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Search Results: 1 - 10 of 464482 matches for " Francis A. Plummer "
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The Microbiological Context of HIV Resistance: Vaginal Microbiota and Mucosal Inflammation at the Viral Point of Entry
John J. Schellenberg,Francis A. Plummer
International Journal of Inflammation , 2012, DOI: 10.1155/2012/131243
Abstract: Immune activation is increasingly recognized as a critical element of HIV infection and pathogenesis, causing expansion of virus founder populations at the mucosal port of entry and eventual exhaustion of cellular immune effectors. HIV susceptibility is well known to be influenced by concurrent sexually transmitted infections; however, the role of commensal vaginal microbiota is poorly characterized. Bacterial vaginosis (BV) is a risk factor for HIV acquisition in studies worldwide; however, the etiology of BV remains enigmatic, and the mechanisms by which BV increases HIV susceptibility are not fully defined. A model of how vaginal microbiota influences HIV transmission is considered in the context of a well-established cohort of HIV-exposed seronegative (HESN) commercial sex workers (CSW) in Nairobi, Kenya, many of whom have increased levels of anti-inflammatory factors in vaginal secretions and reduced peripheral immune activation (immune quiescence). Elucidation of the relationship between complex microbial communities and inflammatory mucosal responses underlying HIV infection should be a priority for future prevention-focussed research. 1. Introduction Fatal opportunistic infections associated with what is now known as the acquired immunodeficiency syndrome (AIDS) were first described in 1981 among young, previously healthy homosexual men in the United States [1]. While global media and health authorities were focussed on stigmatized “risk groups” in North America, largely heterosexually-transmitted epidemics were already well established throughout sub-Saharan Africa by the time the human immunodeficiency virus (HIV) was discovered in 1983. A cohort-based study of commercial sex workers (CSW) in Nairobi, Kenya found that HIV prevalence increased from 4% to over 60% between 1981 and 1985 [2]. Follow-up work identified a subgroup of CSW who were never infected with HIV despite years of exposure, one of the earliest described examples of highly HIV-exposed seronegative (HESN) individuals in the world [3]. HIV infection results in profound, multifactorial immune dysregulation eventually leading to AIDS usually after a period of 7–10 years. This lengthy asymptomatic period is characteristic of the lentiviridae family of viruses to which HIV and a wide variety of simian immunodeficiency viruses (SIV) belong. Progressive destruction of CD4+ T helper (Th) cell populations via direct viral killing is generally believed to explain slow disease progression; however, recent studies in nonhuman primates have revealed that critical events in the earliest
Memory Phenotypes of HIV-Specific CD8+ T Cell Responses Are Independent of Functional Activity as Defined by Cytokine Output  [PDF]
Meika E. I. Richmond, Sandra A. Kiazyk, Lyle R. McKinnon, Billy Nyanga, Charles Wachihi, Makubo Kimani, Joshua Kimani, Francis A. Plummer, T. Blake Ball
Open Journal of Immunology (OJI) , 2014, DOI: 10.4236/oji.2014.43012
Abstract: Objectives: The definition of CD8+ T cell attributes that mediate protective immunity in HIV dis-ease progression has not been clearly defined. Although our ability to characterize these cells continues to improve, the extent to which specific memory phenotypic categories of CD8+ T cells reliably represent their functional attributes remains controversial. Methods: We simultaneously assessed surface phenotype and functionality of HIV-specific CD8+ T cells by multiparametric flow cytometry, measuring five CD8+ T cell functions (CD107a, IFNγ, MIP-1β, TNFα and IL2) and phenotypic markers CCR7, CD45RA, and CD27, in parallel in 24 HIV-infected individuals. Results: Virus-specific responses were contained within all eight phenotypic categories defined using CCR7, CD45RA, and CD27. Phenotypic profiles of HIV-specific cells differed from CEF-specific cells, with HIV-specific cells having higher levels of CD45RA (p = 0.008). Interestingly a large portion of CEF and HIV-specific cells were found within previously undefined phenotypes CCR7+CD27-CD45RA+ (14.6% and 17.2%, respectively) and CCR7+CD27-CD45RA-(14.8% and 15.8%, respectively). In addition, up to 10% - 20% of responding cells were phenotypically “naive”. Additionally, memory phenotypes of cells exhibiting monofunctional and polyfunctional responses frequently differed, and failed to associate with a consistent phenotype representing functionally active cells. Conclusion: These data suggest that particularly after antigen stimulation, that surface phenotypes defined by CCR7, CD27 and CD45RA expression on antigen-specific CD8+ T cells, reflect a wide range of immunological functions, and that no single phenotype defined by memory marker expression can reliably be used to identify functional capacity.
