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Biomedical subjects

F Gotch

Publications and source records attributed to F Gotch.

At least 37 records · Page 2Linked to original sources
PubMed2001

The stability between two HIV-1 RNA measurements one year apart and the relationship with HIV subtype in rural Uganda.

We compared HIV-1 RNA levels using the nucleic acid sequenced based amplification (NASBA) test kit in 2 samples taken one year apart from participants infected with env subtype A or D in a population-based cohort in Uganda. Fifty participants were infected with subtype A and 70 with subtype D. HIV-1 RNA levels were significantly higher in subtype D unadjusted (P=0.001), and after adjusting for age, gender, and CD4 count (P<0.001). Eighty-six participants had HIV-1 RNA measurements in both years and 67 (78%) were within one log10 of their result a year before. There was no relationship between the difference in log viral load and proportion of CD4 change. Individuals infected with subtype D had a higher average increase in viral load and this was statistically significant if adjusted for baseline levels and CD4 count (P=0.015).

Adolescent↗
PubMed2001

Development of immunotherapeutic strategies for HIV-1.

In the majority of untreated patients, HIV-1 infection presents as a progressive disease of the immune system. Recent studies indicate that immune responses can be induced in HIV-1 infected individuals, leading to some immune control of virus replication. Such immune responses are also observed in small numbers of untreated HIV-1 infected long-term non-progressor (LTNP) patients, as well as in other viral infections (including those with human herpes viruses). Emerging novel technologies, animal studies and detailed immunological studies have proven invaluable in defining the immune responses that are associated with a favourable clinical outcome. Central effector and regulatory cells are HIV-1-specific CD8+ cytotoxic T-lymphocytes (CTL) and CD4+ helper T-lymphocytes respectively. Fully functional antigen-presenting cells (APC) are also essential in all stages of HIV-1 infection and possibly some (but not all) antibody responses contribute to beneficial immunity. The availability of combination anti-retroviral drug therapy, which successfully controls viraemia, has enabled a beneficial outcome in many HIV-1 infected individuals. Since no chronically HIV-1 infected patient has been shown to eradicate virus, novel approaches utilising therapeutic immunisation and various cytokines to manipulate immune responses and to induce and steer immunity towards a desired phenotype are required. There is a clear rationale for immunotherapeutic intervention in chronic progressive HIV-1 infection, which forms the foundation for novel approaches aimed at inducing and maintaining immune control. Here we review the immunopathogenesis of HIV-1 infection and discuss the promises of therapeutic immunisation and immunotherapy in general and their potential in the treatment of chronic HIV-1 disease.

Animals↗
PubMed2000

A phase I trial in HIV negative healthy volunteers evaluating the effect of potent adjuvants on immunogenicity of a recombinant gp120W61D derived from dual tropic R5X4 HIV-1ACH320.

Thirty healthy HIV negative volunteers were randomised to receive 200 micrograms of rgp120W61D in either: 3D-MPL and QS21, with an oil and water emulsion (SBAS-2) (13); or 3D-MPL and QS21 (SBAS-1) (11); or alum (six). Immunizations were given at 0, 4 and 28 weeks and 23 (77%) participants completed the schedule. Adverse events were more frequent (P < 0.001) and more severe (P < 0.001) in the SBAS-2 group. Binding antibodies to the homologous rgp120W61D were detected after the first immunisation only in those receiving SBAS-1 and SBAS-2, were maximal after the third immunization in all three groups, and persisted to week 84 only in the novel adjuvant groups. These differences were significant (p = 0.02). Neutralising antibodies to TCLA-strains of HIV-1 were observed after the second immunization in all three groups, were maximal after the third immunization, but did not neutralise homologous or heterologous PBMC derived primary HIV-1 isolates. Proliferative T-cell responses to rgp120W61D were maximal after the second immunization and reached very high values in the SBAS-2 group. HIV-1 specific CD8+ MHC Class I restricted cytotoxic T-lymphocytes were not seen in a subset of participants tested at a single timepoint. SBAS-2 with rgp120W61D induced antibody titres as high as those seen in HIV infection, but the quality of the antibodies remained different in that there was no evidence of primary isolate neutralisation. Although cell-mediated immunity was enhanced by SBAS-2 in terms of lymphoproliferative responses, HIV-1 specific CD8+ cytotoxicity was not demonstrated.

