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Biomedical subjects

Christina M R Kitchen

Publications and source records attributed to Christina M R Kitchen.

15 recordsLinked to original sources
PubMed2007

HIV-1 viral fitness estimation using exchangeable on subsets priors and prior model selection.

The phenotype-genotype problem is a fundamental problem of biology where an organism's genotype (genetic information) predicts its phenotype (observable characteristic). Viral fitness, defined as the reproductive capacity of a virus compared to a standard, is a continuous phenotype. We construct models to predict viral fitness as a function of mutation away from the standard wildtype virus. Data of this nature are difficult to analyse because there are potentially many more parameters than observations. We treat this issue as a regression problem using a prior with both a shrinkage component and a variable selection component. The key to practical implementation of the model is the prior specification for the regression coefficients. We use results from the scientific literature to construct several informative exchangeable within subsets priors (ESP). We use prior model selection (PMS) to select among our priors. Two novel graphics present results from five models each with 71 predictors.

Codon↗
PubMed2006

CD4 expression on activated NK cells: ligation of CD4 induces cytokine expression and cell migration.

NK cells play an important role in the innate immune response. We have isolated NK cells from human lymphoid tissues and found that these cells express the CD4 molecule on their surface at levels higher than those found on peripheral blood NK cells. To study the functional role of the CD4 molecule on NK cells, we developed an in vitro system by which we are able to obtain robust CD4 expression on NK cells derived from blood. CD4+ NK cells efficiently mediate NK cell cytotoxicity, and CD4 expression does not appear to alter lytic function. CD4+ NK cells are more likely to produce the cytokines gamma-IFN and TNF-alpha than are CD4- NK cells. Ligation of CD4 further increases the number of NK cells producing these cytokines. NK cells expressing CD4 are also capable of migrating toward the CD4-specific chemotactic factor IL-16, providing another function for the CD4 molecule on NK cells. Thus, the CD4 molecule is present and functional on NK cells and plays a role in innate immune responses as a chemotactic receptor and by increasing cytokine production, in addition to its well-described function on T cells as a coreceptor for Ag responsive cell activation.

Binding Sites, Antibody↗
PubMed2006

Continued evolution in gp41 after interruption of enfuvirtide in subjects with advanced HIV type 1 disease.

Careful examination of viral dynamics during antiretroviral treatment can provide important insights into HIV pathogenesis. We examined viral evolution during and after enfuvirtide (T-20) treatment with an objective of defining the characteristics of viral evolution during advanced HIV immunodeficiency. Specifically, we examined the viral quasispecies from nine patients who experienced incomplete viral suppression on an enfuvirtide-based regimen, and who subsequently interrupted enfuvirtide while remaining on a stable optimized background regimen (enfuvirtide "partial treatment interruption"). On average, eight clones were sequenced from three time points: pre-enfuvirtide, post-enfuvirtide failure, and post-enfuvirtide interruption. We utilized a Bayesian hierarchical phylogenetic model to assess the evolutionary relatedness of the virus that emerged over time. In most subjects, interruption of enfuvirtide was associated with continued viral evolution as enfuvirtide mutations waned; in no subject did we find clear evidence supporting the reemergence of archived wild-type variants (Bayes factor=30.2, p=0.01). Evidence supporting ongoing viral evolution was particularly strong in subjects whose virus remained diverse or became more diverse during enfuvirtide therapy. In contrast to observations when all drugs are interrupted, loss of resistance during enfuvirtide interruption is most likely due to ongoing viral evolution (and back-mutation), rather than emergence of an archived virus.

Bayes Theorem↗
PubMed2006

Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants.

OBJECTIVES: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder. METHOD: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score > or =3 (mildly ill). RESULTS: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch. CONCLUSIONS: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.

Adult↗
PubMed2005

The CD4 molecule on CD8+ T lymphocytes directly enhances the immune response to viral and cellular antigens.

