 with 1 or more pre-CART viral load (VL) measurement and CD4 count. Based on the first VL measurement from 6 to 12 months after CART initiation, virological failure was defined as a VL of more than 500 copies/mL. We used the following 3 inclusion strategies: (1) including all subjects, with missing VL measurement counted as virological failure (n = 3825; strategy A); (2) including all subjects with VL measurement (n = 3120; strategy B); and (3) including all subjects receiving antiretroviral therapy at VL measurement (n = 2890; strategy C). RESULTS: From 1996 to 2002, risk of virological failure fell from 38.9% to 24.8% for strategy A, 28.4% to 12.0% for strategy B, and 22.8% to 8.2% for strategy C. Estimated relative reductions in risk (95% confidence interval) over the 7-year period, adjusted for cohort, demographic factors, pre-CART VL and CD4 count, and previous AIDS, were 48% (39%-56%), 64% (53%-73%), and 79% (69%-85%) for strategies A, B, and C, respectively. Reductions in risk were greatest from 1996 to 1999, with weaker trends subsequently. Trends remained but were attenuated after further adjustment for the starting regimen. CONCLUSIONS: Over a 7-year period of CART use in clinical practice, risk of initial virological failure of treatment has halved at least. These data suggest the trend is due to improvements in CART regimens and greater effectiveness of their use.

Adult↗

PubMed2006

Deaths in the era of HAART: contribution of late presentation, treatment exposure, resistance and abnormal laboratory markers.

OBJECTIVES: To describe the characteristics of deaths that occur among HIV-positive individuals in the HAART era. DESIGN: Observational database. METHODS: Deaths were reviewed that occurred among HIV-positive individuals seen at the Royal Free Hospital, London between January 1998 and December 2003. RESULTS: Over the study period, there were 121 deaths; death rates declined from approximately 2.0/100 person-years of follow-up in 1998-2000 to approximately 1.0/100 person-years of follow-up in 2001-2003. Approximately one half of deaths (45.5%) were from AIDS-related causes and 74 deaths (61.2%) occurred in individuals who had received HAART: patients had been exposed to a median of seven (range 2-14) antiretroviral drugs and two-fifths had started treatment in the pre-HAART era. Another 15 patients had received only non-HAART treatment regimens prior to death. The median pre-death CD4 cell counts were 68 and 167 cells/microl among those who had and had not received HAART; 23 (31.1%) and 4 (8.5%) had HIV RNA < 400 copies/ml, respectively. Of the patients exposed to HAART for at least 6 months and who experienced viral rebound, information was available on resistance for 26 (21.5% of the total deaths) and 19 of those tested had at least one resistance mutation (median 5, range, 1-16). CONCLUSIONS: While mortality rates among HIV-infected individuals at our centre have fallen since 1988, the deaths that do now occur are more diverse and are the result of a number of factors, including late presentation, delayed uptake of HAART and the previous use of treatment combinations that are now viewed as suboptimal.

Adolescent↗

PubMed2005

Performance of a T-cell-based diagnostic test for tuberculosis infection in HIV-infected individuals is independent of CD4 cell count.

The performance characteristics of the enzyme-linked immunospot assay (ELISPOT) assay (T-SPOT TB) for the diagnosis of latent tuberculosis infection in HIV-infected individuals are unknown. Given that ELISPOT enumerates Mycobacterium tuberculosis antigen-specific IFN-gamma-secreting T cells, HIV-associated immunosuppression might adversely affect test performance. However, we found that 28 out of 29 HIV-positive individuals (97%) gave evaluable test results, and performance was independent of the CD4 T-cell count. ELISPOT test performance appears to be independent of HIV-associated immunosuppression.

Adult↗

PubMed2005

Expression of a novel cytokine, IL-4delta2, in HIV and HIV-tuberculosis co-infection.

