36 Records out of 22207 Records

HIV-specific CD8+ T cell phenotype and HIV-1 genetic diversity : understanding the interplay [kenya].

Author: McKinnon, Lyle

Awarding University: University of Manitoba, Canada

Level : PhD

Year: 2009

Holding Libraries: Dissertation Abstracts International ;

Subject Terms: Biological sciences ; HIV infection ; Genetics ;

Abstract:

Historically, vaccination has been the most effective way to limit the spread of infectious diseases, but candidate HIV vaccines have so far been unsuccessful. Major challenges surrounding HIV vaccination are the genetic diversity and evolutionary capabilities of HIV, and an incomplete understanding of which immune responses are capable of providing protection. This thesis examines relationships between these obstacles in Kenyan populations. While CD8+ T cells responses were rarely observed in HIV-resistant subjects, most HIV-infected subjects had detectable responses. There were several instances in which Glade influenced the detection frequency and evolution in HIV-1 infection. We found a high degree of cross-reactivity and shared epitopes between clades, as well as examples of Glade-specific responses. While many previous studies have focused on IFN-? secretion as a immunological readout, we provide evidence that CD8+ T cell cross-reactivity and epitope specificity differ between IFN-? and proliferation, the latter associated with better disease progression outcomes. Finally, we characterized CD8+ T cells specific for variant-bound HLA class I tetramers and found that different populations of cells may recognize different epitope variants, and that a variant associated with proliferation displayed a weaker interaction with HLA and TCR. In several instances, we found that Env-specific IFN-? secretion was associated with worse clinical outcome. These findings offer a better understanding of the bidirectional interaction between HIV genetic diversity and various attributes of CD8+ T cell responses, and highlight the need for a more thorough immunological assessment of HIV vaccine candidates

Association of interferon regulatory factor-1 polymorphisms with resistance to infection by HIV-1 in Kenyan female sex workers.

Author: Ji, Hezhao

Awarding University: University of Manitoba, Canada

Level : PhD

Year: 2007

Holding Libraries: ;

Subject Terms: Biological sciences/HIV infection/Sexual behavior/Women's studies/Gender/Prostitution/Interferon/Medical immunity/ ;

Abstract:

Resistance to Human Immunodeficiency Virus-1 (HIV-1) infection has been observed in multiple cohort studies including a female sex worker cohort established in Nairobi, Kenya. Both host genetic variations and HIV-1 specific immune responses have been described as important components correlating with resistance to HIV-1. Interferon regulatory factor 1 (IRF-1), a promoter to host immunity and also a transactivator of HIV-1, has a dual role to play in HIV/AIDS. This study reconfirmed our previous finding that 179 allele at microsatellite (MS) region in IRF-1 correlated with HIV-1-resistant phenotype in this cohort. Upon this, by near-complete gene sequencing, we demonstrated that the IRF-1 gene in Kenyan cohort was highly polymorphic. Fifty-three single nucleotide polymorphisms (SNP) (26 newly identified), 2 insertions and 1 deletion mutation were identified. We identified 35 consistent discrepancies between IRF-1 GenBank sequences and our population-based sequencing data, suggesting that the current GenBank reference sequences for IRF-1 is incomplete. The sequence of IRF-1 gene and its upstream promoter region was re-established (GenBank: DQ789232). Statistical analysis revealed that, together with 179 allele at the MS region, SNPs at 619 (A/C) and 6516 (G/T) were also significantly correlated with HIV-1 resistance. Despite their intronic locations, further functional investigations revealed that PBMCs from subjects with protective IRF-1 genotypes/haplotypes showed: (1) significantly depressed IRF-1 protein expression at both a basal expression level and in response to exogenous IFN-? stimulation or infection by an artificially pseudotyped HIV-1 construct; (2) significantly increased chances of skipping exon 2 and 3 which contain the IRF-1 start codon as well as encode the DNA binding domain of IRF-1 protein; (3) significantly decreased frequencies of skipping exon 7 and 8; (4) A clear trend of decreased efficiency of HIV-1 replication early upon infection by HIV-1, suggestive of that these cells are less competent in supporting HIV-1 replication. This study suggests that different IRF-1 genotypes/haplotypes and consequently altered expression and function of IRF-1 likely compose a significant determinant for the heterogeneity of susceptibility to HIV-1 in our Kenyan subject cohort. This study provides insight to natural immunity to HIV-1 infection and suggests that effective anti-HIV-1 strategies should target not only host immunity, but also factors important in the establishment of HIV-1 infection.