CD8+ T lymphocytes play a major role in cellular-mediated immune responses to foreign antigen. We have previously demonstrated that costimulation of purified human CD8+ T cells induces de novo expression of the CD4 molecule and that ligation of CD4 on this cell type modulates CD8+ T cell activity in vitro. Herein, we investigate how the CD4 molecule expressed on murine CD8+ T cells contributes to CD8+ cell responses in vivo by employing adoptive transfer of CD8 cells from CD4 knockout mice into severe combined immunodeficient (SCID) recipients. Transfer of these cells into syngeneic SCID mice resulted in a decreased immune response to infection by lymphocytic choriomeningitis virus. These decreased responses occurred even in the presence of CD4+ T cells, indicating that this was truly a CD8-cell defect. Similarly, transfer of CD8+ T cells incapable of expressing CD4 into allogeneic SCID mice resulted in a decreased response to alloantigens compared with that of normal CD8+ T cells. Therefore, CD4 expression on CD8 T lymphocytes modulates cytotoxic T lymphocyte function and is critical in vivo for optimal cell-mediated immunity to viral and alloantigens.

Animals↗
PubMed2005

Genetic and stochastic influences on the interaction of human immunodeficiency virus type 1 and cytotoxic T lymphocytes in identical twins.

Human immunodeficiency virus type 1 (HIV-1) evolves in vivo under selective pressure from CD8+ T-lymphocyte (CTL) responses, which are in turn determined by host and viral genetic factors, such as restricting major histocompatibility complex molecules and the available viral epitope sequences. However, CTL are derived stochastically through the random gene rearrangements to produce T-cell receptors (TCR), and the relative impact of genetic versus stochastic processes on CTL targeting of HIV and immune-driven viral evolution is unclear. Here we evaluate identical twins infected with HIV-1 as neonates from a common blood transfusion, with subsequently similar environmental exposures, thereby allowing controlled comparisons of CTL targeting and viral evolution. Seventeen years after infection, their CTL targeting of HIV-1 was remarkably similar. In contrast, their overall TCR profiles were highly dissimilar, and a dominant epitope was recognized by distinctly different TCR in each twin. Furthermore, their viral epitopes had diverged, and there was ongoing viral phylogenetic divergence between the twins between 12 and 17 years after infection. These results indicate that while CTL targeting is predominately genetically determined, stochastic influences render the interaction of HIV-1 and host immunity, and therefore viral escape and CTL efficacy, unpredictable.

Acquired Immunodeficiency Syndrome↗
PubMed2004

CD4 on CD8(+) T cells directly enhances effector function and is a target for HIV infection.

Costimulation of purified CD8(+) T lymphocytes induces de novo expression of CD4, suggesting a previously unrecognized function for this molecule in the immune response. Here, we report that the CD4 molecule plays a direct role in CD8(+) T cell function by modulating expression of IFN-gamma and Fas ligand, two important CD8(+) T cell effector molecules. CD4 expression also allows infection of CD8 cells by HIV, which results in down-regulation of the CD4 molecule and impairs the induction of IFN-gamma, Fas ligand, and the cytotoxic responses of activated CD8(+) T cells. Thus, the CD4 molecule plays a direct role in CD8 T cell function, and infection of these cells by HIV provides an additional reservoir for the virus and also may contribute to the immunodeficiency seen in HIV disease.

CD4 Antigens↗
PubMed2004

Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load.

Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation "set point" is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10,000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.

Adult↗
PubMed2004

Evolution of human immunodeficiency virus type 1 coreceptor usage during antiretroviral Therapy: a Bayesian approach.