BACKGROUND: Correcting the Th2 shift in HIV/AIDS represents a potential intervention strategy. However data on interleukin (IL)-4 expression in HIV or AIDS are un-interpretable because of failure to distinguish between IL-4 and its splice variant and natural antagonist, IL-4delta2. OBJECTIVE: To determine Th1 [interferon (IFN)-gamma], IL-4delta2 and Th2 (IL-4) expression in whole blood and lung lavage from healthy volunteers and in HIV or HIV-tuberculosis (TB) co-infection. DESIGN: Cross-sectional with prospective cohort. METHODS: Expression of IL-4delta2, IL-4 and IFN-gamma were determined by quantitative real-time PCR, using unstimulated cells from whole blood and lung lavage, in 20 HIV-TB (pulmonary) co-infected patients, 20 matched HIV-positive controls and 20 HIV-negative healthy volunteers. Results were correlated with plasma viral load, CD4 cell counts, radiological scores and response to anti-TB treatment. RESULTS: Compared to HIV negative donors, stable HIV-positive donors did not have increased levels of mRNA encoding IL-4, IL-4delta2 or IFN-gamma in blood or lavage. By contrast, the HIV-TB co-infected donors had increased IL-4 and IFN-gamma in both compartments. However the antagonist, IL-4delta2 was increased only in lavage. Consequently the dominant form was IL-4delta2 in lavage, but IL-4 itself in blood. The lung IL-4/IFN-gamma ratio correlated with radiological disease extent. With anti-TB treatment, IL-4 levels did not change whilst IL-4delta2 levels increased significantly. CONCLUSIONS: IL-4 and its natural antagonist, IL-4delta2 and are not upregulated in the absence of opportunistic infection. However in HIV-TB co-infection both cytokines increase in lung, but only IL-4 in the periphery. Further studies are required to determine if IL-4 facilitates systemic HIV progression.

AIDS-Related Opportunistic Infections↗

PubMed2005

Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1.

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10-15 d, with a mean reduction of >or=1.6 log(10) copies/ml at all twice daily doses >or=100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

Anti-HIV Agents↗

PubMed2005

The rate of viral rebound after attainment of an HIV load <50 copies/mL according to specific antiretroviral drugs in use: results from a multicenter cohort study.

BACKGROUND: Relatively few data are available on the association between the use of specific antiretroviral drugs and the rate of viral rebound in those attaining a viral load (VL) <50 copies/mL while receiving highly active antiretroviral therapy (HAART). METHODS: Patients achieving a VL <50 copies/mL for the first time while receiving HAART were followed until viral rebound (2 consecutive VLs >500 copies/mL). Pre-HAART antiretroviral-naive patients were analyzed separately from those with nucleoside reverse transcriptase inhibitor (NRTI) experience. RESULTS: Of 3565 suppressed antiretroviral-naive patients, 381 experienced viral rebound (rate, 6.26 events/100 person-years of follow-up [pyrs] [95% confidence interval {CI}, 5.63-6.89 events/100 pyrs]). For those receiving efavirenz, the rate was 4.08 (95% CI, 3.16-5.01) events/pyrs. Compared with this, the rebound rate for those receiving indinavir was 1.52 times higher (rate ratio [RR], 1.52 [95% CI, 0.82-2.84]). RRs (95% CIs) for other drugs were: soft-gel saquinavir, 0.54 (0.07-3.97); nelfinavir, 2.44 (1.68-3.54); indinavir/ritonavir, 1.96 (1.02-3.77); saquinavir/ritonavir, 1.12 (0.48-2.61); lopinavir/ritonavir, 1.23 (0.58-2.59); nevirapine, 1.53 (1.11-2.10); and abacavir, 2.03 (1.26-3.25). Of 810 NRTI-exposed patients, 145 experienced viral rebound (rate, 8.29 [95% CI, 6.94-9.64] events/pyrs). For those receiving efavirenz, the rate was 5.25 (95% CI, 3.11-8.30) events/pyrs. Compared with this, the RRs (95% CIs) were: indinavir, 1.75 (0.82-3.73); hard-gel saquinavir, 3.48 (0.36-33.37); nelfinavir, 2.64 (1.37-5.08); indinavir/ritonavir, 0.32 (0.04-2.49); saquinavir/ritonavir, 0.64 (0.23-1.80); nevirapine, 1.65 (0.90-3.02); and abacavir, 1.82 (0.73-4.52). CONCLUSIONS: We must make comparisons of antiretroviral outcomes in observational data with caution; however, our results suggest that, in those with VLs <50 copies/mL, certain drugs may be associated with higher rebound rates than others.

Adult↗

PubMed2005

Lung remodeling in pulmonary tuberculosis.