Diversity and Frequencies of HLA Class I and Class II Genes of an East African Population  [PDF]
Trevor A. Peterson, Thomas Bielawny, Philip Lacap, Rae-Anne Hardie, Christina Daniuk, Lillian Mendoza, Subotheni Thavaneswaran, Tony Kariri, Joshua Kimani, Charles Wachihi, Maboku Kimani, Terry Blake Ball, Francis A. Plummer, Ma Luo
Open Journal of Genetics (OJGen) , 2014, DOI: 10.4236/ojgen.2014.42013
Abstract:

Human Leukocyte Antigens (HLAs) play an important role in host immune responses to infectious pathogens, and influence organ transplantation, cancer and autoimmune diseases. In this study we conducted a high resolution, sequence-based genotyping of HLA class I and class II genes of more than 2000 women from Kenya, eastern Tanzania and southern Uganda around Lake Victoria and analyzed their allele, phenotype and haplotype frequencies. A considerable genetic diversity was observed at both class I and II loci. A total of 79 HLA-A, 113 HLA-B, 53 HLA-C, 25 HLA-DPA1, 60 HLA-DPB1, 15 HLA-DQA1, 44 HLA-DQB1 and 38 HLA-DRB1 alleles have been identified. The most common class I alleles were A * 02:01:01 (10.90%), B * 58:02 (8.79%), and C * 06:02:01 (16.98%). The most common class II alleles were DPA1*01:03:01 (40.60%), DPB1 * 01:01:01 (23.45%), DQA1 * 01:02:01 (31.03%), DQB1 * 03:01:01 (21.79%), DRB1 * 11:01:02 (11.65%), DRB3 * 02:02:01 (31.65%), DRB4 * 01:01:01 (10.50%), and DRB5 * 01:01:01 (10.50%). Higher than expected homozygosity was observed at HLA-B (P = 0.022), DQA1 (P = 0.004), DQB1 (P = 0.023), and DRB1 (P = 0.0006) loci. The allele frequency distribution of this population is very similar to the ones observed in other sub-Saharan populations with the exception of lower frequencies of A * 23 (5.55% versus 11.21%) and DQA1 * 03 (4.79% versus 11.72%), and higher frequencies of DPB1 * 30 (2.26% versus 0.37%) and DRB1 * 11 (21.51% versus 15.89%). The knowledge of the diversity and allele/ phenotype frequencies of the HLA alleles of this east African population, can contribute to the understanding of how host genetic factors influence disease susceptibility and effective anti-retroviral treatment of HIV infections and future vaccine trials.

Influence of HLA Class I Haplotypes on HIV-1 Seroconversion and Disease Progression in Pumwani Sex Worker Cohort
Raghavan Sampathkumar, Harold O. Peters, Lillian Mendoza, Thomas Bielawny, Elizabeth Ngugi, Joshua Kimani, Charles Wachihi, Francis A. Plummer, Ma Luo
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101475
Abstract: We examined the effect of HLA class I haplotypes on HIV-1 seroconversion and disease progression in the Pumwani sex worker cohort. This study included 595 HIV-1 positive patients and 176 HIV negative individuals. HLA-A, -B, and -C were typed to 4-digit resolution using sequence-based typing method. HLA class I haplotype frequencies were estimated using PyPop 32-0.6.0. The influence of haplotypes on time to seroconversion and CD4+ T cell decline to <200 cells/mm3 were analyzed by Kaplan-Meier analysis using SPSS 13.0. Before corrections for multiple comparisons, three 2-loci haplotypes were significantly associated with faster seroconversion, including A*23:01-C*02:02 (p = 0.014, log rank(LR) = 6.06, false-discovery rate (FDR) = 0.056), B*42:01-C*17:01 (p = 0.01, LR = 6.60, FDR = 0.08) and B*07:02-C*07:02 (p = 0.013, LR = 6.14, FDR = 0.069). Two A*74:01 containing haplotypes, A*74:01-B*15:03 (p = 0.047, LR = 3.942, FDR = 0.068) and A*74:01-B*15:03-C*02:02 (p = 0.045, LR = 4.01, FDR = 0.072) and B*14:02-C*08:02 (p = 0.021, LR = 5.36, FDR = 0.056) were associated with slower disease progression. Five haplotypes, including A*30:02-B*45:01 (p = 0.0008, LR = 11.183, FDR = 0.013), A*30:02-C*16:01 (p = 0.015, LR = 5.97, FDR = 0.048), B*53:01-C*04:01 (p = 0.010, LR = 6.61, FDR = 0.08), B*15:10-C*03:04 (p = 0.031, LR = 4.65, FDR = 0.062), and B*58:01-C*03:02 (p = 0.037, LR = 4.35, FDR = 0.066) were associated with faster progression to AIDS. After FDR corrections, only the associations of A*30:02-B*45:01 and A*30:02-C*16:01 with faster disease progression remained significant. Cox regression and deconstructed Kaplan-Meier survival analysis showed that the associations of haplotypes of