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Biomedical subjects

A Dalgleish

Publications and source records attributed to A Dalgleish.

At least 37 records · Page 2Linked to original sources
PubMed1992

Sequential interleukin-2 and alpha interferon for renal cell carcinoma and melanoma.

There is a theoretical basis for the synergy of interleukin-2 (IL-2) with other cytokines. We have investigated sequential treatment with IL-2 and alpha interferon. 1 of 22 patients with metastatic renal cell carcinoma had a partial response and one a minimal response to continuous infusion IL-2 but none of the 9 patients with melanoma responded. 16 of 17 patients with renal cell cancer, and 8 with melanoma, were then treated with alpha interferon. 2 patients with renal cell cancer responded to alpha interferon with sustained remissions of 30 and 40 months; both had responded to IL-2. The investigation of combination therapy with other cytokines is suggested, by these unusually long responses to alpha interferon.

Adolescent↗
PubMed1992

Localized conformational changes in the N-terminal domain of CD4 identified in competitive binding assay of monoclonal antibodies and HIV-1 envelope glycoprotein.

The CD4 antigen is established as a major cellular receptor for the human immunodeficiency virus (HIV). Previous studies have suggested that certain anti-CD4 monoclonal antibodies (MAbs) can inhibit or enhance the binding of the viral envelope glycoprotein gp120 to CD4 by allosteric effects. In the study reported here, 17 anti-CD4 MAbs were tested for their ability to influence the binding of each other to recombinant soluble CD4 in a solid-phase radioimmunoassay. Marked enhancement of binding between specific pairs of MAbs was seen, as well as inhibition or lack of interaction. Enhancement was seen less often when CD4+ cells were used as the target antigen. Information on patterns of enhancement and inhibition permitted grouping of MAbs on the basis of epitope specificity, and this grouping was in agreement with published findings based on X-ray crystallographic studies. These results demonstrate connectivity between epitopes in the first domain of recombinant CD4 and suggest a high degree of flexibility of surface structure. These findings may be of physiological significance both in the normal function of CD4 and in the interaction of CD4 with HIV. The data have implications for research or therapeutic strategies based on recombinant CD4 or CD4 mutants and highlight the problems of interpreting experimental findings based on abrogation of MAb binding.

Antibodies, Monoclonal↗
PubMed1991

HIV-1 proteinase is required for synthesis of pro-viral DNA.

HIV-1 proteinase activity is thought to occur primarily post-integration by cleaving the viral Gag and Gag-Pol polyproteins. Its role in the pre-integration stages of viral replication, however, has not been studied in detail. Here we report that a synthetic peptide analogue, UK-88,947, which is a specific inhibitor of purified HIV-1 proteinase, inhibits the processing of the viral polyproteins in cultures of HIV-1 infected cells and prevents the formation of mature, infectious virions. Analysis of DNA from HIV-1 infected cells treated with UK-88,947 showed that viral DNA synthesis was inhibited when the compound was added to cultures one hour before infection. Similar results were obtained when AZT was used. Neither HIV-1 reverse transcriptase or the replication of FIV are inhibited by UK-88,947.

Amino Acid Sequence↗
PubMed1991

The naive repertoire of human T helper cells specific for gp120, the envelope glycoprotein of HIV.

The envelope glycoprotein of HIV gp120 is a T cell Ag in experimental animals and in humans infected with HIV or deliberately immunized with gp120 in various forms. Inasmuch as T cell responses result from the interaction of Ag processed and presented by APC with the unprimed T cell repertoire, we have investigated the human T cell repertoire specific for gp120 in seronegative, normal individuals. T cell lines and clones specific for HIV gp120 were generated by repeated in vitro stimulation of peripheral blood T lymphocytes with gp120-pulsed APC, followed by IL-2 expansion. We observed that the T cell response to whole gp120 involved single restricted immunodominant epitopes in gp120 that differ between responding individuals. Focusing of the response to limited regions of gp120 when the whole Ag is used for priming suggests that one or more adjacent epitopes are immunodominant and mask responses to "immunorecessive" epitopes. We have been able to generate primary in vitro responses to recessive epitopes by stimulation in vitro with synthetic peptides of gp120. The results indicate that a much broader T repertoire can be detected when individual peptides are used for priming in vitro rather than gp120. This information has important implications for the development of vaccination protocols aimed at eliciting diverse immune responses to "immunorecessive" regions of envelope glycoprotein.

Epitopes↗
PubMed1990

Failure of ADCC to predict HIV-associated disease progression or outcome in a haemophiliac cohort.

