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Biomedical subjects

K Ariyoshi

Publications and source records attributed to K Ariyoshi.

At least 37 records · Page 2Linked to original sources
PubMed1999

Broadly cross-reactive HIV-specific cytotoxic T-lymphocytes in highly-exposed persistently seronegative donors.

HIV-specific cytotoxic T-lymphocytes (CTL) are believed to play a key part in the control of virus levels throughout HIV infection. An important goal of a potential prophylactic vaccine against HIV is therefore to elicit a strong CTL response which is broadly cross-reactive against a diverse range of HIV strains. We have detected HIV-specific CTL in two groups of highly-exposed but persistently seronegative female sex workers in Africa which show extensive cross-reactivity between different viral sequences. In a small group of women exposed to both HIV-1 and HIV-2 in Gambia, studied over 4 years, we have repeatedly detected HLA-B35-restricted CTL which exhibit cross-reactivity between the HIV-1 and HIV-2 sequences of the CTL epitopes. In women with particularly intense exposure to what are likely to be multiple clades of HIV-1 in Nairobi Kenya, we have detected CTL directed towards epitopes conserved between HIV-1 clades. In neither group is there any evidence that variation in CCR5 sequence or expression is responsible for their apparent resistance to HIV infection. However, in seropositive donors from Oxford infected with African strains of HIV-1, we have defined CTL responses which are specific for particular clades and have mapped some unique A clade CTL epitopes, together with others to highly-conserved regions of the virus. Further information about the extent of cross-reactive CTL immunity will be important for future vaccine design and evaluation.

Amino Acid Sequence↗
PubMed1999

Proviral load and immune function in blood and lymph node during HIV-1 and HIV-2 infection.

Proviral load as well as lymphocyte phenotype and function were compared in peripheral blood and lymph node compartments of 17 HIV-1, 12 HIV-2 and three dually infected patients with lymphadenopathy. The mean percentage (95% confidence interval (CI)) of CD4+ cells was higher in lymph node mononuclear cells (LNMC) than in peripheral blood mononuclear cells (PBMC) in both infections, being 26.7% (21. 1%, 32.3%) and 15.3% (10.4%, 20.2%), respectively, for HIV-1-infected patients (P = 0.0001) and 32.3% (22.7%, 41.9%) and 22. 1% (13.6%, 30.6%), respectively, for HIV-2-infected patients (P = 0. 02). In both types of infection, proviral load adjusted for number of CD4+ cells was higher in LNMC than in PBMC: the geometric mean (95% CI) was 8937 (4991; 16 003) and 4384 (2260; 8503), respectively, for HIV-1 patients (P = 0.02) and 1624 (382; 6898) and 551 (147; 2058) DNA copies, respectively, for HIV-2 patients (P = 0.05). Proviral load in both compartments was closely correlated (HIV-1, r = 0.60, P = 0.01; and HIV-2, r = 0.83, P = 0.0003). In both infections, proliferation and interferon-gamma (IFN-gamma) production in response to purified protein derivative (PPD) was lower in LNMC than in PBMC, both of which, in turn, were lower than in healthy controls. These results indicate that in HIV-2 as in HIV-1 infection, infected cells have a tropism for the lymph nodes resulting in higher viral load in this compartment and lower lymphocyte responses to the recall antigen PPD which may increase susceptibility to tuberculosis.

Adult↗
PubMed1999

Retinal manifestations of HIV-1 and HIV-2 infections among hospital patients in The Gambia, west Africa.

