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Biomedical subjects

C R Bangham

Publications and source records attributed to C R Bangham.

At least 55 records · Page 3Linked to original sources
PubMed1996

Population dynamics of immune responses to persistent viruses.

Mathematical models, which are based on a firm understanding of biological interactions, can provide nonintuitive insights into the dynamics of host responses to infectious agents and can suggest new avenues for experimentation. Here, a simple mathematical approach is developed to explore the relation between antiviral immune responses, virus load, and virus diversity. The model results are compared to data on cytotoxic T cell responses and viral diversity in infections with the human T cell leukemia virus (HTLV-1) and the human immunodeficiency virus (HIV-1).

Antibodies, Viral↗
PubMed1996

High activated and memory cytotoxic T-cell responses to HTLV-1 in healthy carriers and patients with tropical spastic paraparesis.

The cytotoxic T-lymphocyte (CTL) response to HTLV-1 is directed mainly against the Tax protein. Circulating, activated Tax-specific CTL can be found in a majority of healthy carriers and patients with the HTLV-1-associated disease tropical spastic paraparesis (HAM/TSP). In this study we present data on the Tax-specific CTL response of 26 HTLV-1 carriers, including 10 newly recruited subjects. Rex-specific CTL were not found in any subjects investigated. Activated and memory CTL responses were determined separately in 4 healthy carriers, 3 HAM/TSP patients, and 1 "seronegative HAM/TSP." In all subjects, the mean frequency of peptide-specific memory cells per epitope (1/1307) was high. There was no significant difference in mean memory CTL frequency per epitope or in the proportion of subjects with activated CTL between healthy carriers and HAM/TSP patients. One individual with HAM/TSP had an unusually high frequency response to two peptides, suggesting immunodominance of epitope recognition in this individual. We conclude that the magnitude and components of the HLTV-1-specific CTL response do not differ between healthy carriers and HAM/TSP patients. These data do not support a specific CTL-mediated component in the pathogenesis of HAM/TSP.

Amino Acid Sequence↗
PubMed1996

Evolution in a chronic RNA virus infection: selection on HTLV-I tax protein differs between healthy carriers and patients with tropical spastic paraparesis.

HTLV-I causes T-cell leukemia and tropical spastic paraparesis (TSP) in a minority of infected people, whereas the majority remain healthy. The virus differs little in sequence between isolates but has been shown to have a quasispecies structure. Using the Nei and Gojobori algorithm, we have shown that the proportion of nonsynonymous to synonymous changes in HTLV-I proviral tax gene sequences from healthy seropositive subjects (Dn/Ds = 0.9 to 1.3) is significantly higher than those from TSP patients (Dn/Ds = 0.3 to 0.6). Here we show that the distinction between healthy seropositives and TSP patients can only be seen with proviral tax sequences, but not with cDNA, the amino-terminal or carboxy-terminal half of tax, or the rex gene. The Dn/Ds ratio of proviral tax sequences was used to analyze two TSP patients with atypical features and to investigate the influence of cytotoxic T cells (CTL) on the viral quasispecies.

Biological Evolution↗
PubMed1995

Antigenic oscillations and shifting immunodominance in HIV-1 infections.

A typical protein antigen contains several epitopes that can be recognized by cytotoxic T lymphocytes (CTL), but in a characteristic antiviral immune response in vivo, CTL recognize only a small number of these potential epitopes, sometimes only one, this phenomenon is known as immunodominance. Antigenic variation within CTL epitopes has been demonstrated for the human immunodeficiency virus HIV-1 (ref. 11) and other viruses and such 'antigenic escape' may be responsible for viral persistence. Here we develop a new mathematical model that deals with the interaction between CTL and multiple epitopes of a genetically variable pathogen, and show that the nonlinear competition among CTL responses against different epitopes can explain immunodominance. This model suggests that an antigenically homogeneous pathogen population tends to induce a dominant response against a single epitope, whereas a heterogeneous pathogen population can stimulate complicated fluctuating responses against multiple epitopes. Antigenic variation in the immunodominant epitope can shift responses to weaker epitopes and thereby reduce immunological control of the pathogen population. These ideas are consistent with detailed longitudinal studies of CTL responses in HIV-1 infected patients. For vaccine design, the model suggests that the major response should be directed against conserved epitopes even if they are subdominant.

Amino Acid Sequence↗
PubMed1995

Naturally occurring variants of human T-cell leukemia virus type I Tax protein impair its recognition by cytotoxic T lymphocytes and the transactivation function of Tax.

