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Biomedical subjects

F Gotch

Publications and source records attributed to F Gotch.

At least 55 records · Page 3Linked to original sources
PubMed1998

Cross-clade recognition of p55 by cytotoxic T lymphocytes in HIV-1 infection.

OBJECTIVES: To evaluate cross-clade recognition of p55 antigen by cytotoxic T lymphocytes (CTL) in persons infected with diverse clades of HIV-1; to facilitate the development of a CTL-inducing vaccine to prevent transmission of multiple clades of HIV-1. DESIGN: Experiments were designed to evaluate whether persons in Uganda and the United Kingdom, infected with diverse clades of HIV-1, have CTL capable of recognizing and killing autologous target cells infected with recombinant vaccinia viruses (rVV) expressing the Gag protein from A, B, C and D clade HIV-1. The extent of cross-reactivity within such individuals, each infected with characterized virus, might reflect the type of cross-reactive immune response inducible by a monovalent vaccine. METHODS: Asymptomatic HIV-positive individuals were fully tissue-typed by ARMS (amplification of refractory mutation system) polymerase chain reaction. rVV expressing the Gag protein from identified A, B, C and D viruses were prepared. CTL were cultured and tested for cytolytic activity on autologous rVV-infected or peptide-pulsed B cells. RESULTS: Ugandan patients had inducible CTL responses recognizing A, B, C and D clade HIV-1 Gag. The majority of UK patients had inducible CTL responses that recognized two or more clades. No patient showed any HIV-2 cross-reactivity. Cross-reactive responses were characterized in three Ugandan patients. CONCLUSIONS: Most patients tested mounted cross-reactive CTL responses that recognized Gag proteins from clades of HIV-1 other than those with which they were infected.

Amino Acid Sequence↗
PubMed1998

Cross-clade T cell recognition of HIV.1.

Despite considerable advances in antiviral therapy for HIV infection, successful global intervention will require an effective vaccine. Current evidence suggests that cytotoxic T lymphocyte responses will be an important component of such vaccination. Recent evidence suggests that cytotoxic T lymphocytes raised against viral antigens from different clades (subtypes) of HIV.1 can cross-react extensively and such data have major implications for HIV vaccine design.

AIDS Vaccines↗
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↗
PubMed1996

Cytotoxic T cells--protection from disease progression--protection from infection.

We briefly review current evidence which indicates that major histocompatibility complex (MHC)-restricted, virus-specific cytotoxic T cells may be of immunological importance in protection from infection with immunodeficiency virus or with protection from disease progression which would finally result in acquired immunodeficiency syndrome (AIDS) and death. We suggest that prophylactic vaccines should elicit cytotoxic T lymphocyte (CTL) activity in naive individuals. Further, immunotherapy in infected individuals could be aimed at ensuring that levels of virus-specific CTL are kept high, broadening and redirecting their specificity towards conserved parts of the viral genome.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Induction of single and dual cytotoxic T-lymphocyte responses to viral proteins in mice using recombinant hybrid Ty-virus-like particles.

The induction of cytotoxic T-lymphocyte (CTL) responses to viral proteins is thought to be an essential component of protective immunity against viral infections. Methods for generating such responses in a reproducible manner would be of great value in vaccine development. We demonstrate here that the recombinant antigen-presentation system based on the yeast transposon (Ty) particle-forming p1 protein is a potent means of inducing CTL responses to a variety of viral CTL epitopes, including influenza virus nucleoprotein (two epitopes), Sendai virus and vesicular stomatitis virus nucleoproteins, and the V3 loop of human immunodeficiency virus type-1 (HIV-1) gp120. CTL were primed by hybrid Ty-virus-like particles (VLP) carrying the minimal epitope or as much as 19,000 MW of protein. Ty-VLP carrying two different epitopes (dual-epitope Ty-VLP) were capable of priming CTL responses in two different strains of mice or against two epitopes in the same individual. Furthermore, co-administration of a mixture of two different Ty-VLP carrying single epitopes could induce responses to both epitopes in the same individual. Ty-VLP appear to represent a reproducible and flexible system for inducing CTL responses in mice, and warrant further evaluation in primates.

Amino Acid Sequence↗
PubMed1996

Clinical evaluation of a peritoneal dialysis kinetic modeling set.

A closed system kinetic modeling set (KMS) has been fabricated which permits collection of a small 100-mL aliquot from each exchange. The KMS was used to collect aliquots from 65 exchanges in 13 patients. The concentrations of urea nitrogen (UN), creatinine (Cr), glucose (G), and total protein (TP) were measured in each individual aliquot (Cka) and drain bag (Cba), and all aliquots for each dialysis treatment were used to calculate the concentrations expected in total batched dialysate (BaC) for the treatment and were compared to the measured concentrations (BaM) in mixed total dialysate. The ratios Cka/Cba [mean+/- two times coefficient of variation (mean +/- 2CV)] were 1.00 +/- 5%, 1.00 +/- 5%, 1.01 +/- 10%, and 1.00 +/- 6%, respectively, for UN, Cr, G, and TP (each, n = 61). The ratios BaC/BaM (mean +/- 2CV) were 1.00 +/- 2%, 1.00 +/- 5%, 1.01 +/- 3%, and 0.99 +/- 5%, respectively, for UN, Cr, G, and TP (each, n = 15). We concluded that the KMS aliquots can be reliably used for kinetic and total clearance calculations without mixing and transporting large volumes of dialysate.

