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Biomedical subjects

J Kimani

Publications and source records attributed to J Kimani.

14 recordsLinked to original sources
PubMed1999

Broadly cross-reactive HIV-specific cytotoxic T-lymphocytes in highly-exposed persistently seronegative donors.

HIV-specific cytotoxic T-lymphocytes (CTL) are believed to play a key part in the control of virus levels throughout HIV infection. An important goal of a potential prophylactic vaccine against HIV is therefore to elicit a strong CTL response which is broadly cross-reactive against a diverse range of HIV strains. We have detected HIV-specific CTL in two groups of highly-exposed but persistently seronegative female sex workers in Africa which show extensive cross-reactivity between different viral sequences. In a small group of women exposed to both HIV-1 and HIV-2 in Gambia, studied over 4 years, we have repeatedly detected HLA-B35-restricted CTL which exhibit cross-reactivity between the HIV-1 and HIV-2 sequences of the CTL epitopes. In women with particularly intense exposure to what are likely to be multiple clades of HIV-1 in Nairobi Kenya, we have detected CTL directed towards epitopes conserved between HIV-1 clades. In neither group is there any evidence that variation in CCR5 sequence or expression is responsible for their apparent resistance to HIV infection. However, in seropositive donors from Oxford infected with African strains of HIV-1, we have defined CTL responses which are specific for particular clades and have mapped some unique A clade CTL epitopes, together with others to highly-conserved regions of the virus. Further information about the extent of cross-reactive CTL immunity will be important for future vaccine design and evaluation.

Amino Acid Sequence↗
PubMed1999

Resistance to HIV-1 infection among highly exposed sex workers in Nairobi: what mediates protection and why does it develop?

Variability in susceptibility to infection and disease caused by infectious agents is a characteristic of all populations. Among susceptible individuals exposed to an infection, not all become infected and among infected individuals, not all develop disease. It seems logical that variability in susceptibility to infection and disease would apply to infection and disease with human immunodeficiency viruses. However, until recently, it has been generally held that there is no natural immunity to HIV-1 and that once infected, all individuals would ultimately succumb to AIDS.

Cohort Studies↗
PubMed1998

HIV type 1 resistance in Kenyan sex workers is not associated with altered cellular susceptibility to HIV type 1 infection or enhanced beta-chemokine production.

A small group of women (n = 80) within the Nairobi-based Pumwani Sex Workers Cohort demonstrates epidemiologic resistance to HIV-1 infection. Chemokine receptor polymorphisms and beta-chemokine overproduction have been among the mechanisms suggested to be responsible for resistance to HIV-1 infection. This study attempts to determine if any of those mechanisms are protecting the HIV-1-resistant women. Genetic analysis of CCR5 and CCR3 from the resistant women demonstrated no polymorphisms associated with resistance. Expression levels of CCR5 among the resistant women were shown to be equivalent to that found in low-risk seronegative (negative) controls, while CXCR4 expression was greater among some of the resistant women. In vitro infection experiments showed that phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from resistant women were as susceptible to infection to T cell- and macrophage-tropic North American and Kenyan HIV-1 isolates as were the PBMCs from negative controls. No significant difference in circulating plasma levels of MIP-1alpha and MIP-1beta were found between the resistant women and negative or HIV-1-infected controls. In vitro cultures of media and PHA-stimulated PBMCs indicated that the resistant women produced significantly less MIP-1alpha and MIP-1beta than did negative controls and no significant difference in RANTES levels were observed. In contrast to studies in Caucasian cohorts, these data indicate that CCR5 polymorphisms, altered CCR5 and CXCR4 expression levels, cellular resistance to in vitro HIV-1 infection, and increased levels of beta-chemokine production do not account for the resistance to HIV-1 infection observed among the women of the Pumwani Sex Workers Cohort.

Cell Membrane↗
PubMed1998

Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi.

Many people who remain persistently seronegative despite frequent HIV exposure have HIV-specific immune responses. The study of these may provide information about mechanisms of natural protective immunity to HIV-1. We describe the specificity of cytotoxic T lymphocyte responses to HIV in seronegative prostitutes in Nairobi who are apparently resistant to HIV infection. These women have had frequent exposure to a range of African HIV-1 variants, primarily clades A, C, and D, for up to 12 yr without becoming infected. Nearly half of them have CTL directed towards epitopes previously defined for B clade virus, which are largely conserved in the A and D clade sequences. Stronger responses are frequently elicited using the A or D clade version of an epitope to stimulate CTL, suggesting that they were originally primed by exposure to these virus strains. CTL responses have been defined to novel epitopes presented by HLA class I molecules associated with resistance to infection in the cohort, HLA-A*6802 and HLA-B18. Estimates using a modified interferon-gamma Elispot assay indicate a circulating frequency of CTL to individual epitopes of between 1:3,200 and 1:50,000. Thus, HIV-specific immune responses-particularly cross-clade CTL activity- may be responsible for protection against persistent HIV infection in these African women.

Amino Acid Sequence↗
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↗
PubMed1997

Antibody to chlamydial hsp60 predicts an increased risk for chlamydial pelvic inflammatory disease.