AIDS Vaccines↗
PubMed2000

HLA-C and guttate psoriasis.

BACKGROUND: Psoriasis is a heterogeneous disease in its clinical expression. Both genetic and environmental factors are thought to contribute to the pathogenesis of the inflammatory and hyperproliferative components of the typical skin lesions. Predisposing genetic influences include associations with human leucocyte antigens (HLA) of which that with HLA-Cw6 is the strongest. Guttate psoriasis is a specific clinical manifestation of psoriasis frequently associated with group A beta-haemolytic streptococcal throat infection. OBJECTIVES: We set out to determine whether further clinical subdivision of psoriasis is associated with tighter correlation with HLA-C alleles. PATIENTS/METHODS: We determined the HLA-C locus genotype of 29 caucasian patients with guttate psoriasis presenting consecutively with guttate psoriasis associated with a history of a sore throat and/or an antistreptolysin O titre > 200 IU mL-1. Polymerase chain reaction typing using sequence-specific primers was used to detect all known HLA-C alleles. These data were compared with a control population of 604 random caucasian cadaver donors. RESULTS: All patients (100%) with guttate psoriasis carried the Cw*0602 allele compared with 20% of the control population (odds ratio = infinity; 95% confidence limits 25.00-infinity; Pcorrected < 0.0000002). CONCLUSIONS: This result is consistent with HLA-Cw*0602 playing a part directly in the pathogenesis of guttate psoriasis.

Adolescent↗
PubMed2000

Vaccines for the control of HIV/AIDS.

This review discusses the feasibility of an HIV vaccine and describes the history, efficacy and potential to succeed of old and new vaccine concepts.

AIDS Vaccines↗
PubMed2000

T-cell telomere length maintained in HIV-infected long-term survivors.

BACKGROUND AND METHODS: We have used the erosion of telomeric DNA as a measure of cellular division to study the replicative history of isolated T-lymphocyte subpopulations from a group of HIV-infected long-term survivors and age-matched healthy controls. RESULTS: In keeping with previous studies, we found that CD45RO+ (memory) T-cells showed greater telomere erosion than CD45RA+ (naive) T-cells. We did not, however, find any significant differences in the telomere lengths of isolated CD4+, CD8+, CD45RA+ or CD45RO+ T-cells between HIV-infected long-term survivors and age-matched controls. Further, we found no evidence of telomerase activation in T-cells from the HIV-infected groups to account for the lack of telomere erosion. CONCLUSIONS: Our data show no evidence, through telomere shortening, of clonal exhaustion or replicative senescence due to an increased rate of immune cell turnover in HIV-infected long-term survivors.

Adult↗
PubMed1999

HIV-1 RNA levels in an African population-based cohort and their relation to CD4 lymphocyte counts and World Health Organization clinical staging.

Apart from a small number of reports from people who are based in hospitals, data on viral load in HIV-infected people in sub-Saharan Africa, where most infections occur, are lacking. We report serum HIV-1 RNA levels in a population-based cohort in rural Uganda using the nucleic acid sequence-based amplification procedure (NASBA) test kit and describe their relation to CD4 counts and World Health Organization (WHO) clinical staging. The median (interquartile range [IQR]) viral loads were 87,000 copies/ml (37,500-295,000 copies/ml) in 40 prevalent cases infected for >6 years, and 31,000 copies/ml (7800-174,000 copies/ml) in 65 incident cases with seroconversion dates within the previous 6 years. Although we found a correlation between viral load and absolute CD4 count (p < .0001), there was no evidence for an association with CD4 decline (p = .1). Overall, there was a significant trend of increasing viral load with worsening clinical stage from a median viral load of 15,000 for those in WHO stage 1 (asymptomatic) to 150,600 copies/ml for those in stage 4 (AIDS; p < .001). However, the association was seen only in incident cases. Thus, we found that the NASBA test on serum was a useful indicator of disease stage especially in persons known to be infected for <6 years. Such baseline data are important for vaccine research, and if antiretroviral drugs become available to more than a few people in Africa, it will be important that accurate viral load estimations are available at least in a proportion of people to monitor the effectiveness of treatment, and measure the compliance and emerging resistance to these drugs.

