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H Whittle

Publications and source records attributed to H Whittle.

At least 19 recordsLinked to original sources

The frailty hypothesis revisited: mainly weak children die of measles.

It has been suggested that measles infection mainly kills frail children who are likely to die anyhow of other infections. If that were true, the proportion of frail children should increase after the introduction of measles vaccination and post-measles mortality compared with mortality in uninfected children should increase when the case fatality declines and frail children are no longer dying of measles. The latter deduction was investigated in Niakhar, Senegal, where the measles case fatality has declined markedly. Measles has been studied in Niakhar during 12 years from 1983 to 1994. We compared long-term mortality after measles infection in periods with both high and low case fatality. The acute measles case fatality rate (CFR) declined from 6.5% in 1983-1986 to 1.5% in 1987-1994, an age-adjusted decline of 66% (RR=0.34 (0.19-0.58)). Between 1983-1986 and 1987-1994, mortality in the first year after measles infection declined by 35% (RR=0.65 (0.37-1.16)), the pattern being the same in the second and third year after infection (RR=0.63 (0.33-1.21)). This reduction could not be related to introduction of immunization, treatment of measles with Vitamin A, or prophylactic use of antibiotics. Controlling for age, immunization, and season, the decline in post-measles mortality was similar to the fall in non-measles-related mortality between the two periods (mortality rate ratio=0.72 (0.64-0.80)). Since the mortality decline in survivors of measles was as large as the decline in mortality among uninfected children, reduction in acute measles mortality did not lead to accumulation of frail children. We doubt measles infection ever eliminated mainly weak children; it always killed a broad spectrum of children, most of whom were "fit to survive". Hence, it seems unlikely that measles vaccination has contributed to the survival of more frail children.

Child↗

Natural measles causes prolonged suppression of interleukin-12 production.

Among vaccine-preventable diseases, measles is the preeminent killer of children worldwide. Infection with measles virus (MV) is associated with prolonged suppression of cell-mediated immune responses, a phenomenon that is thought to underlie the susceptibility to secondary infections that accounts for most measles-related mortality. Interleukin (IL)-12 is critical for the orchestration of cellular immunity. MV specifically ablates IL-12 production by monocyte/macrophages in vitro through binding to CD46, a complement regulatory protein that is an MV receptor. To address the effect of MV on IL-12 responses in vivo, cytokine production was examined in Gambian patients with measles. IL-12 production by peripheral blood monocytes from such patients is markedly suppressed, which provides a unifying mechanism for many of the immunologic abnormalities associated with measles. This suppression is prolonged, with significant, stimulus-specific inhibition of IL-12 production demonstrable months after recovery from acute infection. However, despite this suppression, IL-12 responsiveness remains intact.

Adolescent↗

Cancer in the Gambia: 1988-97.

We describe the incidence of cancer in The Gambia over a 10-year period using data collected through the Gambian National Cancer Registry. Major problems involved with cancer registration in a developing country, specifically in Africa are discussed. The data accumulated show a low overall rate of cancer incidence compared to more developed parts of the world. The overall age standardized incidence rates (ASR) were 61.0 and 55.7 per 100 000 for males and females, respectively. In males, liver cancer was most frequent, comprising 58% of cases (ASR 35.7) followed by non-Hodgkin lymphoma, 5.4% (ASR 2.4), lung 4.0%, (ASR 2.8) and prostate 3.3% (ASR 2.5) cancers. The most frequent cancers in females were cervix uteri 34.0% (ASR 18.9), liver 19.4% (ASR 11.2), breast 9.2% (ASR 5.5) and ovary 3.2% (ASR 1.6). The data indicate that cancers of the liver and cervix are the most prevalent cancers, and are likely to be due to infectious agents. It is hoped that immunization of children under 1 year against hepatitis B will drastically reduce the incidence of liver cancer in The Gambia.

Adolescent↗

Sequence specificity of the human immunodeficiency virus type 2 (hiv-2) long terminal repeat u3 region in vivo allows subtyping of the principal hiv-2 viral subtypes a and b.

Sequences from the nef/LTR overlap region of the human immunodeficiency virus type 2 (HIV-2) genome were amplified from uncultured peripheral blood mononuclear cells (PBMCs) from 40 HIV-2-infected individuals in The Gambia, West Africa. Additional sequences from the plasma of three blood donors were also derived. Analysis of HIV-2 U3 LTR transcription factor elements (PuB-1, p-ets, PuB-2, peri-kappa B, and NF-kappa B sites) indicated a relatively high level of conservation in vivo. The region immediately 3' of the nef termination codon, which exhibits clade-dependent specificity, was targeted by PCR to differentiate HIV-2 subtype A from subtype B infections, the two principal clinical HIV-2 subtypes. All clinical samples analyzed (n = 43) from The Gambia were identified as HIV-2 subtype A by a combination of LTR sequence analysis and subtype-specific amplification of subtypes A and B. Differential PCR amplification of the HIV-2 U3 LTR region represents a rapid means of differentiating subtype A from subtype B infections, the two dominant HIV-2 subtypes that are important in human disease.

