Mucosal and systemic HIV-1-specific immunity in HIV-1-exposed but uninfected heterosexual men

BACKGROUND: Despite multiple, repeated exposures to HIV-1, some individuals never seroconvert. Mucosal and systemic immune correlates of this condition have been analysed in HIV-1-exposed women but no data are available concerning mucosal immunity and HIV-1-specific immune responses in exposed but uninfected men. DESIGN: We analysed cellular and humoral immune parameters in peripheral lymphocytes, seminal fluid and urethral swabs of 14 recently HIV-1-exposed seonegative (ESN) heterosexual men, seven HIV-seropositive patients and seven healthy controls. RESULTS: HIV-1-specific IgA were detected in urethral swabs of 11 out of 14 ESN and of six out of seven HIV-seropositive patients; Env- and Gag-specific IFNgamma-producing CD4 and CD8 peripheral lymphocytes were present in ESN and HIV-seropositive patients; seminal lymphocytes, but not peripheral blood lymphocytes, of ESN were enriched in activated populations (CD8CD38RO and CD4CD25). p24-specific cytotoxic T lymphocytes were correlated with the percentage of CD4 in the HIV-seropositive partners. High urethral concentrations of HIV-1-specific IgA were seen in those ESN with the most recent unprotected sexual episode. CONCLUSIONS: This is the first report of HIV-specific mucosal immunity in ESN men. These data add to the body of knowledge of the immune correlates present in exposed, uninfected individuals and might be important in vaccine design.     

Systemic immune activation in HIV-1-exposed uninfected Vietnamese intravascular drug users

To assess immunological parameters, including markers of immune activation, in highly HIV-1-exposed uninfected (EU) Vietnamese intravascular drug users (IDUs) in comparison with HIV-1-infected IDUs and HIVunexposed controls, we determined peripheral lymphocyte phenotypes in fresh whole blood samples from 32 EU IDUs, 28 HIV+ IDUs, and 26 blood donors. We found higher levels of activation markers (CD38, HLADR) on CD4+ and CD8+ T cells, lower percentages of naive CD4+ and CD8+ T cells, higher percentages of CD8+ T cells and of CD8+ T cells expressing CD25, and lower levels of CXCR4+CD4+ T cells in EU IDUs than in unexposed controls. Despite several differences in CD4+ and CD8+ T cell subset phenotypes, both EU and HIV+ IDUs exhibited a pattern of peripheral immune activation. Lymphocyte activation in EU IDUs may reflect immune stimulation driven by viral infections other than HIV-1 and/or allogeneic stimulation associated with needle sharing. Our results suggest that immune activation does not necessarily favor HIV-1 transmission, but, on the contrary, may alter the susceptibility of EUs to HIV-1 infection and contribute to their resistance.     

Persistent mitochondrial dysfunction in HIV-1-exposed but uninfected infants: clinical screening in a large prospective cohort

BACKGROUND: Antiretroviral prevention of mother to child HIV-1 is established but tolerance remains to be assessed.AIM To determine the risk for persistent mitochondrial dysfunction in HIV-uninfected children born to seropositive mothers. METHOD: An exhaustive study in a large prospective cohort with predetermined algorithm of the unexplained symptoms compatible with mitochondrial dysfunction. A total of 2644 of 4392 children were exposed to antiretrovirals. Complementary investigations were carried out on a case-by-case basis using classification with a diagnostic probability scale, based on experience with constitutional diseases. A spontaneous notification register for children not included in the cohort was created. RESULTS: Good circumstantial evidence of mitochondrial dysfunction was found for twelve children. Seven were from the cohort. All presented neurological symptoms, often associated with abnormal magnetic resonance image (10 of 12) and/or a significant episode of hyperlactatemia (seven of 12). All had either a profound deficit in one of the respiratory chain complexes (11 of 12) and/or a typical histological pattern (two of 12). All were perinatally exposed to antiretrovirals. None of them had perinatal morbidity that could explain this symptomatology. The 18-month incidence was 0.26% (95% confidence interval, 0.10-0.54) in exposed children, in comparison with the general figure of 0.01% for paediatric neuro-mitochondrial diseases in the general population. Fourteen other children in the cohort, all exposed to antiretrovirals, had unexplained symptoms, mostly neurological, for which one of the possible differential diagnoses was mitochondrial dysfunction. Close similarities in clinical, neuroradiological and histological findings strongly suggest a common pathological process in all these 26 children. CONCLUSION: Children exposed to nucleoside analogues during the perinatal period are at risk of a neurological syndrome associated with persistent mitochondrial dysfunction.     