To determine whether serum antibody to Chlamydia trachomatis antigens alters the risk of C. trachomatis pelvic inflammatory disease (PID), 280 female sex workers were prospectively evaluated over a 33-month period for incident C. trachomatis and Neisseria gonorrhoeae cervical infection and for clinical PID. At enrollment, women were tested for antibody to C. trachomatis elementary bodies by an indirect microimmunofluorescence assay and to recombinant chlamydial hsp60 (Chsp60) by an ELISA format. At each follow-up visit, women were tested for cervical chlamydial and gonococcal infection and were identified as having clinical PID if they complained of lower abdominal pain and were found to have uterine and adnexal tenderness on pelvic examination. The data demonstrate that antibody to Chsp60 predicts a 2- to 3-fold increased risk for C. trachomatis PID.

Adolescent↗
PubMed1997

Risk factors for genital ulcerations in Kenyan sex workers. The role of human immunodeficiency virus type 1 infection.

BACKGROUND AND OBJECTIVES: Genital ulcer disease (GUD) is a major risk factor for human immunodeficiency virus (HIV) transmission. Cross-sectional studies have suggested that HIV infection may itself predispose to genital ulceration (GU). GOAL: To prospectively study the effects of HIV type 1 (HIV-1) infection and behavioral variables on GU incidence. METHODS: A cohort of 302 Kenyan female sex-workers was established in April 1991. Women were scheduled for assessment every 2 weeks, and bloods were collected every 6 months for HIV serology, rapid plasma reagin (RPR) and CD4 counts. Logistic regression was used to study risk factors for incident genital ulcers. RESULTS: 189 women (62.5%) had at least one incident ulcer over 24.3 +/- 15.3 months. GU incidence was higher in seropositive than initially seronegative women (82% vs. 48%; odds ratio [OR]) = 4.33; P < 0.01). Only HIV-1 seropositivity (OR = 3.42), a CD4 count < 200/ml (OR = 1.94), and oral contraceptive use (OR = 1.35) were associated (P < 0.05) with GU incidence in regression analysis. For those ulcers where an etiology was actively sought, Hemophilus ducreyi was confirmed in 54 (19%) of cases, and syphilis in 30 (29%). CONCLUSION: GU incidence in Kenyan sex workers is independently affected by HIV-1 serostatus, degree of immunosuppression, and oral contraceptive use.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Resistance to HIV-1 infection among persistently seronegative prostitutes in Nairobi, Kenya.

BACKGROUND: There is indirect evidence that HIV-1 exposure does not inevitably lead to persistent infection. Heterogeneity in susceptibility to infection could be due to protective immunity. The objective of this study was to find out whether in highly HIV-1-exposed populations some individuals are resistant to infection. METHODS: We did an observational cohort study of incident HIV-1 infection-among 424 initially HIV-1-seronegative prostitutes in Nairobi, Kenya, between 1985 and 1994. 239 women seroconverted to HIV-1 during the study period. Exponential, Weibull, and mixture survival models were used to examine the effect of the duration of follow-up on incidence of HIV-1 infection. The influence of the duration of exposure to HIV-1 through prostitution on seroconversion risk was examined by Cox proportional hazards modelling, with control for other known or suspected risk factors for incident HIV-1 infection. HIV-1 PCR with env, nef, and vif gene primers was done on 43 persistently seronegative prostitutes who remained seronegative after 3 or more years of follow-up. FINDINGS: Modelling of the time to HIV-1 seroconversion showed that the incidence of HIV-1 seroconversion decreased with increasing duration of exposure, which indicates that there is heterogeneity in HIV-1 susceptibility or acquired immunity to HIV-1. Each weighted year of exposure through prostitution resulted in a 1.2-fold reduction in HIV-1 seroconversion risk (hazard ratio 0.83 [95% CI 0.79-0.88], p < 0.0001). Analyses of epidemiological and laboratory data, show that persistent seronegativity is not explained by seronegative HIV-1 infection or by differences in risk factors for HIV-1 infection such as safer sexual behaviours or the incidence of other sexually transmitted infections. INTERPRETATION: We conclude that a small proportion of highly exposed individuals, who may have natural protective immunity to HIV-1, are resistant to HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed1996

The epidemiology of Chlamydia trachomatis within a sexually transmitted diseases core group.

Female sex workers in Nairobi were prospectively evaluated for risk factors of incident Chlamydia trachomatis infection. Independent risk factors included cervical ectopy (P=.007), gonococcal infection (P=.002), human immunodeficiency virus (HIV) seropositivity (P=.003), HIV seroconversion (P=.001), and duration of prostitution (P=.002). Eighteen different C. trachomatis outer membrane protein (omp1) genotypes were identified, with the allelic composition of the C. trachomatis population changing significantly over time (P=.005). Seventeen of 19 reinfections > or = 6 months apart were with different C. trachomatis omp1 genotypes. Women with HIV infection had an increased proportion of visits with C. trachomatis infection (P=.001) and an increased risk of reinfection (P=.008). Overall, the data demonstrate significant fluctuations in the genotype composition of the C. trachomatis population and a reduced rate of same-genotype reinfection consistent with the occurrence of strain-specific immunity.