Base Sequence↗

Cytotoxic T lymphocytes recognize structurally diverse, clade-specific and cross-reactive peptides in human immunodeficiency virus type-1 gag through HLA-B53.

Human immunodeficiency virus type-1 (HIV-1) cytotoxic T lymphocyte (CTL) epitopes have largely been defined in Caucasian populations infected with clade B virus. Identification of potentially protective CTL epitopes in non-B clade-infected African subjects is important for vaccine development. In a study of CTL responses in clade A-infected Gambians, using cytotoxicity, interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISpot) and HLA-B53-peptide tetramer assays, we identified three HLA-B53-restricted epitopes in HIV-1 gag p24. CTL specific for an epitope in a highly immunogenic region of the p24 protein showed no cross-reactivity to other HIV-1 clades. Two of the epitopes would not have been predicted from the peptide-binding motif due to the absence of a proline anchor at position 2. Structural analysis of HLA-B53 and its relative, HLA B35, enabled us to re-define the peptide-binding motif to include other P2 anchors. These results demonstrate the value of combined immunological and structural analyses in defining novel CTL epitopes and have implications for HIV-1 vaccine design.

Amino Acid Sequence↗

Prevalence of HBV core promoter/precore/core mutations in Gambian chronic carriers.

One hundred forty-two precore/core sequences were obtained from Gambian chronic hepatitis B virus (HBV) carriers and the predominant variants defined. The two point mutations, from A to T and G to A at nt positions 1762 and 1764 in the basic core promoter region, were found in only 7/99 (7%) of the samples where this region was sequenced. These mutations were found in both HBeAg-positive and -negative patients. The precore stop-codon mutation at nt position 1896 was found in 14/51 (27%) of HBeAg-negative samples, which is a lower prevalence rate in comparison with other parts of the world with high carrier rates. In HBeAg-positive patients the core amino acid sequences were conserved, but after seroconversion to anti-HBe significantly more changes were apparent. Several of the amino acid substitutions found have been described previously been in wild-type viruses of other genotypes.

Amino Acid Sequence↗

Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis.

BACKGROUND/AIMS: Transmission of hepatitis B virus (HBV) in Africa occurs horizontally, with most people becoming infected between the ages of 1 and 5 years. The index cases in such events have been assumed to come from within the family unit or from sources outside the immediate family, such as other families or inhabitants of the same compound or village. Here, we define these routes of transmission by phylogenetic tree analysis of sequences from the entire pre-core/core region of the virus, in Gambian chronic carriers. METHODS: Amplification by polymerase chain reaction of serum extracted HBV-DNA was followed by direct sequencing of the target region. Following editing and alignment of these sequences, phylogenetic tree analysis was performed using the neighbour-joining and maximum-likelihood methods. RESULTS: Despite the overall conserved nature of the sequences of the pre-core/core region from 142 chronic carriers, distinct clusters were easily defined at the family and village level, but not on a wider geographical separation. CONCLUSIONS: Phylogenetic tree analysis of sequences obtained from family members provided strong evidence of intrafamilial transmission of HBV in at least two-thirds of the families studied from Gambia.

Cluster Analysis↗

Genetic regulation of acquired immune responses to antigens of Mycobacterium tuberculosis: a study of twins in West Africa.

The role of genetic factors in clinical tuberculosis is increasingly recognized; how such factors regulate the immune response to Mycobacterium tuberculosis in healthy individuals is unclear. In this study of 255 adult twin pairs residing in The Gambia, West Africa, it is apparent that memory T-cell responses to secreted mycobacterial antigens (85-kDa antigen complex, "short-term culture filtrate," and peptides from the ESAT-6 protein), as well as to the 65-kDa heat shock protein, are subject to effective genetic regulation. The delayed hypersensitivity response to intradermal tuberculin also demonstrates significant genetic variance, while quantitative T-cell and antibody responses to the 38-kDa cell membrane protein appear to be determined largely by environmental factors. Such findings have implications for vaccine development.

Adolescent↗

Study of HIV type 1 gag/env variability in The Gambia, using a multiplex DNA polymerase chain reaction.