A*23:01-C*02:02, B*07:02-C*07:02, A*74:01-B*15:03, A*74:01-B*15:03-C*02:02, B*14:02-C*08:02 and B*58:01-C*03:02 with differential seroconversion or disease progression are due to the dominant effect of a single allele within the haplotypes. The true haplotype effect was observed with A*30:02-B*45:01, A*30:02-C*16:02, B*53:01-C*04:01 B*15:10-C*03:04, and B*42:01-C*17:01. In these cases, the presence of both alleles accelerated the disease progression or seroconversion than any of the single allele within the haplotypes. Our study showed that the true effects of HLA class I haplotypes on HIV seroconversion and disease progression exist and the associations of HLA class I haplotype can also be due to the dominant effect of a single allele within the haplotype.
Enrichment of Variations in KIR3DL1/S1 and KIR2DL2/L3 among H1N1/09 ICU Patients: An Exploratory Study
David La, Chris Czarnecki, Hani El-Gabalawy, Anand Kumar, Adrienne F. A. Meyers, Nathalie Bastien, J. Neil Simonsen, Francis A. Plummer, Ma Luo
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0029200
Abstract: Background Infection by the pandemic influenza A (H1N1/09) virus resulted in significant pathology among specific ethnic groups worldwide. Natural Killer (NK) cells are important in early innate immune responses to viral infections. Activation of NK cells, in part, depend on killer-cell immunoglobulin-like receptors (KIR) and HLA class I ligand interactions. To study factors involved in NK cell dysfunction in overactive immune responses to H1N1 infection, KIR3DL1/S1 and KIR2DL2/L3 allotypes and cognate HLA ligands of H1N1/09 intensive-care unit (ICU) patients were determined. Methodology and Findings KIR3DL1/S1, KIR2DL2/L3, and HLA -B and -C of 51 H1N1/09 ICU patients and 105 H1N1-negative subjects (St. Theresa Point, Manitoba) were characterized. We detected an increase of 3DL1 ligand-negative pairs (3DL1/S1+ Bw6+ Bw4?), and a lack of 2DL1 HLA-C2 ligands, among ICU patients. They were also significantly enriched for 2DL2/L3 ligand-positive pairs (P<0.001, Pc<0.001; Odds Ratio:6.3158, CI95%:2.481–16.078). Relative to St. Theresa aboriginals (STh) and Venezuelan Amerindians (VA), allotypes enriched among aboriginal ICU patients (Ab) were: 2DL3 (Ab>VA, P = 0.024, Pc = 0.047; Odds Ratio:2.563, CI95%:1.109–5.923), 3DL1*00101 (Ab>VA, P<0.001, Pc<0.001), 3DL1*01502 (Ab>STh, P = 0.034, Pc = 0.268), and 3DL1*029 (Ab>STh, P = 0.039, Pc = 0.301). Aboriginal patients ligand-positive for 3DL1/S1 and 2DL1 had the lowest probabilities of death (Rd) (Rd = 28%), compared to patients that were 3DL1/S1 ligand-negative (Rd = 52%) or carried 3DL1*029 (Rd = 52%). Relative to Caucasoids (CA), two allotypes were enriched among non-aboriginal ICU patients (NAb): 3DL1*00401 (NAb>CA, P<0.001, Pc<0.001) and 3DL1*01502 (CA
Reduced Cellular Susceptibility to In Vitro HIV Infection Is Associated with CD4+ T Cell Quiescence
Catherine M. Card, W. John Rutherford, Suzie Ramdahin, Xiaojian Yao, Makobu Kimani, Charles Wachihi, Joshua Kimani, Francis A. Plummer, T. Blake Ball, Keith R. Fowke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045911
Abstract: Background HIV preferentially establishes productive infection in activated CD4+ T cells. Since proportions of activated CD4+ T cells vary between individuals, this study aimed to determine if individuals with a greater proportion of activated CD4+ T cells would be more susceptible to in vitro HIV infection. Methodology/Principal Findings Unstimulated peripheral blood mononuclear cells (PBMC) from various donors were inoculated with HIVML1956 in vitro. HIV replication was evaluated by HIV p24 ELISA of culture supernatants and intracellular staining for HIV p24, which was detected by flow cytometry. Baseline T cell phenotypes and infected cell phenotypes were also evaluated by flow cytometry. Ex vivo phenotyping at the time of blood draw showed that elevated T cell activation and reduced Tregs were associated with increased cellular susceptibility to in vitro infection. Furthermore, the infected CD4+ T cell population was enriched for activated cells. Conclusion/Significance These data suggest that CD4+ T cell quiescence provides an environment less conducive to the establishment of HIV infection by limiting the pool of activated target cells.