Amino Acid Sequence↗
PubMed1996

Risk factors for Chlamydia trachomatis pelvic inflammatory disease among sex workers in Nairobi, Kenya.

Among 302 female sex workers in Nairobi, Kenya, who were followed for 17.6 +/- 11.1 months, 146 had one or more infections with Chlamydia trachomatis; 102 had uncomplicated cervical infection only, 23 had C. trachomatis pelvic inflammatory disease (PID), and 21 had combined C. trachomatis and Neisseria gonorrhoeae PID. As determined by multivariate logistic regression analysis, risk factors for C. trachomatis PID included repeated C. trachomatis infection (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.3-2.4; P = .0004), antibody to C. trachomatis heat-shock protein 60 (OR, 3.9; CI, 1.04-14.5; P = .04), oral contraceptive use (OR, 0.28; 95% CI, 0.08-0.99; P = .048), and number of episodes of nongonococcal nonchlamydial PID (OR, 1.7; 95% CI, 1.1-2.7; P = .02). Among human immunodeficiency virus (HIV)-seropositive women, a CD4 lymphocyte count of <400/mm3 was an additional independent risk factor for C. trachomatis PID (OR, 21.7; 95% CI, 1.2-383; P = .036); among HLA-typed women, HLA-A31 was independently associated with C. trachomatis PID (OR, 5.6; 95% CI, 1.1-29.4; P = .043). The results suggest an immune-mediated pathogenesis for C. trachomatis PID.

Adult↗
PubMed1995

Comparison of the declines in CD4 counts in HIV-1-seropositive female sex workers and women from the general population in Nairobi, Kenya.

Studies from Kenya have reported rapid clinical disease progression among HIV-infected professional sex workers. The reasons for this rapid decline are unknown. To better understand factors influencing the course of disease, HIV-1 disease progression was explored in terms of declines in CD4 counts. Two samples from Nairobi, Kenya, were studied, one from a cohort of female sex workers and another, as a comparison group, from mothers enrolled in an HIV-1 vertical-transmission study. A Markov model was used to analyze transitions between HIV-1 disease stages as defined by CD4 counts. It appears that sex workers experience a rapid decline in CD4 counts, consistent with earlier findings of rapid clinical disease progression among individuals in this group. The rate of decline in CD4 counts among the mothers appears to be lower. It is speculated that either intensive exposure to sexually transmitted pathogens or infection with several strains of HIV-1 may account for the rapid disease progression among female sex workers.

Adult↗
PubMed1995

Low dose erythromycin regimen for the treatment of chancroid.

Haemophilus ducreyi is the commonest cause of genital ulcer disease in Africa and is associated with heterosexual transmission of human immunodeficiency virus(HIV). The World Health Organization currently recommends erythromycin 500 mg three times a day for seven days as the treatment of choice for Haemophilus ducreyi infection. We studied the effectiveness of a lower dose erythromycin treatment regime, 250 mg three times a day for seven days in the treatment of chancroid. Patients with genital ulcer disease presenting at Nairobi City council clinic between January and March, 1992 were recruited into the study. Swabs were taken from the ulcers for Haemophilus ducreyi and venous blood was screened for syphilis and HIV antibodies. A total of 219 patients were enrolled for the study and were reviewed on days seven and fourteen for side effects, bacteriological and clinical cure rates. 26.4% of the study population were HIV-1 seropositive. The treatment regime was well tolerated and effective in both HIV seropositive and seronegative patients. Complete bacteriological cure rate was achieved in Haemophilus ducreyi culture positives by day seven irrespective of the HIV serostatus. However, the clinical cure rate for HIV seropositive patients was 88% compared to 99% for seronegative patients (p<.001). It is concluded that a low dose erythromycin is an inexpensive and effective treatment for chancroid with complete bacteriological cure rate, although the healing process takes longer in HIV seropositive patients.

Adult↗
PubMed1994

Chlamydia trachomatis from individuals in a sexually transmitted disease core group exhibit frequent sequence variation in the major outer membrane protein (omp1) gene.

60 cervical Chlamydia trachomatis infections identified by antigen detection from 51 prostitute women in Nairobi, Kenya were evaluated for sequence polymorphism in the major outer membrane protein (omp1) gene. DNA from clinical specimens was amplified by the polymerase chain reaction and cycle sequenced through variable domains (VD) 1, 2, and 4.37 (63%) samples had variant VD sequences, 19 (32%) samples had prototype VD sequences, and 4 (6%) samples had prototype VD sequences, and 4 (6%) samples contained omp1 sequences from two or more C. trachomatis strains. Among the 37 variant strains, 18 had two or fewer nucleotide substitutions in one or two VDs and represented point mutational drift variants. 19 strains had a larger number of nucleotide changes and displayed mosaic omp1 sequences that may have been generated by omp1 VD recombination. We conclude that the prevalence of C. trachomatis omp1 DNA polymorphism is substantial among prostitute women in Nairobi, Kenya and that this is the likely result of immune selection pressure.

Amino Acid Sequence↗