BACKGROUND: In developed countries, 50-75% of AIDS patients develop retinal complications and about 20-40% acquire cytomegalavirus (CMV) retinitis. We conducted a cross-sectional survey to determine prevalence of these in The Gambia where both HIV-1 and HIV-2 infection are present and the prevalence of HIV-1 is rising. METHOD: All patients attending hospital whose percentage CD4+ cells (CD4%) was below 14, the level associated typically with an AIDS diagnosis, and one half of those whose CD4% was 14 or above were asked to join the study. Fifty-six HIV-1, 52 HIV-2 and 12 dually infected patients were recruited. Photographs of the fundi were taken and interpreted independently. The findings were related to the patients' percentage CD4+ cells. RESULTS: The CD4% was < 14 in 40 patients and < 7 in 17 patients. Thirty-six patients were male. No cases of CMV retinitis were found. Four patients whose CD4% were 4, 5, 11 and 23 had cotton wool spots ranging in number from 1 to 14 for any one patient. The prevalence of cotton wool spots was 8% (95% CI, 0-16%) among patients with CD4% below 14 and 12% (95% CI, 0-27) among patients with CD4% below 7. One of the 4 patients had associated microaneurysm and blot haemorrhages typical of more advanced HIV microvasculopathy. CONCLUSION: CMV retinitis is less common in The Gambia than in developed countries. Non-infectious retinopathy may also be less common.

AIDS-Related Opportunistic Infections↗
PubMed1999

Second lung adenocarcinoma after combination chemotherapy in two patients with primary non-Hodgkin's lymphoma.

We report a rare complication of a secondary malignant solid tumor in two patients with non-Hodgkin's malignant lymphoma who developed lung adenocarcinoma after treatments with combination chemotherapies. The first was a case of primary malignant lymphoma of the cervical spinal cord which had been previously treated with radiation to the spinal lesion and combination chemotherapies and entered complete remission. The patient was further treated for relapse with autologous bone marrow transplantation preconditioned with high-dose chemotherapy. Lung adenocarcinoma developed 5.5 years after the initial diagnosis. The second case of malignant lymphoma of lymph nodes did not respond to conventional combination chemotherapies and did not enter remission. Lung adenocarcinoma developed 1 year after the initial diagnosis. The two patients died of lung carcinoma. The clinical profiles of these cases are presented and the causal relationship of primary malignant neoplasms to the second malignant neoplasms is discussed.

Adenocarcinoma↗
PubMed1998

Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi.

Many people who remain persistently seronegative despite frequent HIV exposure have HIV-specific immune responses. The study of these may provide information about mechanisms of natural protective immunity to HIV-1. We describe the specificity of cytotoxic T lymphocyte responses to HIV in seronegative prostitutes in Nairobi who are apparently resistant to HIV infection. These women have had frequent exposure to a range of African HIV-1 variants, primarily clades A, C, and D, for up to 12 yr without becoming infected. Nearly half of them have CTL directed towards epitopes previously defined for B clade virus, which are largely conserved in the A and D clade sequences. Stronger responses are frequently elicited using the A or D clade version of an epitope to stimulate CTL, suggesting that they were originally primed by exposure to these virus strains. CTL responses have been defined to novel epitopes presented by HLA class I molecules associated with resistance to infection in the cohort, HLA-A*6802 and HLA-B18. Estimates using a modified interferon-gamma Elispot assay indicate a circulating frequency of CTL to individual epitopes of between 1:3,200 and 1:50,000. Thus, HIV-specific immune responses-particularly cross-clade CTL activity- may be responsible for protection against persistent HIV infection in these African women.

Amino Acid Sequence↗
PubMed1998

Angiogenesis in adenocarcinoma of the uterine cervix.

