Shahed Murad

Presence of HIV-1 Gag-Specific IFN-γ+IL-2+ and CD28+IL-2+ CD4 T Cell Responses Is Associated with Nonprogression in HIV-1 Infection

HIV immunity is likely CD4 T cell dependent. HIV-specific CD4 T cell proliferative responses are reported to correlate inversely with virus load and directly with specific CD8 responses. However, the phenotype and cytokine profile of specific CD4 T cells that correlate with disease is unknown. We compared the number/function of Gag p24-specific CD4 T cells in 17 HIV-infected long-term nonprogressors (LTNPs) infected for a median of 14.6 years with those of 16 slow progressors (SPs), also HIV infected for a median of 14 years but whose CD4 count had declined to <500 cells/μl. Compared with SPs, LTNPs had higher numbers of specific CD4s that were double positive for IFN-γ and IL-2 as well as CD28 and IL-2. However, CD4 T cells that produced IL-2 alone (IL-2+IFN-γ−) or IFN-γ alone (IFN-γ+IL-2−) did not differ between LTNPs and SPs. The decrease in p24-specific CD28+IL-2+ cells with a concomitant increase of p24-specific CD28−IL-2+ cells occurred before those specific for a non-HIV Ag, CMV. p24-specific CD28−IL-2+ cells were evident in LTNPs and SPs, whereas the CMV-specific CD28−IL-2+ response was confined to SPs. The difference between LTNPs and SPs in the Gag p24 IFN-γ+IL-2+ response was maintained when responses to total Gag (p17 plus p24) were measured. The percentage and absolute number of Gag-specific IFN-γ+IL-2+ but not of IFN-γ+IL-2− CD4s correlated inversely with virus load. The Gag-specific IFN-γ+IL-2+ CD4 response also correlated positively with the percentage of Gag-specific IFN-γ+ CD8 T cells in these subjects. Accumulation of specific CD28−IL-2+ helpers and loss of IFN-γ+IL-2+ CD4 T cells may compromise specific CD8 responses and, in turn, immunity to HIV.

Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients

Objectives: To compare the rate of hepatic fibrosis progression in hepatitis C virus (HCV) infected and human immunodeficiency virus (HIV)-HCV coinfected patients, and to identify factors that may influence fibrosis progression. Patients and methods: A total of 153 HCV infected and 55 HCV-HIV coinfected patients were identified from two London hospitals. Eligible patients had known dates of HCV acquisition, were HCV-RNA positive, and had undergone a liver biopsy, which was graded using the Ishak score. Univariate and multivariate logistic regression analyses were used to identify factors associated with fibrosis progression rate and the development of advanced fibrosis (stages 3 and 4). Results: The estimated median fibrosis progression rate was 0.17 units/year (interquartile range (IQR) 0.10–0.25) in HIV-HCV coinfected and 0.13 (IQR 0.07–0.17) in HCV monoinfected patients (p=0.01), equating to an estimated time from HCV infection to cirrhosis of 23 and 32 years, respectively. Older age at infection (p<0.001), HIV positivity (p=0.019), higher alanine aminotransferase (ALT) level (p=0.039), and higher inflammatory activity (p<0.001) on first biopsy were all independently associated with more rapid fibrosis progression. ALT was correlated with histological index (r=0.35, p<0.001). A CD4 cell count ⩽250×106/l was independently associated with advanced liver fibrosis (odds ratio 5.36 (95% confidence interval 1.26–22.79)) and was also correlated with a higher histological index (r=−0.42, p=0.002). Conclusion: HIV infection modifies the natural history of HCV by accelerating the rate of fibrosis progression by 1.4 fold, and the development of advanced fibrosis threefold. A low CD4 cell count was independently associated with advanced disease and correlated with higher histological index, which suggests that early antiretroviral therapy may be of benefit in slowing HCV progression in coinfected patients.

Respiratory symptoms, asthma, exercise test spirometry, and atopy in schoolchildren from a Lima shanty town

BACKGROUND Little is known about the associations between symptoms of asthma, pulmonary function tests, and atopy in developing countries. While asthma in children is often associated with atopy, some studies of wheezing illness have found little or no association, leading to suggestions that there are subgroups of wheezing illness. The ISAAC study recently reported that the prevalence of reported asthma symptoms in Lima, Peru was among the highest in the world, but did not report on the atopic status of the subjects. METHODS A cross sectional survey was conducted of children aged 8–10 years who had previously participated in a cohort study of respiratory and diarrhoeal illnesses in infancy. Questionnaires were administered asking about respiratory symptoms and asthma diagnoses, pulmonary function tests were performed before and after exercise on a treadmill, and atopy was determined from skin prick tests and specific serum IgE levels. RESULTS A total of 793 children participated in the survey. The prevalence of asthma related symptoms in the last 12 months was 23.2%, but only 3.8% of children reported a recent asthma attack. The mean differences in pretest percentage predicted forced expiratory volume in one second (FEV1) were 8.1% (95% CI 2.4 to 13.8) between children who did and did not report an asthma attack in the last 12 months, and 5.3% (95% CI 2.8 to 7.9) in children who did and did not report respiratory symptoms. The corresponding differences in mean percentage fall in FEV1 after exercise were 3.1% (95% CI –1 to 7.1) and 5.1% (95% CI 3.4 to 6.8). Recent asthma or respiratory symptoms were not associated with atopy in this population (odds ratios 1.29 (95% CI 0.56 to 2.97) and 0.91 (95% CI 0.61 to 1.37), respectively). CONCLUSIONS Most asthma in these children was unrecognised and mild. Asthma and asthma symptoms in this population do not seem to be related to atopy.