A multiplex DNA PCR assay was developed for the simultaneous first-round amplification of HIV-1 gag and env fragments for the heteroduplex mobility assay (HMA). This assay was compared with the conventional amplification assay, using DNA extracted from PBMC samples from 30 HIV-1-seropositive individuals from The Gambia, who were enrolled between 1992 and 1997. From 27 of 30 (90%) samples both gag and env HMA fragments were amplified simultaneously. In one sample only the gag HMA fragment could be amplified by multiplex DNA PCR, and in two samples amplification was negative for both gag and env HMA in multiplex as well as the mono-DNA PCR. Of the 28 Gambian isolates subtyped by gag/env HMA or by sequencing and phylogenetic analysis, the majority (19 of 28; 68%) were intersubtype recombinant. Fifteen of 28 (53%) samples were circulating recombinant form (CRF) CRF02.AG variants. Two isolates clustering with the previously documented Gambian isolate GM4 (previously described as an env GC recombinant) are classified as gag A/env J recombinants.

DNA, Viral↗

Development of a one-tube multiplex reverse transcriptase-polymerase chain reaction assay for the simultaneous amplification of HIV type 1 group M gag and env heteroduplex mobility assay fragments.

The emergence of intersubtype recombinant HIV-1 isolates has made it imperative to analyze different regions of HIV-1 genomes. For this purpose a one-tube multiplex RT-PCR, coamplifying first-round amplicons that allow amplification of gag and env heteroduplex mobility assay (HMA) fragments from different HIV-1 group M isolates, was developed, starting with plasma samples. The multiplex RT-PCR assay is sensitive: 115 of 136 (84.5%) samples were positive for both gag and env, positive amplification of the gag fragment was observed in 130 of 136 (95.6%) samples, while for the env fragment 119 of 136 (87.5%) tested positive. The multiplex RT-PCR in combination with gag and env HMA makes large-scale HIV-1 subtyping fast, simple, and more economical.

DNA, Viral↗

Absence of specific mucosal antibody responses in HIV-exposed uninfected sex workers from the Gambia.

OBJECTIVES: Specific antibodies to HIV envelope that inactivate virus at the mucosal surfaces involved in sexual contact are of interest for the design of a vaccine against HIV-1. It has been suggested that, in frequently HIV-exposed but uninfected individuals, HIV-specific mucosal antibody responses may exist and play a role in resistance against HIV. This study investigated HIV-1 envelope specific mucosal antibody responses in HIV-resistant sex workers in west Africa. METHODS: A group of 26 exposed uninfected female commercial sex workers from the Gambia, who have had repeated exposures to HIV-1 and HIV-2 were studied. We assessed the presence of vaginal IgA and IgG in vaginal swabs against a range of HIV-1 and HIV-2 envelope presentations and performed HIV-1 neutralization assays. RESULTS: No significant vaginal IgA or IgG responses against HIV-1 or HIV-2 were detected, and none of the vaginal secretions tested displayed any HIV-1 neutralizing activity. CONCLUSION: Vaginal antibody responses against HIV were not found in Gambian sex workers who resist HIV infection. Resistance against HIV infection can therefore occur in the absence of specific antibodies against HIV at the genital mucosa. A protective role for HIV-envelope specific IgA in resistance against HIV-1 infection in exposed uninfected individuals as reported in the literature is uncertain.

Antibody Formation↗

Environmental and genetic determinants of aflatoxin-albumin adducts in the Gambia.

Aflatoxins together with chronic hepatitis B virus (HBV) infection contribute to the high incidence of hepatocellular carcinoma in developing countries. An understanding of the mechanism of interaction between these factors would provide a strong rationale for developing effective prevention strategies. In this study in The Gambia we examined the effect of environmental (place of residence and timing of sample collection) and host factors (age, sex, HBV status and interindividual variations in carcinogen metabolising enzymes) in determining blood aflatoxin-albumin adduct levels in 357 individuals of whom 181 were chronic HBV carriers. Samples were analysed for aflatoxin-albumin adducts, HBV status and genotypes of glutathione S-transferase (GST) M1, GSTT1, GSTP1 and epoxide hydrolase (EPXH). Urine samples were analysed for 6beta-hydroxycortisol:cortisol ratio as a marker of cytochrome P450 (CYP) 3A4 activity. Adduct levels were significantly higher in subjects resident in rural [geometric mean adduct level 34.9 pg aflatoxin B1-lysine equivalent (28.5-42.8; 95%CI)/mg albumin] than in periurban areas [22.2 pg (14.9-33.4)/mg] and were approximately twice as high in the dry season [mid-February to March; 83.2 pg (53.3-130.8)/mg] than the wet [July to August; 34.9 pg (28.5-42.8)/mg]. In contrast, HBV status, CYP3A4 phenotype, GSTT1, GSTP1 and EPXH genotypes were not associated with aflatoxin-albumin adduct level. However, mean adduct levels were significantly higher in non-HBV infected subjects with GSTM1 null genotype. The main factors which affect aflatoxin-albumin adduct levels in this population are environmental, notably place of residence and timing of sample collection. This study further emphasises the priority to reduce aflatoxin exposure in these communities by primary prevention measures.