The mucosal basis of natural immunity to HIV infection [Kenya].

Author: Iqbal, Shehzad Mustafa

Awarding University: University of Manitoba, Canada

Level :

Year: 2007

Holding Libraries: Dissertation Abstracts International ;

Subject Terms: Health sciences/Immunology/HIV infection/Medical immunity/ ;

Abstract:

The HIV pandemic to date has killed over 20 million and currently infects 40 million people world wide. Through socioeconomic, cultural, demographic and biological factors, the greatest burden of this disease has been upon women with a disproportionately larger number of infections in women compared to men. Despite effective prevention programs and the advent of anti-retroviral therapy this pandemic shows little sign of slowing and after 20 years of research we have not yet achieved what is most desperately needed to halt this pandemic, an effective vaccine against HIV transmission. In Nairobi, Kenya, the discovery of a group of HIV-resistant sex workers offers a unique opportunity to derive insight into factors which may constitute protection against infection. Natural immunity to HIV thus far is extremely rare therefore identifying correlates and protective factors against HIV in these women could have profound implications for development of a protective vaccine. In recent years we have come to recognize the importance of understanding HIV transmission at the primary site at which the virus enters the body, the mucosal barrier. Here, the characterization of the genital tract mucosal immune system among HIV-resistant women is described. A characteristic phenotype of elevated levels of CD4+ T cells as well as high levels of a (mown inhibitor of HIV, the chemokine RANTES, in the genital mucosa of HIV-resistant women was found. In addition, a novel proteomics approach was employed to screen the cervical secretions of these women and discovered a novel inhibitor of HIV, trappin-2, a protein that is highly associated with HIV resistance. These findings may lead to the development of new prevention tools against HIV infection, in particular, the development of a microbicide which could protect women from the disease

HIV-1 viral genetics and superinfection within a cohort of commercial sex workers : epidemiological, virological and clinical consequences [Kenya].

Author: Stuart, Tammy Leigh

Awarding University: University of Manitoba, Canada

Level : PhD

Year: 2007

Holding Libraries: Dissertation Abstracts International ;

Subject Terms: Biological sciences/Genetics/Epidemiology/Viruses/HIV infection/Sexual behavior/ ;

Abstract:

Understanding HIV-1 genetic diversity and host-virus relationship is essential to the development of new treatments and vaccine design. A cohort of HIV-1 positive, drug-na?ve commercial sex workers from Kenya was studied in order to investigate these issues. The research was driven by three global hypotheses: (1) Single HIV-1 infections would reveal; an array of genetically distinct viruses, a dynamic distribution of viral subtypes, and differences in disease progression. (2) Infection with HIV-1 would provide protection against HIV-1 superinfection. (3) Rapid disease progression would be seen in superinfected/dually infected individuals and recombinant viruses would be present in most cases. Analysis of HIV-1 sequence data revealed multiple circulating subtypes, the distribution of which significantly changed over time. Recombinant forms were detected early in the epidemic in this cohort and diversity was seen within the amino acid sequences of a major drug target (HIV-1 protease). No associations between viral subtypes and disease progression were found, but non-subtype associated viral genetic characteristics may impact upon disease progression. These data highlight the importance of a candidate vaccine capable of providing immunity against an array of viral subtypes and the need for continued monitoring of the viral composition within populations. The discovery of only four confirmed cases of superinfection within a nested cohort study revealed that HIV-1 infection has a protective effect against the acquisition of a second HIV infection (Hazard ratio=0.14 [CI95% 0.05-0.39]). This provides hope that a cross protective vaccine may be possible. In total 11 of 213 sex workers had evidence of superinfection/dual infections. Recombinant viruses were found in 10/11 cases (90.9%) and became the predominant form in 60% of these cases. This extreme ability of HIV to evolve creates new challenges for treatment, diagnostic tests and vaccine design. Where it was possible to estimate the timing of superinfection, an increase in viral load and decrease in CD4+ T cells were observed concurrently. Contrary to the hypothesis, infection with multiple viruses (superinfection/dual infection cases) did not always lead to rapid progression. Given that the clinical progression of dually/superinfected individuals was not homogeneous the true impact of multiple virus infections is likely dependent on both host genetics and the viruses involved. The studies reported in this thesis serve to better define viral genetics within a sex worker cohort and to more clearly define the host-virus relationship.

Effect of HIV-1 viral characteristics on mother-child transmission of HIV-1 [Kenya].

Author: Murray, Melanie Caroline Margaret

Awarding University: University of Manitoba, Canada

Level : PhD

Year: 2006

Holding Libraries: Dissertation Abstracts International ;

Subject Terms: Biological sciences ; HIV infection ; Women ; Pregnancy ;

Abstract:

It has now been a sobering 24 years since the hallmark cases of the AIDS pandemic began to be noticed. Since that time a great deal of energy has gone into halting the progression and spread of this plague. But we are still not there, and despite our best efforts at prevention and treatment, the outbreak goes on unabated. In the developed world the available prevention and treatment has almost eliminated the threat of mother to child transmission of HIV-1. However, in the developing world, this type of transmission is still a cruel reality. Mother-child HIV-1 transmission can be prevented in two ways, through prevention of maternal infection with a vaccine, or through prevention of a child's infection with drugs and avoidance of breast-feeding. Studying and understanding viral genetic factors which influence transmission, and give the virus its virulence will be important for the design of new drugs which may be used in treatment and prevention, and may provide targets for a vaccine. We began our study of viral genetic factors by looking at the influence of viral subtype on mother-child transmission of HIV-1. Our examination of the subtype of the HIV-1 protease gene led us to the conclusion that in Kenya, there is no difference between HIV-1 subtype and rates of transmission from a mother to her child. But, as oft happens in science, one study led us to another question. Our inability to amplify the protease genes of a number of women in our study group led us to the observation that these women seldom transmit HIV-1 to their children. Use of epidemiological methods helped us establish that women for whom the protease gene was non-amplifiable were significantly less likely to transmit HIV-1 to their children, possessed better cellular markers of disease progression (i.e. CD4 and CD8 counts and percentages), and were more likely to become long term non-progressors than women for whom the protease gene was amplifiable. We have hypothesized that these women are infected with virus which is somehow less virulent than that infecting women with amplifiable virus, and that this virulence is associated with viral factors because the group was isolated based on our inability to amplify a gene with primers in the region of it. Sequence analysis has shown that significant variability of p7, p1 and p6 genes exists in active motifs from both amplifiers and non-amplifiers in the study group. These changes are significantly more likely to be found in the 'PEPTAPPA' motif of p6 gag , and the 'LWQRPLVT' motif of p6 pol . We have also seen that there were significantly more changes in proline residues located in the p1 protein as compared to amplifiers. Though these changes may not be the whole answer as to why the virus in these women appears less pathogenic, they may certainly be a part of it. Finally, we have shown that in a few individuals at least, our inability to amplify the protease gene is associated with a significantly decreased ability to grow and produce progeny in cell culture, a finding which adds credibility to our hypothesis that viral genetic factors play an important role in the pathogenicity and transmissibility of the HIV-1 virus.