Epitope Mapping of HIV-Specific CD8+ T cells in a Cohort Dominated by Clade A1 Infection
Lyle R. McKinnon, Xiaojuan Mao, Joshua Kimani, Charles Wachihi, Christina Semeniuk, Mark Mendoza, Binhua Liang, Ma Luo, Keith R. Fowke, Francis A. Plummer, T. Blake Ball
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006965
Abstract: Background CD8+ T cell responses are often detected at large magnitudes in HIV-infected subjects, and eliciting these responses is the central aim of many HIV-1 vaccine strategies. Population differences in CD8+ T cell epitope specificity will need to be understood if vaccines are to be effective in multiple geographic regions. Methodology/Principal Findings In a large Kenyan cohort, we compared responsive CD8+ T cell HIV-1 Env overlapping peptides (OLPs) to Best Defined Epitopes (BDEs), many of which have been defined in clade B infection. While the majority of BDEs (69%) were recognized in this population, nearly half of responsive OLPs (47%) did not contain described epitopes. Recognition frequencies of BDEs were inversely correlated to epitopic sequence differences between clade A1 and BDE (P = 0.019), and positively selected residues were more frequent in “new” OLPs (without BDEs). We assessed the impact of HLA and TAP binding on epitope recognition frequencies, focusing on predicted and actual epitopes in the HLA B7 supertype. Conclusions/Significance Although many previously described CD8 epitopes were recognized, several novel CD8 epitopes were defined in this population, implying that epitope mapping efforts have not been completely exhausted. Expansion of these studies will be critical to understand population differences in CD8 epitope recognition.
HIV-1 RNA Dysregulates the Natural TLR Response to Subclinical Endotoxemia in Kenyan Female Sex-Workers
Richard T. Lester, Xiao-Dan Yao, T. Blake Ball, Lyle R. McKinnon, Were R. Omange, Rupert Kaul, Charles Wachihi, Walter Jaoko, Kenneth L. Rosenthal, Francis A. Plummer
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005644
Abstract: Background Subclinical endotoxemia has been reported in HIV-1 infected persons and may drive systemic immune activation and pathogenesis. Proinflammatory responsiveness to endotoxin (LPS) is mediated by Toll-like receptor 4 (TLR4). We therefore examined the association between plasma LPS levels, HIV RNA, and TLR4 expression and cytokine responses in the blood of HIV infected and uninfected participants in a cohort of female sex-workers in Kenya. Methodology/Principal Findings Ex vivo plasma and peripheral blood mononuclear cells (PBMC) were assessed for LPS and TLR mRNA, respectively. The effects of HIV single stranded RNA, a TLR8 ligand, on TLR4 and LPS signaling were further assessed in short term PBMC culture. Both HIV uninfected and infected subjects frequently had low detectable LPS levels in their plasmas. Significantly increased LPS levels were associated with chronic HIV-1 infection, both treated and untreated, but not with other acute or semi-chronic conditions reported. In HIV-uninfected subjects, TLR4 mRNA expression levels correlated inversely with plasma LPS levels, suggesting chronic endotoxin ‘tolerance’ in vivo. A similar effect of reduced TLR4 mRNA was seen in short term PBMC culture after stimulation with LPS. Interestingly, the apparent in vivo tolerance effect was diminished in subjects with HIV infection. Additionally, pre-stimulation of PBMC with LPS lead to proinflammatory (TNF-α) tolerance to subsequent LPS stimulation; however, pre-treatment of PBMC with HIV single-stranded RNA40, could enhance TLR4-mediated LPS responsiveness in vitro. Conclusions/Significance Thus, dysregulation of endotoxin tolerance by HIV-1 RNA may exacerbate HIV chronic immune activation and pathogenesis.