There is a high degree of intraisolate sequence heterogeneity in the tax gene of human T-cell leukemia virus type I (HTLV-I), although the sequence variation between patients is small compared with that of human immunodeficiency virus type 1. In the present study, we investigated whether naturally occurring amino acid substitutions changed the properties of the Tax protein in two respects: first, recognition of the protein by cytotoxic T lymphocytes (CTL), and second, the ability of the Tax protein to transactivate various promoters. We found that (i) all of the observed amino acid substitutions that occur in known CTL epitopes abolished the recognition of the synthetic peptide representing the respective epitope; (ii) these substitutions occurred significantly more frequently in subjects carrying HLA-A2; and (iii) most of the amino acid substitutions severely reduced the ability of Tax protein to transactivate three promoters: the HTLV-I long terminal repeat, the c-fos promoter, and the interleukin-2 receptor alpha chain promoter.

Amino Acid Sequence↗
PubMed1994

Cycles, chaos, and evolution in virus cultures: a model of defective interfering particles.

Defective interfering particles (DIP) are spontaneous deletion mutants of viruses that replicate at the expense of the parent virus. DIP have complex effects on the growth of viruses in vitro, including the establishment of persistent infection, cyclical variation in virus titer, eradication of replicating virus, and rapid evolution of the virus. We show here that a simple mathematical model, based only on experimental observations, can explain all of the major effects of DIP on the population dynamics of virus growth. The variation in virus titer caused by DIP has many features that are characteristic of deterministic chaos: it follows that the quantitative effects of DIP are intrinsically unpredictable beyond a short time. We conclude (i) that other factors, such as temperature-sensitive virus mutants or interferons, need not be invoked to explain the complex effects of DIP; and (ii) that dominantly interfering viruses should only be used with great caution for therapeutic purposes, since their effects are, in principle, unpredictable.

Biological Evolution↗
PubMed1994

Cytokine response to respiratory syncytial virus stimulation of human peripheral blood mononuclear cells.

A key impediment to developing respiratory syncytial virus (RSV) vaccines is a lack of understanding of enhanced disease that occurred in children who received a formalin-inactivated RSV (FI-RSV) vaccine. Studies in mice have suggested that the FI-RSV vaccine induces a TH2 and live RSV induces a TH1 memory T cell response. In this study, the cytokine mRNA response of peripheral blood mononuclear cells (PBMC) from adults and children with and without previous RSV infection was characterized using a semiquantitative polymerase chain reaction (PCR). PBMC from 22 subjects previously infected with RSV usually had RSV-specific increases in TH1 cytokine-specific mRNA (interferon-gamma [IFN-gamma] mRNA, 20; interleukin [IL]-2 mRNA, 12; IL-5 mRNA, 6; and IL-4 mRNA, 0). PBMC from RSV antibody-negative children had no RSV-specific increases in IFN-gamma, IL-2, or IL-4 mRNA; 1 of 7 had an increase in IL-5 mRNA. These data indicate that naturally acquired RSV induces a TH1 memory T cell response.

Adolescent↗
PubMed1994

Analysis of substrate cleavage by recombinant protease of human T cell leukaemia virus type 1 reveals preferences and specificity of binding.

Human T cell leukaemia virus type 1 (HTLV-1) protease (PR14) was expressed in bacteria and purified by gel filtration. A continuous spectrophotometric assay was used to measure the kinetic parameters of substrate hydrolysis by PR14. Several peptide substrates containing HTLV-1 sequences known to be cleaved by PR14 were used. Cleavage analysis showed that the affinity with which PR14 binds these substrates is higher than that previously reported for HTLV-1 Gag peptides. Also, the affinities of peptides containing the sites involved in autocleavage of protease from its precursor are higher than for the peptides containing sites required for structural protein maturation. This suggests that the autocatalysis of protease from its own precursor has priority over other cleavage reactions and supports similar observations of an ordered hierarchy of processing events by retroviral proteases. As the N- and C-terminal regions of retroviral aspartic proteases are known to contribute to stability of the dimer by forming antiparallel beta-strands, short peptides corresponding to these terminal sequences of HTLV-1 protease were tested for their ability to inhibit cleavage of substrates by PR14. Inhibition was seen with a C-terminal peptide corresponding exactly to the C-terminal 11 amino acids of the processed PR14, whereas a peptide containing a sequence situated further from the C terminus was less effective. An inhibitor of the protease of human immunodeficiency virus type 1, Ro 31-8959, was found to be a poor inhibitor of PR14.

Amino Acid Sequence↗
PubMed1994

The transactivator gene of human T-cell leukemia virus type I is more variable within and between healthy carriers than patients with tropical spastic paraparesis.