Socio-demographic and epidemiological characteristics associated with human immunodeficiency virus type I (HIV-1) infection in HIV-1-exposed but uninfected individuals, and in HIV-1-infected patients from a southern Brazilian population

The ability to control human immunodeficiency virus type 1 (HIV-1) infection and progression of the disease is regulated by host and viral factors. This cross-sectional study describes the socio-demographic and epidemiological characteristics associated with HIV-1 infection in 1,061 subjects attended in Londrina and region, south of Brazil: 136 healthy individuals (Group 1), 147 HIV-1-exposed but uninfected individuals (Group 2), 161 HIV-1-infected asymptomatic patients (Group 3), and 617 patients with AIDS (Group 4). Data were obtained by a standardized questionnaire and serological tests. The age of the individuals ranged from 15.1 to 79.5 years, 54.0% and 56.1% of the Groups 3 and 4 patients, respectively, were men. The major features of groups 2, 3, and 4 were a predominance of education level up to secondary school (55.8%, 60.2% and 62.4%, respectively), sexual route of exposure (88.4%, 87.0% and 82.0%, respectively), heterosexual behavior (91.8%, 75.2% and 83.7%, respectively), and previous sexually transmitted diseases (20.4%, 32.5%, and 38.1%, respectively). The patients with AIDS showed the highest rates of seropositivity for syphilis (25.6%), of anti-HCV (22.3%), and anti-HTLV I/II obtained by two serological screening tests (6.2% and 6.8%, respectively). The results documenting the predominant characteristics for HIV-1 infection among residents of Londrina and region, could be useful for the improvement of current HIV-1 prevention, monitoring and therapeutic programs targeted at this population.     

Mucosal immune responses in the genital tract of HIV-1-exposed uninfected women

The development of HIV-1 vaccines and microbicides remains hindered by our limited understanding of correlates of immune protection to infection. Evidence indicating that resistance to HIV-1 infection is indeed possible comes from HIV-1-exposed yet uninfected individuals, including cohorts of commercial sex workers and discordant couples. Despite their uninfected status some of these individuals have mucosal and systemic HIV-1-specific humoral and cellular immune responses in addition to their innate immune response. The combined contribution of innate and adaptive immunity as well as genetic factors is most likely of great importance for this protection against infection. Here we review data on the antibody responses and secreted immune molecules of the innate immune system in the female genital tract with emphasis on individuals who seem to resist HIV-1-infection despite repeated exposure to the virus.     

Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma

The prognostic value of chromosomal abnormalities was studied in untreated multiple myeloma patients who were registered into a prospective randomised multicentre phase 3 study for intensified treatment (HOVON24). A total of 453 patients aged less than 66 years with stage II and III A/B disease were registered in the clinical study. Cytogenetic analysis was introduced as a standard diagnostic assay in 1998. It was performed at diagnosis in 160 patients and was successful in 137/160 patients (86%). An abnormal karyotype was observed in 53/137 (39%) of the patients. Abnormalities of chromosome 1p and 1q were found in 19 (36% of patients with an abnormal karyotype) and 21 patients (40%). There was a strong association between chromosome 1p and/or 1q abnormalities and deletion of chromosome 13 or 13q (n = 27, P < 0.001). Patients with karyotypic abnormalities had a significantly shorter overall survival (OS) than patients with normal karyotypes. Complex abnormalities, hypodiploidy, chromosome 1p abnormalities, chromosome 1q abnormalities, and chromosome 13 abnormalities were associated with inferior OS on univariate analysis, as well as after adjustment for other prognostic factors. In conclusion, chromosome 13 abnormalities and chromosome 1p and/or 1q abnormalities were highly associated, and are risk factors for poor outcome after intensive therapy in multiple myeloma.     