Evaluation of a Quantitative Real-Time PCR Assay to Measure HIV-Specific Mucosal CD8+ T Cell Responses in the Cervix
Duncan Chege,Yijie Chai,Sanja Huibner,Lyle McKinnon,Charles Wachihi,Makubo Kimani,Walter Jaoko,Joshua Kimani,T. Blake Ball,Francis A. Plummer,Rupert Kaul,Anuradha Rebbapragada
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013077
Abstract: Several candidate HIV vaccines aim to induce virus-specific cellular immunity particularly in the genital tract, typically the initial site of HIV acquisition. However, standardized and sensitive methods for evaluating HIV-specific immune responses at the genital level are lacking. Therefore we evaluated real-time quantitative PCR (qPCR) as a potential platform to measure these responses. β-Actin and GAPDH were identified as the most stable housekeeping reference genes in peripheral blood mononuclear cells (PBMCs) and cervical mononuclear cells (CMCs) respectively and were used for normalizing transcript mRNA expression. HIV-specific cellular T cell immune responses to a pool of optimized CD8+ HIV epitopes (HIV epitope pool) and Staphylococcal enterotoxin B (SEB) superantigen control were assayed in HIV infected PBMC by qPCR, with parallel assessment of cytokine protein production. Peak HIV-specific mRNA expression of IFNγ, IL-2 and TNFα occurred after 3, 5 and 12 hours respectively. PBMCs were titrated to cervical appropriate cell numbers to determine minimum required assay input cell numbers; qPCR retained sensitivity with input of at least 2.5×104 PBMCs. This optimized qPCR assay was then used to assess HIV-specific cellular T cell responses in cytobrush-derived cervical T cells from HIV positive individuals. SEB induced IFNγ mRNA transcription was detected in CMCs and correlated positively with IFNγ protein production. However, qPCR was unable to detect HIV-induced cytokine mRNA production in the cervix of HIV-infected women despite robust detection of gene induction in PBMCs. In conclusion, although qPCR can be used to measure ex vivo cellular immune responses to HIV in blood, HIV-specific responses in the cervix may fall below the threshold of qPCR detection. Nonetheless, this platform may have a potential role in measuring mitogen-induced immune responses in the genital tract.
Interferon Regulatory Factor 1 Polymorphisms Previously Associated with Reduced HIV Susceptibility Have No Effect on HIV Disease Progression
Aida Sivro, Lyle R. McKinnon, Hezhao Ji, Joshua Kimani, Walter Jaoko, Francis A. Plummer, Ruey-Chyi Su, T. Blake Ball
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066253
Abstract: Introduction Interferon regulatory factor 1 (IRF1) is induced by HIV early in the infection process and serves two functions: transactivation of the HIV-1 genome and thus replication, and eliciting antiviral innate immune responses. We previously described three IRF1 polymorphisms that correlate with reduced IRF1 expression and reduced HIV susceptibility. Objective To determine whether IRF1 polymorphisms previously associated with reduced HIV susceptibility play a role in HIV pathogenesis and disease progression in HIV-infected ART-na?ve individuals. Methods IRF1 genotyping for polymorphisms (619, MS and 6516) was performed by PCR in 847 HIV positive participants from a sex worker cohort in Nairobi, Kenya. Rates of CD4+ T cell decline and viral loads (VL) were analyzed using linear mixed models. Results Three polymorphisms in the IRF1, located at 619, microsatellite region and 6516 of the gene, previously associated with decreased susceptibility to HIV infection show no effect on disease progression, either measured by HIV-1 RNA levels or the slopes of CD4 decline before treatment initiation. Conclusion Whereas these three polymorphisms in the IRF1 gene protect against HIV-1 acquisition, they appear to exert no discernable effects once infection is established.
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