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J Habeshaw

Publications and source records attributed to J Habeshaw.

15 recordsLinked to original sources
PubMed1993

Alloactivated cytotoxic T cells recognize the carboxy-terminal domain of human immunodeficiency virus-1 gp120 envelope glycoprotein.

Infection with the human immunodeficiency virus (HIV) virus leads to clinical disease in humans but not in chimpanzees. Progression to disease is associated with activation of the immune system followed by loss of T helper cell function and a slow decline in CD4-positive lymphocytes. The presence of autoreactive and cytotoxic cells in humans but not chimpanzees suggests that mechanisms other than, or in addition to, direct virus-induced cell killing, are required for disease to develop. The observed changes are similar to those seen in chronic allogeneic disease. Here we show that a peptide from the carboxy terminus of gp120, predicted to have a structure similar to the major alpha-helices of major histocompatibility complex (MHC) class I and class II, acts as a cytolytic target when presented on syngeneic cells for alloactivated cytotoxic T effector cells. These data add further evidence to the hypothesis that HIV can act as an allostimulant due to its dual properties of CD4 binding and MHC mimicry. The ability to signal nonspecifically through the T cell receptor could explain the initially paradoxical responses of proliferation, anergy and apoptosis.

Amino Acid Sequence↗
PubMed1992

T-cell receptor variable gene products and early HIV-1 infection.

To assess the hypothesis that the human immunodeficiency virus (HIV) might mimic major histocompatibility complex (MHC) allodeterminants and interact with T-cell receptors (TCRs) of alloreactive T-cells, we have done a preliminary analysis of the range of alpha beta TCR gene products in 16 HIV-1-seropositive individuals with normal CD4 counts and in 16 healthy HIV-1-negative controls. Using a panel of monoclonal antibodies with a two-colour direct immunofluorescence method, we found a significant increase in the expression of the V beta 5.3 subfamily in the HIV-positive patient group compared with controls (p less than 0.01). Selected increase in expression of V beta sequences has been described in various autoimmune conditions and our findings raise the possibility that the immunopathological damage from HIV infection may be due to the induction of autoreactivity. If HIV does mimic MHC II, the normal immune response to the virus could represent an autoimmune process similar to graft-versus-host disease.

Gene Expression↗
PubMed1992

Does the HIV envelope induce a chronic graft-versus-host-like disease?

Evidence is accumulating that susceptibility to disease following HIV infection is genetically restricted. In addition, activation of the immune response appears to play an important role in disease progression. Here, John Habeshaw and colleagues propose that HIV envelope glycoproteins mimic foreign MHC molecules and, in doing so, stimulate alloreactive lymphocytes. This activation may explain the marked clinical and immunological similarities between chronic GVHD and AIDS.

Acquired Immunodeficiency Syndrome↗
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↗
PubMed1992

HIV-induced deletion of antigen-specific T cell function is MHC restricted.

When antigen-specific T cells are pulsed by antigen-presenting cells (APC) in the presence of HIV they are functionally deleted following subsequent exposure to syngeneic APC in the absence of HIV. Recombinant soluble HIV envelope (gp120) is able to induce a similar effect which, unlike that induced by HIV, is reversible. Neither HIV nor gp120 affect the ability to respond to IL-2. Thus it is only antigen-specific responses involving the T cell receptor pathways and CD4/MHC class II interaction that appear to be inhibited by HIV-1 and gp120. Furthermore, the functional impairment caused by HIV-1 is specific to the T cells that respond to the antigen in co-culture with HIV, as there is no apparent effect on 'bystander'-activated T cells specific for another antigen. Antigen-specific T cell lines may be deleted by a signalling mechanism which involves molecules other than gp120/CD4 but still requires MHC class II restriction.

Animals↗
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↗
PubMed1991

A proposed molecular model for the carboxy terminus of HIV-1 gp120 showing structural features consistent with the presence of a T-cell alloepitope.

A computer graphics molecular model of the C terminus of gp120 of HIV has been constructed using predicted secondary structure based on homologies with proteins for which X-ray crystallographic data have been published. The model shows sequences known to be important in CD4 binding in close proximity to regions with a high probability of forming alpha helical and beta strand motifs. The orientation adopted by these domains approximates to the known 3D structure of HLA-A2 alpha 2 chain without constraints based on HLA-A2 as a template being introduced. The model may therefore represent an energetically favourable conformation for a part of gp120 which mimics the binding domain for the T-cell receptor on MHC molecules. Recognition of gp120 as an alloepitope in high affinity association with CD4 would explain many of the sequelae of acquired immune deficiency on HIV infection.

Amino Acid Sequence↗
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↗
PubMed1984

Human T-cell leukemia virus (HTLV) in the United Kingdom.

Ten out of 26 leukaemic patients who had emigrated from the Caribbean region to the United Kingdom had adult T-cell leukaemia with associated serum antibodies to HTLV I. Antibodies to HTLV were also detected in sera from a small proportion of non-leukaemic Caribbean immigrants but not in any sera from other (non-ATL) T-cell leukaemias or a variety of control groups. The long period between immigration to the UK and diagnosis of leukaemia (up to 30 years) suggests that an extensive latent period in disease development may exist. Cell lines were isolated from two patients with HTLV antibody-positive ATL and were shown to be virus-positive by electron microscopy and immunofluorescence using antibodies to the p19 and p24 viral proteins. HTLV1 provirus integration and active transcription were demonstrated by Southern blotting of DNA and in situ hybridization respectively using molecularly cloned HTLV1 probes. Virus from one of these cell lines could be transmitted to normal T cells by co-cultivation.

Adolescent↗