Submicroscopic deletions at 7q region are associated with recurrent chromosome abnormalities in acute leukemia

BACKGROUND AND OBJECTIVES: Loss of heterozygosity (LOH) on the long arm of chromosome 7 (7q) has been frequently reported in several types of human cancer including hematologic malignancies. Moreover, monosomy of chromosome 7 and 7q deletions have been associated in acute myeloid leukemia (AML) with aggressive disease and poor prognosis. DESIGN AND METHODS: Using a panel of 11 polymorphic microsatellite markers at bands 7q21-q36, we investigated fifty patients (acute myeloid leukemia [AML], n=33 and acute lymphoid leukemia [ALL], n=17) for LOH, a hallmark of possible involvement of tumor suppressor genes. In parallel, the same acute leukemia (AL) cases were studied by conventional cytogenetics. RESULTS: A total of 48 spots of allelic loss were observed in 16 (32%) out of 50 patients (AML, n=11 and ALL, n=5). Among LOH+ve cases 3 showed chromosome 7 monosomies, whereas no cytogenetically detectable abnormalities were observed in chromosome 7 in the remaining 13. INTERPRETATION AND CONCLUSIONS: Comparison with karyotypic results indicated that presence of LOH at 7q21-q36 was significantly associated with other chromosomal aberrations. In fact, an altered karyotype was detectable in 87% of LOH+ve and in 52% of LOH(-ve) AL cases (p=0.024). In addition, LOH at 7q was prevalently associated with unfavorable cytogenetic lesions (p=0.013). Our study represents the first report of a significant association between LOH and recurrent chromosomal abnormalities in AL patients suggesting that the 7q21-q36, region may be an unstable area prone to chromosome breakage in patients with an abnormal karyotype.     

Polymorphisms in chromosome region 12q13 and their influence on age at onset of type 1 diabetes

Aims/hypothesis  

A complex region covering numerous genes in 12q13 was first associated with type 1 diabetes in the Wellcome Trust Case–Control Consortium (WTCCC) study. Two studies performed in a white population have tested the association of polymorphisms within this region with age at onset of the disease, with seemingly contradictory results. We aimed at replicating three of the strongest signals in a group of patients with early and late disease onset.     

Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23

OBJECTIVE: To identify chromosome regions likely to harbor genes that predispose to the development of systemic lupus erythematosus (SLE) by analyzing a full genome scan in nuclear families ascertained for siblings with SLE. METHODS: Approximately 400 multiallelic markers spaced an average of 10 cM apart were genotyped in a multiethnic panel of 238 individuals from 62 multiplex SLE families having 88 affected sibling pairs and 456 total sibling pairs. Findings were analyzed by 2 model-free statistical linkage procedures. RESULTS: Evidence supporting linkage to 4 previously reported (1q23, 2q33, 16q12-13, and 17q21-23) and 4 novel (3p24, 10q23-24, 13q32, and 18q22-23) chromosome regions was revealed. Stratification by family ethnicity indicated that linkage to 3 regions, 2q33, 10q23-24, and 18q22-23, was derived primarily from the Caucasian families, while linkage to 17q21-23 was seen primarily in the non-Caucasian families. CONCLUSION: Linkage to the same chromosome regions in independent cohorts is a critical step in finding the genes that predispose to a complex disorder such as SLE. Four linked regions also seen in independent SLE cohorts lend credibility to the 4 novel regions identified by these analyses. Substantial linkage information was gleaned by genotyping and analyzing the unaffected siblings. These results provide additional evidence that the SLE clinical phenotype is genetically complex, multigenic, and heterogeneous.     

Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.

We report the results of two studies examining the genetic overlap between schizophrenia and velocardiofacial syndrome. In study A, we characterize two interstitial deletions identified on chromosome 22q11 in a sample of schizophrenic patients. The size of the deletions was estimated to be between 1.5 and 2 megabases. In study B, we examine whether variations in deletion size are associated with the schizophrenic phenotype in velocardiofacial syndrome patients. Our results show that a region of the genome that has been previously implicated by genetic linkage analysis can harbor genetic lesions that increase the susceptibility to schizophrenia. Our findings should facilitate identification and cloning of the schizophrenia susceptibility gene(s) in this region and identification of more homogeneous subgroups of patients.     