Adult↗
PubMed1999

'Naïve' and 'memory' CD4+ T-cells and T-cell receptor (TCR) V beta repertoire dynamics are independent of the levels of viremia following HIV seroconversion.

The progression of 'naive' and 'memory' T-cells and the T-cell receptor Vbeta (TCR Vbeta) repertoire dynamics within the peripheral CD4+ T-cell compartment were studied in individuals following HIV seroconversion. Profound TCR Vbeta repertoire perturbations were observed within the CD4+ T-cell pool in treatment-naive patients regardless of their levels of viremia during the first 6-8 months after seroconversion. The ratio of 'naive' to 'memory' CD4+ T-cells as well as the TCR Vbeta repertoire dynamics did not appear to correlate with absolute numbers of CD4 T-cells.

Adolescent↗
PubMed1999

Effect of intradialytic parenteral nutrition on delivered Kt/V.

The purpose of the study is to determine the effect of intradialytic parenteral nutrition (IDPN) and its components on delivered Kt/V (Kt/Vd). Nineteen patients undergoing routine outpatient hemodialysis and receiving IDPN were enrolled onto this prospective, crossover study. To reduce the confounding of time, assigned treatment in the first week was random, with patient crossover in the fourth week. Patients served as their own controls. In the successive 6 weeks, patients received IDPN solutions differing in whether amino acids (AAs), dextrose, or lipids were included or excluded. The primary end point was Kt/Vd, measured with a single-pool, variable-volume urea kinetic model. Other factors with the potential to impact on Kt/Vd were controlled and/or monitored. The administration of IDPN with all three components resulted in a significantly reduced mean Kt/Vd. When patients received AA-containing solutions, mean Kt/Vd was significantly less than when IDPN was withheld. Administration of solutions without AA resulted in a mean Kt/Vd not significantly different from mean Kt/Vd when IDPN was withheld. The mean prescribed Kt/V did not differ from mean Kt/Vd when IDPN was withheld. Simulation analyses of increased urea generation (Gu) showed an increase in patient urea volume and decreased Kt/V similar to the study findings. AA-containing IDPN solutions resulted in a significant reduction in Kt/Vd, possibly mediated by increased Gu. Administration of IDPN solutions may have important clinical and economic consequences that warrant further investigation.

Aged↗
PubMed1999

Therapeutic vaccines in HIV.1 infection.

In this review we address questions which must be considered if better attempts are to be made to treat all persons presently infected with human immunodeficiency virus (HIV). There are thirty million people in the world presently living with HIV, only 10% of whom are likely to be able to access currently available drug therapy. Even when available, such therapy causes considerable inconvenience and undesirable clinical side effects, and fails to eradicate virus from a small reservoir of latently infected cells. Thus, we must ask what forms of alternative therapy might be used. One strategy that may be considered is to reduce virus levels as low as possible using highly active antiretroviral therapy (HAART), followed by modulation of host immunity with immunotherapy in order to effect an appropriate and efficient response mimicking that found in long-term asymptomatic patients, with the aim of indefinitely maintaining the asymptomatic period following discontinuation of chemotherapy, or even of eradicating the virus from the latent reservoirs. In 1987, long before the advent of highly active antiretroviral therapy, J. Salk proposed the use of a 'suitable potent non-infectious (HIV) immunogen' to delay or prevent the development of AIDS in infected individuals (1). The objective of administering such an agent was to 'enhance and prolong the presence of (immunologically) protective factors'. The stated aim at that time was 'to destroy virus and viral antigen producing cells by the induction of the immune system's cytotoxic mechanisms known to rid the host of virus and virus producing cells'. Twelve years later, and after a quarter of a century living with HIV, and with the advent of HAART, is it time to use our knowledge of the host's own immune system to fight this seemingly intractable invader?