Human T-cell leukemia virus type I (HTLV-1) causes T-cell leukemia and tropical spastic paraparesis (TSP) in a minority of infected people, whereas the majority remain healthy. No association between a particular HTLV-I sequence and disease manifestation has been found in previous studies. We studied here the sequence variability of the gene for the HTLV-I Tax protein, which is the dominant target antigen of the very strong cytotoxic T-lymphocyte response to the virus. In HTLV-I infection, the intraisolate nucleotide variability is much greater than the variability between isolates. The predicted protein sequence of Tax was significantly more variable in the healthy seropositive individuals' provirus than in those of the patients with TSP. Thus, tax sequence heterogeneity, rather than the presence of particular sequences, distinguishes healthy HTLV-I-seropositive individuals from patients with TSP.

Base Sequence↗
PubMed1994

Circulating anti-Tax cytotoxic T lymphocytes from human T-cell leukemia virus type I-infected people, with and without tropical spastic paraparesis, recognize multiple epitopes simultaneously.

CD8+ T cells were freshly isolated from a human T-cell leukemia virus type I (HTLV-I)-infected patient with tropical spastic paraparesis. These cells, which were specific for HTLV-I Tax, simultaneously recognized a minimum of five, and possibly as many as seven, distinct peptide epitopes within the protein. A further Tax epitope was recognized after a short period of culture without exogenous peptide stimulation. All but one of these epitopes were clustered in the N-terminal third of Tax, and one of the epitopes was clearly immunodominant on two separate occasions of testing. Recognition of the immunodominant epitope was restricted by human leukocyte antigen (HLA) B15, and recognition of all the others was by HLA A2. Similar patterns of cytotoxic T lymphocyte recognition of the HLA A2-restricted Tax peptides in two healthy HTLV-I-seropositive individuals, each of whom carried the HLA A2 allele, were observed.

Adult↗
PubMed1993

Human T-cell leukaemia virus type I and neurological disease.

Tropical spastic paraparesis is thought to be caused either directly by human T-cell leukaemia virus type I (HTLV-1), or by the immune response to the virus. Recent work has identified differences between tropical spastic paraparesis patients and healthy carriers of HTLV-I, both in the virus and in the host's T-cell response to the virus. These differences may provide clues to the pathogenesis of tropical spastic paraparesis.

Carrier State↗
PubMed1993

Defective interfering particles and virus evolution.

Almost all viruses produce replication-defective mutants that have complex effects on the growth and evolution of the virus in culture. These effects can be explained qualitatively by a simple mathematical model. However, the model shows that the quantitative effects of these mutants are intrinsically unpredictable.

Biological Evolution↗
PubMed1993

Retrovirus infections of the nervous system.

Mammalian retroviruses of all three subfamilies infect the nervous system. The leukemia viruses (oncovirinae) and lentiviruses (lentivirinae, eg, human immunodeficiency virus) cause serious disease, while the foamy viruses (spumavirinae) have not yet been shown to cause any disease. This review illustrates these diseases by referring particularly to three viruses: the human and murine leukemia viruses (human T-cell leukemia-lymphoma virus type I and murine leukemia virus), and the human immunodeficiency viruses, HIV-1 and 2. Other lentiviruses cause important encephalitides in other animals, notably cats (feline immunodeficiency virus), sheep (maedi/visna virus), and goats (caprine arthritis/encephalitis virus).

AIDS Dementia Complex↗
PubMed1992

Activated, HTLV-1-specific cytotoxic T-lymphocytes are found in healthy seropositives as well as in patients with tropical spastic paraparesis.

In human T cell lymphoma/leukemia virus (HTLV-1)-infected people with tropical spastic paraparesis (TSP), there are activated HTLV-1-specific cytotoxic T lymphocytes (CTL) in the circulation and lymphocytic infiltrates in spinal cord lesions that are rich in CD8+ T cells. These observations suggest a role for virus-specific CTL in the pathogenesis of TSP. We have examined the anti-HTLV-1 cytotoxic activity of freshly isolated CD8+ T cells from peripheral blood lymphocytes of eight subjects seropositive for HTLV-1. Four of five subjects with TSP had circulating activated anti-Tax CTL. However, two of three seropositive subjects without TSP also had activated anti-Tax CTL. These observations show that such activated CTL are not confined to patients with TSP and raise some uncertainty about their significance in the pathogenesis of the disease. In cultures of CD8+ T cells from two TSP subjects, we detected CTL with other HTLV-1 specificities, without exogenous antigenic stimulation. A CTL epitope in the middle region of Tax and one in the C terminus of Pol have been mapped at the peptide level and the HLA Class 1 molecules restricting their recognition have been defined.

Amino Acid Sequence↗