The nerve growth factor receptor gene is at human chromosome region 17q12-17q22, distal to the chromosome 17 breakpoint in acute leukemias.

Genomic and cDNA clones for the human nerve growth factor receptor have been used in conjunction with somatic cell hybrid analysis and in situ hybridization to localize the nerve growth factor receptor locus to human chromosome region 17q12-q22. Additionally, part, if not all, of the nerve growth factor receptor locus is present on the translocated portion of 17q (17q21-qter) from a poorly differentiated acute leukemia in which the chromosome 17 breakpoint was indistinguishable cytogenetically from the 17 breakpoint observed in the t(15;17)(q22;q21) translocation associated with acute promyelocytic leukemia. Thus the nerve growth factor receptor locus may be closely distal to the acute promyelocytic leukemia-associated chromosome 17 breakpoint at 17q21.     

Loss of heterozygosity on chromosome 10q22-10q23 and 22q11.2-22q12.1 and p53 gene in primary hepatocellular carcinoma

AIM: To analyze loss of heterozygosity (LOH) and homozygous deletion on p53 gene (exon2-3, 4 and 11), chromosome 10q22-10q23 and 22q11.2 -22q12.1 in human hepatocellular carcinoma (HCC). METHODS: PCR and PCR-based microsatellite polymorphism analysis techniques were used. RESULTS: LOH was observed at D10S579 (10q22-10q23) in 4 of 20 tumors (20%), at D22S421 (22q11.2-22q12.1) in 3 of 20(15%), at TP53.A (p53 gene exon 2-3) in 4 of 20(20%), at TP53.B (p53 gene exon 4) in 6 of 20(30%), and at TP53.G (p53 gene exon 11) in 0 of 20(0%). Homozygous deletion was detected at 10q22-10q23(8/20; 40%), 22q11.2-22q12.1(8/20; 40%), p53 gene exon 2-3(0/20;0%), p53 gene exon 4(6/20; 30%), and p53 gene exon 11(2/20; 10%). CONCLUSION: There might be unidentified tumor suppressor genes on chromosome 10q22-10q23 and 22q11.2-22q12.1 that contribute to the pathogenesis and development of HCC.     

Hypodiploidy and 22q11 rearrangements at diagnosis are associated with poor prognosis in patients with multiple myeloma

Our aim was to evaluate the clinical use of cytogenetic analysis as a prognostic factor in the outcome of newly diagnosed multiple myeloma (MM) patients. The present series includes 111 newly diagnosed MM patients treated with one of three standard-dose regimens or autologous transplantation over an 8-year time interval. As expected, the presence of an abnormal karyotype (39% of patients) correlated with poor prognosis (progression rate 63% v 47%, P =  0.042), shorter event-free (EFS, P  = 0.014) and overall (OS, P  = 0.005) survival. Two distinct cytogenetic abnormalities were the most significant variables that influenced EFS and OS in the univariate analysis. The presence of hypodiploid karyotypes or rearrangements of band 22q11 were associated with higher progression rate ( P =  0.001) and shorter EFS ( P  < 0.024) and OS ( P  < 0.004). The median EFS and OS for patients with hypodiploidy was 4 and 7 months respectively. Multivariate analysis showed that absence of hypodiploidy was the most favourable prognostic variable for OS ( P =  0.022) followed by stage ≤IIA, serum calcium ≤2875 μmol/l, and absence of abnormalities 22q. The data suggest that the presence of hypodiploid karyotypes and rearrangements on 22q11 band show a higher progression rate and shorter survival in MM patients.     

S-1 induced secondary acute erythroid leukemia with a chromosome inv（12）（p13;q13）

Adjuvant chemotherapy by S-1 following gastrectomy is considered standard treatment in Japan.Analysis of follow-up data have proved the effi cacy of S-1 admin-istration,and that hematological adverse events were relatively rare.Pyrimidine anti-metabolites,including S-1,have shown relatively lower risks for secondary hematological malignancies in comparison to alkylat-ing agents and topoisomerase-Ⅱ inhibitors.We here report a case of therapy-related leukemia after S-1 administration.A patient who had receive...