Adolescent↗

Plasma RNA viral load predicts the rate of CD4 T cell decline and death in HIV-2-infected patients in West Africa.

OBJECTIVE: To examine whether the levels of plasma RNA and DNA provirus predict the rate of CD4 cell decline and patient death. DESIGN: Retrospective analysis of HIV-2 cohort subjects. METHODS: Fifty-two subjects were recruited between January 1991 and December 1992. HIV-2 RNA levels in plasma and DNA levels in peripheral blood mononuclear cells (PBMC) were measured using in-house quantitative PCR assays. The annual rate of CD4 cell decline was calculated using the least-squares method. The survival data on 31 December 1997 were used. RESULTS: The mean percentage of CD4 cells at baseline was 30.7 (SD, 9.5). In a linear regression model, the annual rate of CD4 cell decline was 1.76 CD4% faster for every increase in one log10 RNA copies/ml [95% confidence interval (CI), 0.81-2.7; P = 0.0006; r = 0.46; n = 52] and 1.76 CD4% faster for every increase in log10 DNA copies/10(5) PBMC (95% CI 0.46-3.1; P = 0.01; r = 0.33; n = 42). In a multiple linear regression model, RNA load was related to CD4 decline independently of DNA load (P = 0.02). The overall mortality rate was 7.29/100 person-years. In a Cox regression model, the hazard rate increased by 2.12 for each log10 increase in RNA load (95% CI, 1.3-3.5; P = 0.0023) but only by 1.09 for each log10 increase in DNA load (95% CI, 0.64-1.87; P = 0.8). CONCLUSION: This longitudinal study shows for the first time that a baseline HIV-2 RNA load predicts the rate of disease progression. HIV-2-infected patients with a high viral load may need to be treated as vigorously as HIV-1 patients.

Adolescent↗

Maternal plasma viral RNA levels determine marked differences in mother-to-child transmission rates of HIV-1 and HIV-2 in The Gambia. MRC/Gambia Government/University College London Medical School working group on mother-child transmission of HIV.

OBJECTIVES: To determine the rates of, and risk factors for, mother-to-child transmission (MCT) of HIV-1 and HIV-2 infection in The Gambia. DESIGN: A blinded, prospective, community-based cohort study of 29.549 pregnant women attending the eight largest antenatal clinics in The Gambia. METHODS: Women were tested for HIV-1 and HIV-2 infection. Infected subjects and a group of HIV-seronegative women were followed with their babies until 18 months after delivery. Maternal CD4 cell count percentages were measured before and 18 months after delivery, and the antenatal plasma viral load was determined. Babies were tested for HIV by the polymerase chain reaction and/or serology at 2, 9 and 18 months of age. RESULTS: The study enrolled 144 women positive for HIV-1 and 294 for HIV-2 plus 565 seronegative pregnant women: the mean antenatal percentage CD4 cell counts of 96 HIV-1-positive, 223 HIV-2-positive and 125 HIV-seronegative mothers were 31% [95% confidence interval (CI) 28-33], 41% (95% CI 39-42) and 47% (95% CI 45-49), respectively. The geometric mean antenatal plasma viral load of 94 HIV-1-infected women was 15,100 copies x 10(3) ml (95% CI 10,400-19,000) which was much higher than that of 60 randomly selected HIV-2-infected women, which was 410 copies x 10(3) ml (95% CI 150-910) (P < 0.001). The estimated transmission rate of HIV-1 was 24.4% (95% CI 14.6-33.9) and that of HIV-2 was 4.0% (95% CI 1.9-7.4). Five of 17 HIV-1-positive and three of eight HIV-2-positive babies were infected after 2 months of age. Birth in the rainy season [odds ratio (OR) 2.9; 95% CI 1.2-7.2], a low postnatal CD4 cell percentage (OR for a 10% fall 2.4; 95% CI 1.1-5.1) and a high maternal plasma viral load (OR for a 10-fold increase 2.9; 95% CI 1.1-7.8) were risk factors for transmission that applied equally to both viruses. CONCLUSION: Low maternal HIV-2 RNA levels, which on average are 37-fold less than in HIV-1 infection, relate to the low MCT rate of HIV-2.