Tuberculosis is a global public health catastrophe responsible for >8 million cases of illness and 2 million deaths annually. Pulmonary cavitation with cough-generated aerosol is the principle means of spread, and lung remodeling (healed cavitation, fibrosis, and bronchiectasis) is a major cause of lung disability, surpassing all other diffuse parenchymal lung diseases combined. Efficient granuloma turnover is mycobactericidal, and extracellular matrix is disbanded without scarring. In many with progressive disease, however, there is dysregulated granuloma turnover, liquefactive necrosis, and pathological scarring. The pathological mechanisms and the related immunological pathways underpinning these phenomena are reviewed in the present article. Further studies are needed to identify and develop specific immunotherapeutic interventions that target immunopathology, since they have the potential to substantially reduce spread.

Humans↗

PubMed2005

Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy?

OBJECTIVES: To assess whether highly active anti-retroviral therapy (HAART) contributes to the presentation of active tuberculosis (TB). DESIGN: Retrospective single-centre cohort study. METHODS: A total of 111 HIV-infected individuals with active TB were identified at an urban teaching hospital between February 1997 and April 2004. Those receiving HAART at the time of TB diagnosis were assessed. RESULTS: Nineteen of 111 (17%) were receiving HAART when TB developed. Within this group there appeared to be two distinct populations. Thirteen of 19, 12 from ethnic or social groups with high background rates of TB, developed disease a median of 41 days (range, 7-109) after starting HAART ('early TB' group). In six of 19 ('late TB' group), TB occurred a median of 358 days after HAART initiation (range, 258-598). The 'early TB' group had lower CD4 cell counts when starting HAART in comparison with the 'late TB' group (median; 87 versus 218 x 10 cells/l; P = 0.04); however no difference was observed in the rate of change of CD4 cell count (P = 0.5) or HIV load. Paradoxical reaction rate in the 'early TB' group was significantly greater than in the 'late-TB' group (62 versus 0%, P = 0.02) and greater than in a similar control population who started HAART while taking anti-TB therapy (62 versus 30%, P = 0.05). CONCLUSIONS: These data suggest anti-HIV treatment may amplify the presentation of active TB. This has implications for antiretroviral programmes in countries with high TB rates and warrants prospective investigation of a larger cohort.

AIDS-Related Opportunistic Infections↗

PubMed2005

In vivo and in vitro studies of a novel cytokine, interleukin 4delta2, in pulmonary tuberculosis.

RATIONALE: Tuberculosis progresses despite potent Th1 responses. A putative explanation is the simultaneous presence of a subversive Th2 response. However, interpretation is confounded by interleukin 4delta2 (IL-4delta2), a splice variant and inhibitor of IL-4. OBJECTIVE: To study levels of mRNA encoding IL-4 and IL-4delta2, and their relationship to treatment and clinical parameters, in cells from lung lavage and blood from patients with pulmonary tuberculosis. METHODS: IL-4delta2, IFN-gamma, IL-4, and soluble CD30 (sCD30) levels were measured by polymerase chain reaction and relevant immunoassays in 29 patients and matched control subjects lacking responses to tuberculosis-specific antigens. RESULTS: mRNA levels for IL-4 and IL-4delta2 were elevated in unstimulated cells from blood and lung lavage of patients versus control subjects (p < 0.005). In control subjects, there were low basal levels of IL-4 and IL-4delta2 mRNA expressed mainly by non-T cells (p < 0.05). However, in patients, there were greater levels of mRNA for both cytokines in both T- and non-T-cell populations (p < 0.05 compared with control subjects). Radiologic disease correlated with the IL-4/IFN-gamma ratio and sCD30 (p < 0.005). After chemotherapy, IL-4 mRNA levels remained unchanged, whereas IL-4delta2 increased in parallel with IFN-gamma (p < 0.05). Sonicates of Mycobacterium tuberculosis upregulated expression of IL-4 relative to IL-4delta2 in mononuclear cell cultures from patients (p < 0.05). CONCLUSIONS: A Th2-like response, prominent in T cells and driven by tuberculosis antigen, is present in tuberculosis and modulated by treatment, suggesting a role for IL-4 and IL-4delta2 in the pathogenesis of tuberculosis and their ratio as a possible marker of disease activity. The specific antigens inducing the IL-4 response require identification to facilitate future vaccine development strategies.

Adult↗