Blood Glucose↗
PubMed1995

Immunogenic HIV variant peptides that bind to HLA-B8 can fail to stimulate cytotoxic T lymphocyte responses.

Cytotoxic T lymphocyte responses in HIV infection can be impaired through variation in the epitope regions of viral proteins such as a gag. We report here an analysis of variant epitope peptides in three gag epitopes presented by HLA B8. Fifteen variant peptides were examined for their binding to HLA-B8; all but one bound at concentrations comparable to known epitopes. All except two of those that bound could be recognized by CTL from an HLA-B8 positive HIV-1-infected patient and were therefore immunogenic. However, in a hemophiliac patient studied in detail, there was a failure to respond to two immunogenic peptide epitopes representing virus present as provirus in the patient's peripheral blood. In one case, the patient's CTL had previously responded to the peptide; in the other case, there was a good response to a peptide of closely related sequence. Thus there was a selective failure of the CTL response to some proviral epitopes. This impaired reaction to new variants could contribute to the loss of immune control of the infection.

Animals↗
PubMed1995

Identification of conserved antigenic components for a cytotoxic T lymphocyte-inducing vaccine against malaria.

Several cellular and humoral mechanisms probably play a role in natural immunity to Plasmodium falciparum malaria, but the development of an effective vaccine has been impeded by uncertainty as to which antigens are targeted by protective immune responses. Experimental models of malaria have shown that cytotoxic T lymphocytes (CTL) which kill parasite-infected hepatocytes can provide complete protective immunity against certain species of Plasmodium in mice, and studies in The Gambia have provided indirect evidence that CTL play a protective role against P falciparum in humans. By using an HLA-based approach, termed reverse immunogenetics, we have previously identified peptide epitopes for CTL in liver-stage antigen-1 and the circumsporozoite protein of P falciparum. We have extended this work to identify CTL epitopes for HLA class I antigens that are found in most individuals from Caucasian and African populations. Most of these epitopes are in conserved regions of P falciparum. CTL peptide epitopes were found in a further two antigens, thrombospondin-related anonymous protein and sporozoite threonine and asparagine rich protein, indicating that a subunit vaccine designed to induce a protective CTL response may need to include parts of several parasite antigens. However, CTL levels in both children with malaria and in semi-immune adults from an endemic area were low suggesting that boosting these low levels by immunisation might provide substantial or even complete protection against infection and disease.

Adult↗
PubMed1995

Immunogenicity of the yeast recombinant p17/p24:Ty virus-like particles (p24-VLP) in healthy volunteers.

In this Phase I study, immunisation with the yeast-derived p24 virus-like particles Ty p24-VLP (3 x 100 or 3 x 500 micrograms subcutaneously) in 16 healthy male subjects elicited p24 antibody responses in 4 of 16 (25%) subjects. After a fourth, intramuscular, immunisation (500 micrograms), p24 antibody responses were detected in 11 of 15 (70%) subjects. In addition to p24 antibody responses, T cell proliferative responses were also observed, although no HLA restricted p24-specific cytotoxic T cell responses were detected. The results demonstrate that Ty p24-VLP is immunogenic and well-tolerated in healthy male subjects.

AIDS Vaccines↗
PubMed1995

HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women.

A crucial requirement in the rational design of a prophylactic vaccine against the human immunodeficiency virus (HIV) is to establish whether or not protective immunity can occur following natural infection. The immune response to HIV infection is characterized by very vigorous HIV-specific cytotoxic T-lymphocyte (CTL) activity. We have identified four HIV-1 and HIV-2 cross-reactive peptide epitopes, presented to CTL from HIV-infected Gambians by HLA-B35 (the most common Gambian class I HLA molecule). These peptides were used to elicit HIV-specific CTLs from three out of six repeatedly exposed but HIV-seronegative female prostitutes with HLA-B35. These women remain seronegative with no evidence of HIV infection by polymerase chain reaction or viral culture. Their CTL activity may represent protective immunity against HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The use of heated citric acid for dialyzer reprocessing.

Dialyzer reprocessing with heated water (100 to 105 degrees C) for 20 h can be used safely in lieu of chemical methods for disinfection. All infective agents including spores are destroyed and depyrogenation may occur. However, these temperatures may result in structural damage to the dialyzer, limiting reuse. Dialyzer reprocessing by using 1.5% citric acid heated to 95 degrees C for 20 h is an alternative method that produces equivalent microbiologic effects. Citric acid is well known as a disinfecting agent used for dialysis equipment. Because there is little structural damage to dialyzer components at 95 degrees C, reuse statistics are improved (mean reuse increased to 12.8). Both small and large molecule clearances and the sieving coefficient for protein are insignificantly altered by the process. Whereas the procedure is relatively simple, quality-assurance indicators are essential. The method has appeal because it avoids the use of chemical germicides. However, at present it has only been tested thoroughly in polysulfone dialyzers with heat-resistant polycarbonate casings and polyurethane resin. The clinical experience is favorable.