BACKGROUND: Angiogenesis is essential for tumor growth, progression, and metastases. Microvessel density (MVD), a measure of tumor angiogenesis, has been found to have prognostic significance in many tumor types for predicting metastasis and survival. METHODS: Between 1979-1989, 56 cases of FIGO Clinical Stage I and II adenocarcinoma of the uterine cervix treated by hysterectomy were reviewed histologically. All hysterectomy specimens were stained immunohistologically for factor VIII-related antigen. MVD was counted in a x200 field (0.785 mm2 per field) in the most active area of neovascularization. Results were expressed as the highest number of microvessels identified within any single x200 field. MVD and several other prognostic parameters were examined for correlation with progression free survival (PFS) and overall survival (OS) by a multivariate analysis according to the Cox proportional hazards model. RESULTS: In early adenocarcinoma of the uterine cervix, MVD was increased significantly in invasive areas compared with adjacent nonneoplastic areas (median: 62.5 [range, 30-105] vs. median: 36.5 [range, 23-47]; P=0.0003). MVD also was significantly correlated with ascites cytology (P=0.0377). There was no correlation between microvessel count and lymph node status, depth of invasion, disease stage, lymph-vascular space invasion, grade, or parametrial involvement. Patients with high MVD (> or=75) had significantly worse PFS and OS than those with low MVD (< 75) (log rank test, P=0.0180 and 0.0199, respectively). Multivariate analysis showed that MVD correlated significantly and independently with PFS and OS. CONCLUSIONS: In adenocarcinoma of the cervix, MVD is an independent prognostic factor for PFS and OS.

Adenocarcinoma↗
PubMed1998

Improved detection of HIV-2 proviral DNA in dually seroreactive individuals by PCR.

OBJECTIVE: To improve the detection rate of HIV-2 proviral DNA in primary uncultured peripheral blood mononuclear cells (PBMC) of HIV-2-seroreactive and HIV-1-HIV-2 dually seroreactive individuals. MATERIALS AND METHODS: Two newly designed HIV-2 PCR primer pairs in the long terminal repeat (LTR) gag and gag-pol regions and a previously described env and LTR HIV-2 PCR primer pairs were tested on samples from 66 confirmed HIV-2-seropositive individuals (The Gambia, 40; Côte d'Ivoire, 17; Guinea-Bissau, nine), 209 dually seroreactive individuals (The Gambia, 82; Côte d'Ivoire, 127), 24 genetically characterized isolated HIV-1 strains (group M subtypes A-H and group O), one simian immunodeficiency virus (SIV) strain cpz, 10 HIV-2 isolates (subtype A, B and unidentified), two SIVsm isolates, and 10 seronegative samples. RESULTS: All HIV-2 primers evaluated showed 100% specificity since there was no amplification observed with 24 HIV-1, one SIVcpz and 10 seronegative samples. One single copy of the HIV-2 genome could be detected with all outer primer pairs as well as all inner primer pairs on one PCR round used. Sensitivity of primers (at least one of the four primer pairs was positive) to HIV-2-seropositive samples was 100% (all nine) in Guinea-Bissau, 71% (12/17) in Côte d'Ivoire, 100% (all 20) in Gambian AIDS patients, and 85% (17/20) in Gambian pregnant women. Doubling the PBMC of dually seroreactive individuals from 7.5 x 10(4) to 1.5 x 10(5) in the PCR revealed the presence of both HIV-1 and 2 proviral DNA in 72% (92/127) in Côte d'Ivoire and 72% (59/82) in The Gambia. By doubling the number of PBMC, HIV-2 detection in dually seroreactive individuals by PCR was increased from 65 to 77% in Côte d'Ivoire and from 67 to 83% in The Gambia. CONCLUSIONS: The use of 1.5 x 10(5) primary uncultured PBMC and the newly designed HIV-2 primer pairs allowed us to document the highest percentage (72%) ever reported of HIV-1-HIV-2 dual infections amongst HIV-1-HIV-2 dually seroreactive individuals in Côte d'Ivoire and The Gambia. Improved detection of HIV-2 proviral DNA, rather than exposure to both viruses, infection with only one virus, or infection with a unique third virus containing epitopes common to both HIV-1 and HIV-2, contributes to a more accurate monitoring of the prevalence of HIV-1-HIV-2 dual infections.

DNA Primers↗
PubMed1998

A case of therapy-related acute myeloblastic leukemia with t(16;21)(q24;q22) after chemotherapy with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and the alkylating agent, cyclophosphamide.