Cost-effectiveness analysis of three HIV prevention interventions in Kenya : a mathematical modelling approach.

Author: Stirling, Bridget Veronica

Awarding University: University of Manitoba, Canada

Level : PhD

Year: 2003

Holding Libraries: Dissertation Abstracts International ;

Subject Terms: Health sciences/HIV infection/Statistics/Disease control/ ;

Abstract:

Background . In the research for this thesis, the incremental cost per case of HIV averted and the cost per DALY saved were assessed for three HIV prevention interventions from the Strengthening STD/AIDS Control in Kenya Project. These interventions were peer interventions for commercial sex workers (CSWs), occupationally focussed interventions with men, and syndromic management of sexually transmitted infections (STIs). The programmes directly reached 5,000, 3,015 and 6,637 people respectively. Methods . The project began with a thorough and systematic review of the literature including reports, budgets, raw data and published documents. Direct observation and a Project staff discussion group also were used in order to seek out the best possible information for the model. Actual programme costs were collected from the provider's perspective. Next, a model was built to simulate the sexual behaviour of people living in the city of Nairobi. The model allowed for estimation of the reduction in cases of HIV that are directly prevented, as well as the prevention of secondary cases. The impact of the project's interventions were simulated and subtracted from the baseline model (the expected outcome without the interventions). From the cumulative HIV incidence, numbers of cases averted, the cost per case of HIV averted and disability adjusted life years saved were calculated. A sensitivity analysis was performed which showed the model and the ranked results to be robust. Results . The CSW peer intervention project was found to be the most cost-effective of the three interventions, preventing 983 cases of HIV in one year and costing Can$101.24 (KSh 4,556) per case of HIV averted and $6.25 per DALY saved. The syndromic management of STI project ranked next, showing a reduction in annual cases of HIV of 726 and costing $164.26 (KSh 7,392) for each case averted and $10.14 per DALY saved. Finally, interventions for men in occupations that are at high-risk for HIV reduced the annual HIV incidence by 369 cases and cost $241.84 (KSh 10, 883) per case of HIV averted and $14.93 per DALY saved. Implication . These three projects were all found to be highly cost-effective, and should be replicated on a larger scale.

Analysis of serovar-specific immunity to Neisseria gonorrhoeae.

Author: Fudyk, Trevor Charles

Awarding University: University of Manitoba, Canada

Level : PhD

Year: 2002

Holding Libraries: University Microfilms International ;

Subject Terms: Immunology ; Neisseria gonorrhoeae ; Neisseria infections ; Gonorrhea ; Pumwani, Nairobi, Kenya ;

Abstract:

Infection with Neisseria gonorrhoeae constitutes an important cause of morbidity in human populations. The Porin protein (Por) is the major outer membrane protein of the gonococcus and displays considerable antigenic diversity among gonococcal strains. Two hypotheses to explain the diversity and dynamics of gonococcal populations is that protective, serovar- specific immunity, mediated by antibody to Por, develops following gonococcal infection, and that the development of protective immune responses within the core group act as a selective force for por antigenic heterogeneity in the gonococcal population. One core group in which gonococcal epidemiology has been studied extensively includes a collection of women working the commercial sex trade in the lower socioeconomic district of Pumwani in Nairobi, Kenya. Two experimental strategies were used to evaluate these hypotheses in a more recent longitudinal study of these female, sex workers in Nairobi, Kenya. The first line of experiments sought to examine the nature and distribution of genetic polymorphism in the Por genes of the gonococcal serovars infecting the Nairobi cohort. Nucleotide substitutions were observed predominantly in surface-exposed encoding segments of the 1a and 1b por genes. The majority of substitutions, particularly those occurring in surface- exposed encoding gene segments, resulted in amino acid change. The second line of experiments sought to determine the effect of the antibody response to por on serovar-specific gonococcal infection. Cohort women were assayed for baseline antibody responses to a recombinant 1b2 porin and a collection of polypeptides corresponding to 1b Por surface-exposed loops and followed longitudinally for gonococcal infection. Overall, antibody to the 1b2 porin appeared to provide limited protection from 1b infection, although this protective effect did not appear to extend to infection with 1a serovars. Women with antibody to 1b2 Por experienced significantly fewer homologous 1b2 and heterologous 1b3 serovar infections, compared to women without antibody. The data observed in this study support the hypothesis that the humoral immune response to Por is an important component in the ecologic interaction of human and gonococcal populations, while the generation of antigenically diverse pathogen populations act a mechanism to ensure endemic infection and pathogen survival in the face of this immune barrier. (Abstract shortened by UMI.)