AIDS Vaccines↗
PubMed1999

Identification of human herpesvirus 8-specific cytotoxic T-cell responses.

Human herpesvirus 8 (HHV-8) (or Kaposi's sarcoma-associated herpesvirus) is implicated in the etiopathogenesis of Kaposi's sarcoma (KS) and certain lymphoproliferations. The introduction of more effective therapies to treat human immunodeficiency virus infection has led to a decline in the incidence of KS and also in the resolution of KS in those already affected. This suggests that cellular immune responses including cytotoxic T lymphocytes (CTLs) could play a vital role in the control of HHV-8 infection and in KS pathogenesis. Here we elucidate HLA class I-restricted, HHV-8-specific cellular immune responses that could be important in the control of HHV-8 infection and subsequent tumor development. We show the presence of CTLs against HHV-8 latent (K12), lytic (K8.1), and highly variable (K1) proteins in infected individuals.

AIDS-Related Opportunistic Infections↗
PubMed1999

HLA-A, -B, -C, -DRB1, DRB3, DRB4, DRB5 and DQB1 polymorphism detected by PCR-SSP in a semi-urban HIV-positive Ugandan population.

PCR-SSP was used to HLA-type a cohort of Ugandan HIV-positive individuals. The results represent a more comprehensive description of HLA in an African population than previously described and are in concordance with data from a general Black population. Substantial differences exist between this population and Caucasoid populations in which immunological responses to HIV have been investigated; this emphasises that the main HLA-restrictive elements for HIV-specific cytotoxic T lymphocytes will most likely be different for each population.

Base Sequence↗
PubMed1998

Association between a defective CCR-5 gene and progression to disease in HIV infection.

We measured the effect(s) of CCR-5 genotype on disease progression by studying the frequency of a defective CCR-5 delta32 allele within a cohort of long-term infected individuals. An elevated frequency of CCR-5 delta32 heterozygotes within the cohort compared with a control population of blood donors was observed. An association between progression rate and CCR-5 delta32 heterozygosity was observed. Furthermore, analysis of proviral DNA V3 sequences from a subset of the cohort predicted that the majority of individuals (39 of 44) were infected with viruses predicted to utilize the beta-chemokine receptor CCR-5. The marked association between CCR-5 genotype and disease progression observed in this study may be a consequence of the predicted low frequency of CXCR-4-utilizing viruses present within the selected cohort.

Alleles↗
PubMed1998

Mechanisms of protection induced by attenuated simian immunodeficiency virus. II. Lymphocyte depletion does not abrogate protection.

To determine the role that cellular immune responses play in the protection conferred by vaccination with attenuated SIVmac32H (pC8), we have attempted to deplete macaques of their CD8+ cells prior to challenge with wild-type SIVmac32H (pJ5). In two of four pC8-infected macaques, N109 and N112, a transient partial depletion of CD8+ cells by antibody treatment was achieved. On the day of challenge peripheral CD2+CD4-CD8+ cell counts were reduced by 92 and 95%, respectively, in animals N109 and N112 and their lymph nodes revealed a 46 and 58% reduction, respectively, in CD2+CD4-CD8+ cells. Two other pC8-immunized macaques, N110 and N111, treated in the same way, did not show significant depletion of CD8+ cells. None of these four pC8-immunized animals became infected when challenged with 50 MID50 of pJ5. Treatment of a further four pC8-infected and protected macaques and two naive control animals with Campath-1H antibody successfully depleted peripheral CD3+ cell counts by >99% in all treated animals. Campath-1H depletion resulted in enhanced, longer lasting lymphoid depletion. Yet subsequent challenge with 20 MID50 of pJ5 still failed to infect the pC8-immunized animals. All eight of the naive controls, including two Campath-1H-treated animals, became infected following challenge. In summary, partial depletion of circulating CD8+ cells or total lymphocytes prior to challenge failed to abrogate the protection conferred by vaccination with pC8.

Animals↗
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↗