Citric Acid↗
PubMed1995

Recognition of viral antigens at the cell surface.

There is now a very good understanding of the way in which epitope peptides are generated from virus proteins and how the peptides bind to the class I MHC molecules. This gives a framework in which to analyse the potentially protective cytotoxic T lymphocyte response in human immunodeficiency virus infection. A detailed understanding of the specificity of the responding T cells, the clonality of these T cells and the effects of virus variation on the CTL gives a possible explanation for the ultimate failure of the CTL response to control this virus infection.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Cytotoxic T cells in HIV2 seropositive Gambians. Identification of a virus-specific MHC-restricted peptide epitope.

A preliminary study of gag-specific, MHC-restricted CD8+ CTL has been performed in nine Gambian patients infected with HIV2. Such CTL were present in at least 55% of patients in fresh peripheral blood mononuclear cells without the requirement for in vitro restimulation. We have identified a nonamer peptide from HIV2 gag that is recognized by CD8+ HLA-B53 CTL using an amino acid sequence motif predicted from analysis of endogenous peptides eluted from HLA-B53 molecules. This peptide, from an HIV2/SIV conserved sequence, has previously been reported to be recognized by CTL from non-human primates vaccinated with recombinant vaccinia virus expressing the gag protein of SIV or infected with SIV virus. HLA-B53-restricted, HIV2 gag-specific CTL did not recognize target cells expressing HIV1 gag proteins, indicating that no cellular cross protection to HIV1 could be expected in this case.

Amino Acid Sequence↗
PubMed1993

HIV-specific cytotoxic T-cell activity in an HIV-exposed but uninfected infant.

The factors necessary for protective immunity against HIV-1 are unknown. Important information about these factors should come from study of people at high risk of HIV infection who have not apparently become infected. Among these are the estimated 60-85% of children who may be exposed in utero or perinatally to HIV-1 but do not become infected. We observed the transient appearance of HIV-specific cytotoxic T-lymphocyte (CTL) activity in a baby born to HIV-1-infected parents, in whom all standard markers of infection remained negative. These findings suggest that HIV-specific CTLs may be a marker for recently exposed, but uninfected, individuals.

CD4-CD8 Ratio↗
PubMed1993

A sequence pattern for peptides presented to cytotoxic T lymphocytes by HLA B8 revealed by analysis of epitopes and eluted peptides.

HLA B8-restricted cytotoxic T lymphocytes (CTL) specific for influenza A virus were generated and shown to recognize the nucleoprotein (NP). The dominant epitope was mapped using recombinant vaccinia viruses that expressed fragments of the NP and then synthetic peptides based on the NP amino acid sequence. The peptide 380-393 was first identified and further refined; it was shown that the glutamic acid at position 380 was essential for recognition by CTL and that the nonamer 380-388 was the optimum peptide. Six HLA B8-positive influenza immune donors that we have tested respond to this peptide as part of their influenza-specific CTL response. The amino acid sequence of the peptide epitope was compared to six other known virus peptides known to be restricted by HLA B8 and a sequence homology was identified, which predicted nonamer and octamer epitope sequences. Probable anchor residues were identified at peptide residues 3 (lysine/arginine), 5 (lysine/arginine) and 9 (leucine/isoleucine). Support for this pattern came from sequencing peptides eluted from purified HLA B8 molecules, where lysines were predominant at positions 3 and 5. One of the predicted epitope peptides was made and shown to be recognized by specific CTL. These and the two others were shown to compete with NP 380-388 for binding to HLA B8. A model was made of the HLA B8 molecule and negatively charged pockets predicted, which could accommodate the positively charged side chains of the peptide anchor residues.

Amino Acid Sequence↗
PubMed1993

CAPD prescription in current clinical practice.

A total of 132 patients from 15 dialysis centers were studied. Analyses were made of each drained dialysate exchange over 24 hours to determine total peritoneal urea clearance (KpT, liters/day), and a 24-hour urine was collected to determine total renal urea clearance (KrT, liters/day) and the sum of KpT+KrT or KprT, liters/day. Body water volume (V, L) was estimated from gender and surface area, and daily fractional urea clearance (KprT/V) was calculated. Normalized protein catabolic rate (PCRN, grams/kilogram/day) was also calculated from the urea data. Major results were the following: KrT comprised 25% of KprT; the mean KprT/V was 0.28, but ranged from 0.10-0.50; an equivalent thrice-weekly hemodialysis KT/V was calculated from the KprT/V values and showed mean KT/V = 1.07, but 67% of values were less than 1.0. In contrast, the Health Care Finance Administration (HCFA) consensus criteria indicated 91% of prescriptions were adequate. These data indicate the need for clinical outcome studies with KprT/V randomized over the range 0.20-0.30 to better define the domain of adequate CAPD.

Creatinine↗