A genetic basis for resistance to infection by HIV-1.

Author: Ball, Terry Blake

Awarding University: University of Manitoba, Canada

Level : PhD

Year: 2002

Holding Libraries: University Microfilms International ;

Subject Terms: HIV infection ; HIV infection ; Immune system ; Genetics ; Nairobi, Kenya ;

Abstract:

The Human Immunodeficiency Virus 1 (HIV-1) pandemic continues unabated despite increasing public health efforts and intense research. Considerable effort has gone into the development of HIV vaccines, and natural model of resistance to HIV-1 would be invaluable in this endeavor. Within a sex worker cohort in Nairobi, Kenya we have identified a group of women who are resistant to infection by HIV-1. Resistance correlates with cellular and mucosal immune responses to HIV-1 suggesting that these women have developed acquired immunity to HIV-1 thus providing a natural model of immunity. The question remains however as to why do these women appear to be able to mount an effective immune response to HIV-1 while the vast majority of individuals are unable to? It is our hypothesis that resistance to HIV-1 is mediated by genetic factors that are involved in the regulation of protective immune responses to HIV-1. Using the tools of epidemiology, immunology, and genetics we provide data to show that there is a genetic basis for resistance to infection by HIV-1. We show that individuals related to a HIV resistant woman are less likely to become infected by the HIV-1 virus compared to individuals related to an HIV susceptible woman. This strongly suggests that there is a genetic component responsible for resistance to infection by HIV-1. To further investigate this finding we investigated polymorphisms in a number of genes involved in immune responses to HIV-1. These included microsatellite markers in a region important in regulating cellular and humoral immune responses. We identified an allele in the immunoregulatory molecule Interferon Regulatory Factor 1 (IRF-1) that was found at an increased frequency in HIV resistant women. This allele (IRF-1 179) was associated with the resistance phenotype and was shown to protect against HIV infection. This is the first report of a polymorphism in a transcription factor that may account for differential susceptibility to HIV-1. We believe that individuals with the IRF-1 179 allele are better able to respond to HIV with what has been proposed to be protective cellular immune responses. This finding confirms our hypothesis that there are genetic factors responsible for resistance to infection by HIV-1.

The hinterland concept and port development in Ghana.

Author: Amoyaw, Benjamin Kwadwo Banforo

Awarding University: University of Manitoba, Canada

Level : MA

Year: 1999

Holding Libraries: University Microfilms International ;

Subject Terms: Ports ; Shipping industry ; Mombasa, Kenya ;

Abstract:

The hinterland -the port's collecting and distributing area -is a significant part of every port's development. The large body of literature on the subject attests to this fact. Following previous studies on the subject, this thesis sets out to demonstrate the significance of the hinterland to port development in Ghana. The study concentrated on two spatial levels. The first was the national level; between the two Ghanaian ports of Takoradi and Tema, while, the other, at the international level, compared the Ghanaian ports with the East African ports of Mombasa (Kenya) and Dar es Salaam (Tanzania). Based on the premise that a port's overall traffic is a function of its performance and hinterland, the ports' performance contribution to their overall traffic were assessed using regression analysis and the shift-and-share technique.