Ethnic differences in stage of presentation of adults newly diagnosed with HIV‐1 infection in south London

To establish whether there were ethnic differences in demographic characteristics, the stage at HIV diagnosis and reasons for and location of HIV testing between 1998 and 2000 in a large ethnically diverse HIV‐1‐infected clinic population in south London in the era of highly active antiretroviral therapy.

High Rates of Clustering of Strains Causing Tuberculosis in Harare, Zimbabwe: a Molecular Epidemiological Study

ABSTRACT We examined the pattern of tuberculosis (TB) transmission (i.e., reactivation versus recent transmission) and the impact of human immunodeficiency virus (HIV) infection in Harare, Zimbabwe. Consecutive adult smear-positive pulmonary TB patients presenting to an urban hospital in Harare were enrolled. A detailed epidemiological questionnaire was completed, and tests for HIV type 1 and CD4 cell counts were performed for each patient. Molecular fingerprinting of the genomic DNA recovered from cultures of sputum was performed by two molecular typing methods: spacer oligonucleotide typing (spoligotyping) and analysis of variable number of tandem DNA repeats (VNTRs). A cluster was defined as isolates from two or more patients that shared the same spoligotype pattern or the same VNTR pattern, or both. DNA suitable for typing was recovered from 224 patients. The prevalence of HIV infection was 79%. Of 187 patient isolates (78.6%) typed by both spoligotyping and analysis of VNTRs, 147 were identified as part of a cluster by both methods. By spoligotyping alone, 84.1% of patient isolates were grouped into 20 clusters. The cluster size was generally <8 patient isolates, although three large clusters comprised 68, 25, and 23 patient isolates. A total of 89.4% of the patient isolates grouped into 12 clusters defined by analysis of VNTRs, with 2 large clusters consisting of 127 and 13 patient isolates, respectively. Thirty-six percent of patient isolates with a shared spoligotype and 17% with a shared VNTR pattern were geographically linked within Harare, but they were not linked on the basis of the patients home district. In a multivariate analysis, there were no independent predictors of clustering, including HIV infection status. Comparison with the International Spoligotype database (Pasteur Institute, Pointe à Pitre, Guadeloupe) demonstrated that our three largest spoligotype clusters are well recognized and ubiquitous in Africa. In this epidemiologically well characterized urban population with a high prevalence of HIV infection, we identified a very high level of strain clustering, indicating substantial ongoing recent TB transmission. Geographic linkage could be detected in a proportion of these clusters. A small group of actively circulating strains accounted for most of the cases of TB transmission.

Epidemiological risk factors for hypersensitivity reactions to abacavir

We investigated risk factors for hypersensitivity reactions (HSR) to abacavir in a case–control study. In a multivariate analysis, white race [odds ratio (OR), 5.16; 95% confidence interval (CI), 1.16–22.97] and a higher CD8 cell count at initiation of abacavir (>850 vs. ≤850 cells: OR, 3.74; 95% CI, 1.19–11.77) were found to be significantly associated with the development of HSR. Age, gender, stage of disease, prior antiretroviral exposure and type of concurrent antiretroviral therapy were not associated with HSR. Differences in predisposition to HSR according to ethnicity and baseline CD8 cell count may be explained by the reported MHC genetic associations with HSR.

Possession of human leucocyte antigen DQ6 alleles and the rate of CD4 T‐cell decline in human immunodeficiency virus‐1 infection