Antibody-dependent cell-mediated cytotoxicity (ADCC) has been described in a number of virus infections and occurs in HIV infection. In spite of numerous studies on the ability of HIV-positive sera to mediate ADCC, it remains unclear whether ADCC has any functional significance. Here we examine serial serum samples from a cohort of haemophilia patients who became infected from a common source in 1984, and show that there is no significant difference in ADCC values between those who remained asymptomatic and those who progressed to disease. This study does not compare effector cell function and clinical status and does not exclude activity against different target cell lineages in vivo.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1990

Differences in affinity of anti-CD4 monoclonal antibodies predict their effects on syncytium induction by human immunodeficiency virus.

A panel of 20 anti-CD4 monoclonal antibodies (mAb) was ranked in terms of affinity, using an inhibition radioimmunoassay. The ability of these antibodies to inhibit the induction of syncytia by human immunodeficiency virus (HIV) and to prevent binding of the HIV envelope glycoprotein 120 (gp120) to CD4 was also measured. Syncytium inhibition correlated strongly with affinity (P less than 0.001) but only weakly with inhibition of gp120 binding (P = 0.038). Some antibodies partially blocked binding of gp120 to CD4 but did not inhibit syncytia, and some antibodies inhibited syncytia but only weakly blocked binding of gp120. These results suggest that the syncytium inhibition assay is highly affinity-dependent, and that epitopes on CD4 concerned with virus binding are distinct from those involved in syncytium formation.

Antibodies, Monoclonal↗
PubMed1989

Assessment of responses of normal human B lymphocytes to different isolates of human immunodeficiency virus: role of normal donor and of cell line used to prepare viral isolate.

The effect of different HIV-1 isolates on normal human B lymphocyte function has been studied in vitro. Production of IgM and IgG was measured by ELISA using a "standard" non-T preparation of B cells depleted of macrophages and T cells (but not of low-density accessory cells, LDC). Only one (H9/CBL-4) of five different isolates induced polyclonal production of immunoglobulin. Apart from intrinsic differences between isolates, important inherent variables were shown to affect the response. One was the mix of cell types in the responding preparation of B cells. This was tested by examining the effects of HIV-1 isolates independently on the accessory function of LDC and on B cell function when the LDC were removed. Isolate H9/HTLV-IIIRf was nonstimulatory on a B cell preparation containing LDC and suppressive on LDC accessory function yet could enhance function of B cells when the LDC were depleted. Another variable was the donor of the normal B cells. The B cell response was consistent with each donor but varied greatly with different donors. Thus, no single explanation emerges for the hypergammaglobulinemia in some adult AIDS patients and for the hypogammaglobulinemia in some pediatric cases. Additionally, the cell lines used to propagate the virus particularly affected the assay of B cells depleted of LDC. Uninfected supernatants had different effects on the B cell function, and these host cell effects (perhaps by release of cytokines or other mediators) may be exacerbated in infected cell lines. Our data show the complexity of the abnormal B cell function in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1988

HTLV-1 infection in tropical spastic paraparesis: lymphocyte culture and serologic response.

All 17 patients with tropical spastic paraparesis (TSP) in a series seen in the United Kingdom have antibodies to the human T cell leukemia virus type 1 (HTLV-1). Cultured peripheral blood lymphocytes from these patients formed multinucleated giant cells and reacted with sera and monoclonal antibodies to HTLV-1 in a manner identical to adult T cell leukemia-lymphoma (ATLL) patient lymphocytes. Western blot analysis failed to reveal any marked difference in the antigens recognized by sera from TSP and ATLL patients. The sera from TSP patients, their asymptomatic relatives and ATLL patients were titrated using the following assays: enzyme-linked immunosorbent assays (ELISA), particle agglutination, antibody-dependent cell-mediated cytotoxicity, and pseudotype neutralization. There were significantly stronger serologic responses in the TSP patients than in their relatives or ATLL patients. High antibody titers in the presence of replicating virus often reflect the antigen load; however, these data are also consistent with the suggestion that neurologic damage in TSP may be immunologically mediated.

Adult↗
PubMed1987

Antibody to human T-lymphotropic virus type 1 in West-Indian-born UK residents with spastic paraparesis.

Of 13 West-Indian-born UK residents with spastic paraparesis of unknown cause, 11 were tested for serum antibody to human T-cell lymphotropic virus type 1 and all were positive. Their magnetic resonance imaging scans were normal or showed only minor abnormalities in the brain, and the spinal cord was normal in the 5 investigated. Of 48 patients with multiple sclerosis, mainly caucasian, none had antibody to HTLV-1 in the blood.

Adult↗
PubMed1987

Human immunodeficiency virus (HIV) infection in the regular sexual partners of homosexual men with AIDS and persistent generalised lymphadenopathy.