There is substantial evidence for ongoing replication and evolution of human immunodeficiency virus type 1 (HIV-1), even in individuals receiving highly active antiretroviral therapy. Viral evolution in the presence of antiviral therapy needs to be considered when developing new therapeutic strategies. Phylogenetic analyses of HIV-1 sequences can be used for this purpose but may give rise to misleading results if rates of intrapatient evolution differ significantly. To improve analyses of HIV-1 evolution relevant to studies of pathogenesis and treatment, we developed a Bayesian hierarchical model that incorporates all available sequence data while simultaneously allowing the phylogenetic parameters of each patient to vary. We used this method to examine evolutionary changes in HIV-1 coreceptor usage in response to treatment. We examined patients whose viral populations exhibited a shift in coreceptor utilization in response to therapy. CXCR4 (X4) strains emerged in each patient but were suppressed following initiation of new antiretroviral regimens, so that CCR5-utilizing (R5) strains predominated. By phylogenetically reconstructing the evolutionary relationship of HIV-1 obtained longitudinally from each patient, it was possible to examine the origin of the reemergent R5 virus. Using our Bayesian hierarchical approach, we found that the reemergent R5 virus detectable after therapy was more closely related to the predecessor R5 virus than to the X4 strains. The Bayesian hierarchical approach, unlike more traditional methods, makes it possible to evaluate competing hypotheses across patients. This model is not limited to analyses of HIV-1 but can be used to elucidate evolutionary processes for other organisms as well.

Antiretroviral Therapy, Highly Active↗
PubMed2004

Targeting c-Mpl for revival of human immunodeficiency virus type 1-induced hematopoietic inhibition when CD34+ progenitor cells are re-engrafted into a fresh stromal microenvironment in vivo.

The inhibition of multilineage hematopoiesis which occurs in the severe combined immunodeficiency mouse with transplanted human fetal thymus and liver tissues (SCID-hu Thy/Liv) due to human immunodeficiency virus type 1 (HIV-1) infection is also accompanied by a severe loss of c-Mpl expression on these progenitor cells. Inhibition of colony-forming activity (CFA) of the CD34(+) progenitor cells is partially revived to about 40% of mock-infected Thy/Liv implants, following reconstitution of the CD34(+) cells that were exposed to HIV-1 infection, in a new Thy/Liv stromal microenvironment of irradiated secondary SCID-hu recipients at 3 weeks post-re-engraftment. In addition, in these reconstituted animals, the proportion of c-Mpl(+) CD34(+) cells relative to c-Mpl(-) CD34(+) cells increased by about 25%, to 35% of mock-infected implants, suggesting a reacquirement of c-Mpl phenotype by the c-Mpl(-) CD34(+) cells. These results suggest a correlation between c-Mpl expression and multilineage CFA of the human CD34(+) progenitor cells that have experienced the effects of HIV-1 infection. Treatment of the secondary-recipient animals with the c-Mpl ligand, thrombopoietin (Tpo), further increased c-Mpl expression and CFA of re-engrafted CD34(+) cells previously exposed to virus in the primary implants to about 50 to 70% over that of those re-engrafted CD34(+) cells derived from implants of untreated animals. Blocking of c-Mpl with anti-c-Mpl monoclonal antibody in vivo by injecting the SCID-hu animals resulted in the reduction or loss of CFA. Thus, inhibition, absence, or loss of c-Mpl expression as in the c-Mpl(-) CD34(+) subset of cells is the likely cause of CFA inhibition. Further, CFA of the CD34(+) cells segregates with their c-Mpl expression. Therefore, c-Mpl may play a role in hematopoietic inhibition during HIV-1 infection, and control of its expression levels may aid in hematopoietic recovery and thereby reduce the incidence of cytopenias occurring in infected individuals.

Animals↗
PubMed2003

Identification of T cell-signaling pathways that stimulate latent HIV in primary cells.

Eradication of HIV infection depends on the elimination of a small, but stable population of latently infected T cells. After the discontinuation of therapy, activation of latent virus can rekindle infection. To purge this reservoir, it is necessary to define cellular signaling pathways that lead to activation of latent HIV. We used the SCID-hu (Thy/Liv) mouse model of HIV latency to analyze a broad array of T cell-signaling pathways and show in primary, quiescent cells that viral induction depends on the activation of two primary intracellular signaling pathways, protein kinase C or nuclear factor of activated T cells (NF-AT). In contrast, inhibition or activation of other important T cell stimulatory pathways (such as mitogen-activated protein kinase, calcium flux, or histone deacetylation) do not significantly induce virus expression. We found that the activation of NF-kappaB is critical to viral reactivation; however, all pathways that stimulate NF-kappaBdonot reactivate latent virus. Our studies further show that inhibition of NF-kappaB does not prevent activation of HIV by NF-AT, indicating that these pathways can function independently to activate the HIV LTR. Thus, we define several molecular pathways that trigger HIV reactivation from latency and provide evidence that latent HIV infection is maintained by the functional lack of particular transcription factors in quiescent cells.