CD4 Lymphocyte Count↗

Hepatitis B infection and aflatoxin biomarker levels in Gambian children.

OBJECTIVES: To examine the relationship between hepatitis B virus (HBV) infection and biomarkers of aflatoxin exposure in West African children. METHODS: Sera from 444 children aged 3-4 years who were selected to be representative of their communities were analysed for aflatoxin-albumin (AF-alb) adducts and markers of hepatitis B infection. RESULTS: There was large interindividual variation in adduct levels (range: 2.2 to 459 pg AF-lysine eq./mg albumin). Adduct level was strongly correlated with season, with an approximately twofold higher mean level in the dry season than the wet. Geometric mean adduct levels in uninfected children, chronic carriers and acutely infected children were 31.6 (n = 404), 44.9 (n = 34) and 96.9 (n = 6) pg/mg, respectively. The relationship of AF-alb level to ethnicity, month of sampling and HBV status was examined in a multiple regression model. Month of obtaining the blood sample (P = 0.0001) and HBV status (P = 0.0023) each made a highly significant contribution to the model; the high AF-alb levels were particularly associated with acute infection. Elevated serum transaminase levels were significantly (P < 0.002) associated with HBV status, with acutely infected children having the highest levels. Ethnicity was not significantly associated with AF-alb adduct levels in the model (P = 0.09). CONCLUSIONS: HBV infection and month of sampling both significantly influence AF-alb adduct levels. The effect of seasonality on adducts was also observed in a previous study of 347 Gambian adults, although there was no correlation between adduct level and HBV status in that population. This difference between children and adults may reflect a more severe effect of HBV infection, particularly acute infection, in childhood on hepatic AF metabolism.

Aflatoxins↗

A longitudinal study of in vitro IFNgamma production and cytotoxic T cell responses of tuberculosis patients in the gambia.

SETTING: This study was carried out at the MRC Laboratories, The Gambia. OBJECTIVES: To characterize the antigen-specific IFNgamma production and cytotoxic T cell (CTL) responses of patients during active tuberculosis, treatment, and following recovery. DESIGN: PBMC were isolated from 37 patients with tuberculosis and incubated with either PPD, live M. bovis BCG, or no antigen and IFNgamma production measured after 7 days. CTL activity against these antigens was determined using autologous antigen-pulsed monocyte-derived macrophages as target cells. A subset of these patients (7-18 depending on antigen and assey used) were tested 2 months into drug treatment and 3 months after discharge. A group of blood bank donors (n= 21) were also tested to evaluate IFNgamma responses in endemic controls; a subset (n= 16) were also tested for CTL activity. RESULTS: The ability to produce IFNgamma in response to mycobacterial antigens correlated with the Mantoux skin test status of the patient. IFNgamma production to live M. bovis BCG was diminished at diagnosis but returned after 2 months of drug treatment, and was sustained after completion of drug therapy. The CTL responses to both PPD and live M. bovis BCG were reduced during the period of drug treatment compared to those at diagnosis, but returned to the original levels after recovery. CONCLUSIONS: Drug treatment induced marked alterations in the immune responses of tuberculosis patients with induction of IFNgamma production in response to stimulation with live M. bovis BCG. This may indicate activation of both CD4 and CD8 T cells.

Adolescent↗

Sex-associated differences in the antibody-dependent cellular cytotoxicity antibody response to measles vaccines.

In some countries, excessive non-measles-related mortality has been observed among female recipients of high-titer measles vaccines. We determined if differences in the immune response to measles vaccines underlie the excessive female mortality by measuring the measles virus (MV)-specific antibody-dependent cellular cytotoxicity (ADCC) antibody response in 65 3-year-old Gambian children immunized with Edmonston-Zagreb medium-titer (EZ) or Schwarz standard vaccines during infancy. Among the 20 females and 22 males with undetectable anti-MV antibodies at the time of immunization, females had significantly lower ADCC than males (median cytotoxicities of 1/100 serum dilutions = 8.4 and 12%, respectively; P = 0.04). This sex-associated difference was present only among the six female and seven male recipients of EZ vaccine (median cytotoxicities = 5.1 and 19.0%, respectively; P = 0.02). There were no significant sex-associated differences in neutralizing antibody activity. Decreased ADCC antibody activity may contribute to the lower survival rate observed in females receiving high-titer measles vaccination.

Antibody-Dependent Cell Cytotoxicity↗