Thirty-five homosexual men who had been the regular sexual partners (for at least 6 months) of anti-HIV-positive patients with AIDS (N = 18) or PGL (N = 17) were studied. Twenty-one (60%) were seropositive, but 14 (40%) were consistently anti-HIV-negative. The duration of relationship with the index case was not statistically different in seropositive compared to seronegative partners; median 26 months (range 7-60) vs 30 months (range 7-60). However, seropositive partners had a significantly higher monthly number of other sexual partners and sexually transmitted diseases and a higher frequency of insertive and receptive anal intercourse in the preceding five years. The risk of acquiring HIV infection was significantly increased by frequent receptive anal intercourse when the frequency of insertive was controlled for but not the converse. Seronegative partners had undetectable antibodies by live and fixed cell immunofluorescence and by radioimmunoprecipitation and were repeatedly negative by competitive enzyme immunoassay. Furthermore, the sera of seronegative partners lacked HIV neutralising activity. Peripheral blood mononuclear cells (PBMCs) from seronegative partners, stained with monoclonal antibodies to seven different CD4 epitopes, revealed no differences when compared to those from heterosexual controls and no qualitative differences from cells from seropositive individuals. In addition, PBMCs from seronegative partners could be productively infected by HIV in vitro. If resistance to infection in seronegative partners exists, then it is likely that mechanisms other than a specific humoral immunity or CD4 polymorphisms are involved.

AIDS-Related Complex↗
PubMed1986

Acquired immunodeficiency with disseminated cryptococcosis.

A 9 year old Portuguese boy presented with severe wasting and a disseminated cryptococcal infection that resolved after massive doses of intrathecal and parenteral antifungal agents. Clinical and laboratory findings were consistent with AIDS. Apart from neonatal blood transfusions, there were no identified risk factors for HTLV III infection.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain.

2000 persons in the UK were examined serologically for antibodies to human T-lymphotropic virus type III (HTLV-III). Sera reacting in a membrane immunofluorescence assay (IFA) to HTLV-III were also positive when tested against cells infected with lymphadenopathy virus (LAV-1), and cross-adsorption tests indicated that these retroviruses are probably identical. A competitive radioimmunoassay (RIA), which was wholly concordant with IFA, was used to screen the sera. 30/31 patients with the acquired immunodeficiency syndrome (AIDS) were seropositive, as were 89% patients with persistent generalised lymphadenopathy (PGL), 17% symptomless homosexual men, 34% haemophiliacs receiving pooled clotting factors, and 1.5% intravenous drug abusers. None of more than 1000 unselected blood donors was seropositive. These data confirm the close association between HTLV-III and AIDS and PGL and show that infection with HTLV-III is also prevalent in the populations in whom these syndromes are most likely to develop. However, it would be unwise to presume that AIDS will necessarily develop in seropositive subjects.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Clinical findings and serological evidence of HTLV-III infection in homosexual contacts of patients with AIDS and persistent generalised lymphadenopathy in London.

Between 1980 and 1984 28 homosexual men who had had ano-genital intercourse with patients with either acquired immunodeficiency syndrome (AIDS) or persistent generalised lymphadenopathy (PGL) were followed up. The pattern of the sexual links indicated that within this group there were two clusters, one consisting of 7 men and the other of 13.17 of the 28 contacts became ill with either AIDS or PGL; among those in the clusters, 4 died of AIDS and 11 had PGL, and of the rest 2 had PGL. 16 of the 19 men in the clusters who were tested for HTLV-III antibodies were seropositive, as were 7 of those not in the clusters. 111 men attending a genitourinary medicine clinic who had not had known contact with either AIDS or PGL patients and who were being screened for syphilis served as controls. Of these, 19/86 who were homosexual and 0/25 who were heterosexual were positive for HTLV-III antibodies. None of the 4 who died of AIDS had had contact with each other. The 2 in the first cluster seemed to have been linked by a symptomless HTLV-III-negative man, who was also probably the link between the two clusters, while in the second cluster the chief "carrier" seemed to be a seropositive man in whom PGL developed. These findings are consistent with the hypothesis that HTLV-III is the sexually transmitted causative agent of AIDS and PGL.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Low prevalence in the UK of HTLV-I and HTLV-II infection in subjects with AIDS, with extended lymphadenopathy, and at risk of AIDS.

Antibodies reacting selectively with human T-cell leukaemia virus type I (HTLV-I) were detected in approximately 5% patients with extended lymphadenopathy syndrome (ELAS) and in less than 1% of unselected homosexual patients and drug abusers. None of 22 patients with acquired immunodeficiency syndrome (AIDS) had HTLV-I antibodies and neither did 85 haemophiliacs and 940 blood donors. 3 out of 113 drug addicts had high titres of antibodies to human T-cell leukaemia virus type II (HTLV-II). A T-cell line was derived from 1 of the seropositive ELAS patients. This line was found to be infected with, and releasing, HTLV-I. Infection by HTLV-I and HTLV-II retroviruses thus occurs more frequently in ELAS patients and drug addicts than in the UK population as a whole, but the low prevalence of these infections in ELAS and AIDS patients indicates that these two strains of lymphotropic retroviruses have no aetiological role in ELAS and AIDS.

Acquired Immunodeficiency Syndrome↗