A 59-year-old female suffering from malignant lymphoma developed therapy-related acute myeloblastic leukemia (t-AML) after chemotherapy consisting of treatment with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and an alkylating agent, cyclophosphamide. The cumulative dose of etoposide administration was 5500 mg; 1500 mg given intravenously and 4000 mg orally. One year later, she suddenly developed AML of FAB M2. Cytogenetic analysis of bone marrow cells revealed deletion of 7q and a rare translocation, t(16;21)(q24;q22). Southern blot analysis of bone marrow cells did not detect rearrangement of the AML1 gene, however, fluorescence in situ hybridization (FISH) analysis of bone marrow cells at interphase and metaphase revealed a translocational splitting between chromosome 21 involving AML1 gene and chromosome 16. These results suggest that the breakpoint is not located in the breakpoint cluster region for t(8;21). The patient was treated with chemotherapy and entered complete remission.

Alkylating Agents↗
PubMed1998

HIV-2 and T cell recognition.

HIV-2 is less pathogenic and less transmissible than HIV-1. Recent research in relation to deletions in the HIV nef gene and to immune cross-reactions between infections by HIV-2, HIV-1 and simian immunodeficiency virus suggests that T cell recognition and the control of viral replication may be more efficient in HIV-2 infection than in HIV-1 infection. These insights may be crucial to the design of effective vaccines.

AIDS Vaccines↗
PubMed1998

Mortality among human immunodeficiency virus type 2-positive villagers in rural Guinea-Bissau is correlated with viral genotype.

We present the results of a 6-year study of 131 human immunodeficiency virus (HIV) type 2 (HIV-2)-infected individuals from a rural population in Guinea-Bissau. Proviral DNA sequences 1.3 kb in length were obtained from each individual and, together with clinical data, including proviral load and CD4 and CD8 levels, were used to assess whether viral genotype influences clinical outcome. With a phylogenetic model, a correlation was found between viral genotype and mortality; this correlation was not due to confounding factors, such as age-specific viral strains or cohabitation of patients. The data provide strong evidence for the involvement of viral genetic factors in determining HIV disease progression in vivo. The pattern of association found suggests that virulence factors are multiple and scattered throughout the HIV-2 genome and can be rapidly gained or lost by the virus through a combination of mutation and recombination. These findings may lead to the identification of viral determinants of HIV disease progression.

Adolescent↗
PubMed1998

Cytotoxic T cells from human immunodeficiency virus type 2-infected patients frequently cross-react with different human immunodeficiency virus type 1 clades.

Knowledge of immune mechanisms responsible for the cross-protection between highly divergent viruses such as human immunodeficiency virus type 1 (HIV-1) and HIV-2 may contribute to an understanding of whether virus variability may be overcome in the design of vaccine candidates which are broadly protective across the HIV subtypes. We demonstrate that despite the significant difference in virus amino acid sequence, the majority of HIV-2-infected individuals with different HLA molecules possess a dominant cytotoxic T-cell response which is able to recognize HIV-1 Gag protein. Furthermore, HLA-B5801-positive subjects show broad cross-recognition of HIV-1 subtypes since they mounted a T-cell response that tolerated extensive amino acid substitutions within HLA-B5801-restricted HIV-1 and HIV-2 epitopes. These results suggests that HLA-B5801-positive HIV-2-infected individuals have an enhanced ability to react with HIV-1 that could play a role in cross-protection.

Cells, Cultured↗
PubMed1998

A broad range of chemokine receptors are used by primary isolates of human immunodeficiency virus type 2 as coreceptors with CD4.