Animals↗
PubMed2003

Impairment of antimicrobial activity and nitric oxide production in alveolar macrophages from smokers of marijuana and cocaine.

Human alveolar macrophages (AMs) were recovered from the lungs of healthy nonsmokers (NS) or smokers of tobacco (TS), marijuana (MS), or crack cocaine (CS) and challenged in vitro with Staphylococcus aureus. AMs from NS and TS exhibited potent antibacterial activity that correlated with the production of nitric oxide (NO) and induction of NO synthase without the requirement for priming with exogenous cytokines. In contrast, AMs from MS and CS exhibited minimal antibacterial activity and failed to produce NO unless primed with additional cytokines. These results confirm that NO plays a significant role as an effector molecule used by normal human AMs, but this capacity is suppressed in AMs from MS and CS because of a lack of intrinsic cytokine priming.

Adult↗
PubMed2003

Molecular characterization, reactivation, and depletion of latent HIV.

Antiretroviral therapy is unable to eliminate HIV infection in a small, long-lived population of latently infected T cells, providing a source for renewed viral replication following cessation of therapy. Analysis of individual latently infected cells generated in the SCID-hu (Thy/Liv) mouse demonstrated no functional viral RNA produced in the latent state. Following reactivation viral expression was dramatically increased, rendering the infected cells susceptible to an anti-HIV immunotoxin. Treatment with the immunotoxin in conjunction with agents that activate virus expression without inducing cell division (IL-7 or the non-tumor-promoting phorbol ester prostratin) depleted the bulk of the latent reservoir and left uninfected cells able to respond to subsequent costimulation. We demonstrate that activation of latent virus is required for targeting by antiviral agents and provide the basis for future therapeutic strategies to eradicate the latent reservoir.

Adjuvants, Immunologic↗
PubMed2003

Hierarchical phylogenetic models for analyzing multipartite sequence data.

Debate exists over how to incorporate information from multipartite sequence data in phylogenetic analyses. Strict combined-data approaches argue for concatenation of all partitions and estimation of one evolutionary history, maximizing the explanatory power of the data. Consensus/independence approaches endorse a two-step procedure where partitions are analyzed independently and then a consensus is determined from the multiple results. Mixtures across the model space of a strict combined-data approach and a priori independent parameters are popular methods to integrate these methods. We propose an alternative middle ground by constructing a Bayesian hierarchical phylogenetic model. Our hierarchical framework enables researchers to pool information across data partitions to improve estimate precision in individual partitions while permitting estimation and testing of tendencies in across-partition quantities. Such across-partition quantities include the distribution from which individual topologies relating the sequences within a partition are drawn. We propose standard hierarchical priors on continuous evolutionary parameters across partitions, while the structure on topologies varies depending on the research problem. We illustrate our model with three examples. We first explore the evolutionary history of the guinea pig (Cavia porcellus) using alignments of 13 mitochondrial genes. The hierarchical model returns substantially more precise continuous parameter estimates than an independent parameter approach without losing the salient features of the data. Second, we analyze the frequency of horizontal gene transfer using 50 prokaryotic genes. We assume an unknown species-level topology and allow individual gene topologies to differ from this with a small estimable probability. Simultaneously inferring the species and individual gene topologies returns a transfer frequency of 17%. We also examine HIV sequences longitudinally sampled from HIV+ patients. We ask whether posttreatment development of CCR5 coreceptor virus represents concerted evolution from middisease CXCR4 virus or reemergence of initial infecting CCR5 virus. The hierarchical model pools partitions from multiple unrelated patients by assuming that the topology for each patient is drawn from a multinomial distribution with unknown probabilities. Preliminary results suggest evolution and not reemergence.

Animals↗