Characterization of type-1/type-2 cytokine and IGE responses of HIV-1 resistant Kenyan women; characterization of Neonatal type-1/type-2 cytokine responses.

Author: Trivedi, Harsha N

Awarding University: University of Manitoba, Canada

Level : PhD.

Year: 1998

Holding Libraries: Dissertation Abstracts International ;

Subject Terms: Health sciences/Cytokines/Immunology/HIV infection/Women/Neonatal care/ ;

Abstract:

Part I. Characterization of type-1/type-2 cytokine and IgE responses of HIV-1 resistant Kenyan women. A group of HIV-1 resistant Kenyan female prostitutes has been previously identified who remain HIV-1 specific serum antibody (Ab) and polymerase chain reaction (PCR) negative despite chronic ongoing exposure to human immunodeficiency virus type 1 (HIV-1) (3-14 years). The overall objective of this study was to characterize the type-1/type-2 cytokine and IgE responses of these women. Toward this goal, the initial hypothesis that the resistant women exhibit enhanced HIV-1 driven type-1 and reduced type-2 cytokine responses was tested. Results revealed that the resistant women exhibited markedly enhanced virus driven IFN-$gamma$ and significantly reduced IL4 responses compared to susceptible women. Resistant women also exhibited marginally enhanced IL-5 and similar IL-13 and IL-10 responses. Analysis of virus driven type-2:type-1 cytokine balance revealed a selective imbalance in IL-4:IFN-$gamma$, but not in other type-2:type-1 ratios examined. Furthermore, recall Ag (streptokinase (SK) and purified protein derivative (PPD)) driven cytokine responses indicated that the resistant women exhibited similar levels of Ag driven IFN-$gamma$ and markedly reduced IL-4 responses compared to low risk Kenyan women. Subsequently, the hypothesis that HIV-1 resistant women exhibit enhanced responsiveness to IL-12 and IP-10 (both of which promote IFN-$gamma$ synthesis) was tested. Although the resistant women exhibited significantly enhanced IL-12 and IP-10 responsiveness on virus mediated activation compared to susceptible women, they did not differ from low risk women. Finally, the hypothesis that HIV-1 resistant women may exhibit deficient HIV-1 specific IgE Ab was tested. Examination of their plasma confirmed this hypothesis. However, the resistant women did not exhibit a generalized defect of class switching to IgE isotype because their plasma levels of cat and dust mite allergen specific IgE antibodies and total IgE were similar to that of low risk women. In summary, this study has identified a potential cytokine mediated immune mechanism associated with the clinical resistance to HIV-1 infection among Kenyan women. These results may have implications in the prevention and treatment of HIV-1 infection and AIDS. Part II. Characterization of neonatal type-1/type-2 cytokine responses. It is widely believed that enhanced vulnerability of human neonates to infections is due to the immaturity of their immune system. In the present study, two hypotheses were tested: (1) neonatal T cells are immature with regard to type-1/type-2 cytokine synthesis; and (2) neonatal antigen presenting cells (APC) have a defect in stimulating type-1/type-2 cytokine synthesis. Comparison of neonatal cytokine responses to phytohemagglutinin (PHA) indicated an impaired IFN-$gamma$ and similar IL4, IL-5 and IL-10 responses compared to adults. In contrast, examination of a more physiologically relevant, alloantigen mediated response revealed that neonates have very similar IFN-$gamma$, IL-4 and IL-10 responses but higher IL-5 responses compared to adults. Finally, the capacity of neonatal versus adult APC to induce cytokine synthesis was assessed. Results indicated that neonatal APC exhibit a selective defect in stimulating IFN-$gamma$ and IL-10, but not IL-4 and IL-5 synthesis. In summary, these data argue that, whereas neonatal T cells are functionally mature, their APCs exhibit a selective defect which may contribute to the vulnerability of neonates to pathogens.