Like human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), HIV-2 requires a coreceptor in addition to CD4 for entry into cells. HIV and SIV coreceptor molecules belong to a family of seven-transmembrane-domain G-protein-coupled receptors. Here we show that primary HIV-2 isolates can use a broad range of coreceptor molecules, including CCR1, CCR2b, CCR3, CCR4, CCR5, and CXCR4. Despite broad coreceptor use, the chemokine ligand SDF-1 substantially blocked HIV-2 infectivity of peripheral blood mononuclear cells, indicating that its receptor, CXCR4, was the predominant coreceptor for infection of these cells. However, expression of CXCR4 together with CD4 on some cell types did not confer susceptibility to infection by all CXCR4-using virus isolates. These data therefore indicate that another factor(s) influences the ability of HIV-2 to replicate in human cell types that express the appropriate receptors for virus entry.

Adaptation, Biological↗
PubMed1998

The role of cytotoxic T-cells in HIV infection.

HIV-specific cytotoxic T lymphocytes (CTL) are believed to play a major role in controlling virus levels through the asymptomatic period of HIV infection. For the rational design of an HIV vaccine, we need to know whether protective immunity can ever develop following HIV exposure in people who remain uninfected. We have detected HIV-specific CTL in 5/6 repeatedly exposed, persistently seronegative female sex-workers in The Gambia. Their CTL, repeatedly detected over two years, recognise epitopes presented by HLA-B35 which are cross-reactive between HIV-1 & HIV-2, suggesting they could have been primed first by HIV-2 exposure and subsequently boosted by exposure to HIV-1. Using previously identified clade B HIV-1 epitope peptides, we have now detected HIV-specific CTL in 6/15 highly exposed and apparently HIV-resistant Kenyan prostitutes, predominantly towards epitopes highly conserved between B and the Kenyan A & D clades of HIV-1. This CTL activity towards conserved virus epitopes may represent protective immunity to HIV generated in response to repeated exposure, and prophylactic HIV vaccines should aim to generate similar CTL responses.

Cells, Cultured↗
PubMed1997

Naturally occurring A pocket polymorphism in HLA-B*2703 increases the dependence on an accessory anchor residue at P1 for optimal binding of nonamer peptides.

Previous studies have shown the B*2703 subtype of HLA-B27, which differs from B*2705 and other MHC class I molecules by having a His substituted for Tyr at position 59 in the A pocket, inefficiently presents certain B*2705-restricted peptides. The current work investigates the influence of the first peptidic amino acid (P1) on peptide binding to B*2705 and B*2703. Results show P1 has a marked effect for both subtypes, with relative affinities (EC50) of P1-substituted peptides spanning four orders of magnitude. All peptides tested bind better to B*2705 than to B*2703. However, Lys, Arg, Phe, or Trp at P1 result in a < or = 2-fold difference between subtypes, while other amino acids produce greater differences (maximum approximately 50-fold for Leu). Self peptides eluted from B*2703, as well as two viral epitopes, have a motif similar to B*2705 peptides, except for a stronger preference for Lys or Arg at P1, consistent with peptide binding data. Computer modeling of B*2703 reveals movement of a water molecule and the alpha1 alpha-helix to allow His at position 59 to maintain important hydrogen bonds with the peptide N terminus in the A pocket. However, these bonds are weaker, and the water molecule movement results in the loss of a hydrogen bond with Glu-45 in the B pocket. We conclude that B*2703, as a consequence of its unique A pocket polymorphism, appears to have a greater dependency on an accessory anchor residue at P1 to maintain tight binding of peptides.

Alleles↗
PubMed1997

HIV type 2 pathogenicity is not related to subtype in rural Guinea Bissau.

Data from an MRC case-control study in rural Guinea Bissau suggest older HIV-2 carriers (aged 55 to 80 years) appear, over a period of 2 years, to have a mortality similar to that of uninfected controls, whereas in HIV-2 carriers under the age of 55 there is a significantly higher mortality, compared with uninfected controls. Genotyping of viruses from both groups revealed only subtype a to be circulating. Thus, although putative nonpathogenic HIV-2 subtypes have been described in patients from West Africa, these do not appear to be contributing significantly to the nonpathogenic clinical phenotype in this population.

Aged↗