Polymorphism amongst the human leucocyte antigen (HLA) class II genes could influence antigen presentation and the ability to control human immunodeficiency virus (HIV)‐1 by modulating the virus specific CD4 immune response. To examine the effect of such polymorphisms on disease progression, we studied a cohort of 46 HIV‐1 infected long‐term non‐progressors (LTNPs), 87 intermediate progressors (IPs) and 26 rapid progressors. Kaplan–Meier survival analysis of all patients in the cohort on time to a CD4 count less than 350 cells/µl, showed a trend for a slower rate of CD4 decline in patients with, compared to those without, the DRB1*15‐DQB1*06 haplotype (hazard ratio (HR) 0·69, 95% CI 0·46–1·01, P = 0·06). A similar effect was not observed with the DRB1*13‐DQB1*06 haplotype (HR 1·18, 95% CI 0·75–1·88, P = 0·46), but was observed when DQB1*06 alleles were considered irrespective of their DR association (HR 0·74, 95% CI 0·52–1·05, P = 0·06). Major HLA‐DQ6 alleles encode aspartate (Asp) at position 57 on the DQβ chain, a phenotype associated with protection from other immune disorders. We therefore examined the frequency of all DQβ57 Asp+ alleles, but could not detect a significant effect on the rate of CD4 decline. To examine whether the genotype associated with slower CD4 decline was over‐represented in patients with a slow rate of disease progression, we conducted a categorical analysis of a subset of patients with an extended follow‐up of 14+years. We found a higher proportion of LTNPs at 14+ years possessed the DRB1*15‐DQB1*06 haplotype compared to IPs at 14+ years (38·46 versus 18·18%), though this difference did not reach statistical significance. When DQB1*06 alleles irrespective of their DR association were considered, the protective effect was greater (76·9% LTNPs versus 18·18% IPs, P = 0·04). Our results highlight the potential protective effect of HLA DQB1*06 alleles on the course of HIV disease.

CD4 responses to conserved HIV-1 T helper epitopes show both negative and positive associations with virus load in chronically infected subjects

Characterization of immune responses to immunodominant CD4 epitopes in HIV‐1 that are associated with control of HIV infection could be used to strengthen the efficacy of polyepitope HIV vaccines. We measured both the proliferative and the CD4 interferon (IFN)‐γ and interleukin (IL)‐2 cytokine responses specific for 11 previously identified HIV‐1 T helper epitopes in 10 HIV‐infected non‐progressors (LTNPs) (infected for a median of 15 years with a stable CD4 count of >500 cells × 106/l), and seven slow progressors (SPs) (infected for a median of 15 years with a CD4 count that had declined to <500 cells × 106/l). Both groups were antiretroviral treatment‐naive at the time of evaluation. The median virus load of SP group was higher than that of the LTNP group (P = 0·0002). The CD4 response to a peptide pool representing all potential CD4 Gag epitopes and to Gag p24 protein was also studied. Compared to SPs, LTNPs had higher numbers of Gag‐specific IFN‐γ+IL‐2+ CD4s (P = 0·0059). The Gag‐specific cytokine and proliferative responses correlated inversely with virus load (P = 0·03 and 0·0002, respectively), highlighting the potential importance of this response in immunity to HIV. A direct correlation was noted between proliferation and the Gag‐specific IL‐2 (P = 0·0053) rather than IFN‐γ response (P = 0·1336), demonstrating that the proliferation assay reflected the IL‐2 rather than the IFN‐γ secreting capacity of CD4 cells. Several subjects with diverse class II DRB1 alleles responded, confirming the 11 selected peptides to be both antigenic and conserved. CD4 cytokine responses to one Gag and two conserved Pol peptides correlated negatively with virus load. The cytokine response to two additional Pol peptides correlated positively with virus load. The data indicate that there is not an absolute correlation between the CD4 immune response to conserved and broadly antigenic helper T cell epitopes in HIV non‐progression.

Use of flexibility tests in the manufacturing process of 60° björk-shiley convexo-concave valves and the risk of outlet strut fracture☆

OBJECTIVES Outlet strut fracture remains a concern for 30,000 patients living with a Björk-Shiley convexo-concave heart valve (Shiley, Inc, Irvine, Calif, a subsidiary of Pfizer, Inc). Previous studies (Netherlands and United Kingdom) investigating valve manufacturing aspects identified multiple performance of the hook deflection test as a risk factor for 60 degrees valves. The present study validated this finding using new data with a greater number of valves implanted worldwide. Risks of outlet strut fracture associated with other manufacturing aspects were also investigated. METHODS A matched case-control study design was used including 416 outlet strut fracture cases and 803 controls. RESULTS Analyses similar to that of the Dutch and United Kingdom studies produced odds ratios of 3.4 (95% confidence interval [CI]: 1.1-10.3) and 2.8 (95% CI: 1.1-7.3), respectively, for multiple hook deflection tests. Load deflection test, which replaced the hook deflection test, showed a statistically significant association with outlet strut fracture: odds ratio of 5.0 (95% CI: 2.1-11.8) and 6.2 (95% CI: 2.2-18.0) for single and multiple load deflection tests, respectively. An analysis where hook deflection tests were separated from load deflection tests showed significantly elevated odds ratios with performance of any type of flexibility test, and the highest odds ratio was observed with a combined performance of load and hook deflection tests. CONCLUSIONS Multiple hook deflection tests can now be considered for inclusion in the risk model used for guidelines on explant surgery to improve prediction of outlet strut fracture and provide patient reassurance. Load deflection tests and combined performance of hook and load deflection tests were found to be significant risk factors. No outlet strut fractures were reported for valves manufactured after March 1984 when the load deflection test was still in place. Examining manufacturing documents for these valves may identify new risk factors that could be responsible for the outlet strut fractures risk that remains unexplained to date.