455 research outputs found
Molecular-Detailed Computational Tools to Study HIV Pathogenesis and Design Anti-HIV Stem Cell Therapies
No full textCombination antiretroviral therapy (cART) ensures that millions of people with HIV lead normal lives. However, cART is not a cure and if stopped, even after decades, HIV hidden in the latent reservoir can activate and lead to viral rebound. Given the drawbacks of cART particularly cost and difficulties of adherence to chronic treatment, HIV cures could significantly reduce the burden on patients while reducing the healthcare cost.
In 2008, the “Berlin Patient” was treated with myeloablative irradiation and hematopoietic stem cell transplant (HSCT) from a donor with a CCR5Δ32 mutation conferring resistance to HIV. Since then, the recipient has been “functionally cured”, i.e. has shown no signs of active HIV-1 replication in the absence of cART. This success renewed hope that replacing HIV-susceptible cells with more resistant cells by inserting genes or gene networks into patients’ or matched donors’ stem cells before transplantation could provide HIV-resistance to progeny target cells and lead to cure. This approach was recently shown in macaques to reduce viral load and return T cell counts to normal levels. Key questions remain: (a) given that donor chimerism occurs, what percentage of the cells must be HIV-resistant in order to block HIV; (b) what is the minimal level of anti-HIV activity needed in these cells; (c) which anti-HIV genes will work best, and for which patients; and (d) will combinations of anti-HIV genes synergize?
As few patients have undergone transplants, we built novel molecular-detailed mechanistic models of HIV infection to answer these questions. The models are validated against independent in vitro and in vivo experimental data. Using the models, we study the complex pathogenesis of HIV, design gene-augmented stem cell therapies, and calculate the probability of cure for each therapy. We focus on HSCTs that include knocking out CCR5 and/or inserting anti-HIV genes or gene circuits such as the APOBEC3 family, SAMHD1, and on-demand apoptosis-inducing circuits. Instead of studying a single average course of HIV infection in a typical patient, we apply our models, parameterized using real patient data, to simulate a population of HIV-infected patients. Using this population of models, we run virtual clinical trials of different treatments. We validate the model by predicting recent clinical data from CCR5-modified T-cell therapy. The model has the ability to help design stem cell-based therapies and predict the results in clinical studies
Using imagery to solve spatial problems
No full textThis report focuses on the use of imagery to solve a range of spatial problems. The research projects reviewed in this report offer some insight into the range of strategies used by solvers of spatial problems and point to relationships between spatial and verbal skills
Paternalism and the alleviation of poverty
No full textTypically the tools available for redistribution are price subsidies and direct cash transfers. Conventional economic theory indicates that the efficiency loss is minimized if cash transfers are used instead of price subsidies. But in almost all economies, including advanced economies, price subsidies are implemented and cash transfers are seldom used. The author argues that taxpayers enjoy the poorer citizen's specific consumption package more than improving the poorer citizen's general economic welfare. Her objective is to identify the conditions under which price subsidies represent a more efficient way of alleviating poverty than cash payments, given taxpayers'paternalistic preferences. She concludes that when the taxpayers'prevalent behavior is paternalism, and taxpayers have more weight in society, the option for redistribution would be to target price subsidies to the poor. This brings about a greater improvement in overall social welfare and happier taxpayers than any other policy. With this solution, the poor are somewhat better off, even though they would rather receive cash transfers, which would represent the same financial cost to the economy.Safety Nets and Transfers,Services&Transfers to Poor,Rural Poverty Reduction,Economic Theory&Research,Environmental Economics&Policies
Characterization of a Membrane-Associated Protein Implicated in Visna Virus Binding and Infection
No full textAbstractThe identity of the cellular receptor(s) for visna virus, an ovine lentivirus, is currently unknown; however, previous studies from our laboratory have identified membrane-associated proteins expressed selectively in susceptible cells which bind visna virus. Moreover, a polyclonal antibody (2-23), raised against a 45-kDa visna virus binding protein, bound specifically to the surface of susceptible cells in immunofluorescence assays and significantly reduced binding of visna virus to cells (S. E. Crane et al., 1991, J. Virol., 65, 6137–6143). In this report we extend our studies of this antibody (2-23), showing both that 2-23 significantly reduces visna virus infection of susceptible cells and that 2-23 immunoprecipitates a putative protein complex consisting of a prominent 30-kDa protein, as well as the 45-kDa immunogen, specifically from radiolabeled virus-susceptible sheep cells. Further, we demonstrate that the 30-kDa protein is a membrane-associated proteoglycan substituted with a chondroitin sulfate glycosaminoglycan (GAG) chain(s) and that treatment of susceptible cells with an inhibitor of GAG synthesis significantly reduces visna virus production. Collectively, these data support a role for a proteoglycan in visna virus cell binding and infection
DESIGN AND DEVELOPMENT OF BISPECIFIC ANTIBODIES FOR HIV-1 RESERVOIR ELIMINATION
No full textCurrently, there are over 38.4 million people worldwide living human immunodeficiency virus type 1 (HIV-1), and despite advances in HIV-1 prevention, there are still 1.5 million new cases annually. Although antiretroviral therapy (ART) regimens suppress viral replication and prevent immunodeficiency, ART is not curative and cessation of treatment results in viral rebound within weeks. The inability of ART to cure HIV-1 stems from the persistence of a population of resting memory CD4+ T cells that contain integrated and transcriptionally silent HIV-1 proviral DNA. This CD4+ T cell population, referred to as the latent reservoir, eludes the immune system and can resume viral production and disease progression if ART is interrupted. Thus, the latent reservoir represents the major barrier to an HIV-1 cure and novel therapeutics are urgently needed to eliminate the latent reservoir.
Efforts to achieve a cure for HIV-1 infection have largely focused on the strategy known as ‘shock and kill’. In this approach, reversal of HIV latency (‘shock’) would be achieved through treatment with small molecule drugs capable of inducing HIV-1 gene expression without toxic global T cell activation. This latency reversing agent (LRA) would be administered while maintaining ART to prevent new infection events. Renewed expression of HIV-1 gene products would allow for clearance of infected cells (‘kill’) through viral cytopathic effects or immune-mediated clearance, resulting in a reduction in the size of the latent reservoir.
However, despite observations of transient increases in plasma and cell-associated viral RNA, indicative of latency reversal, in some LRA clinical trials, no significant reduction in reservoir size has been achieved to date. Several lines of evidence suggest the lack of reservoir size reduction observed may be partially explained by inefficient immune-mediated elimination of reactivated infected cells. To overcome limitations to CTL- and NK cell-mediated clearance of infected CD4+ T cells after reversal of latency in persons with HIV-1 (PWH), immunotherapies capable of augmenting cell-mediated cytolytic activity may be necessary. In this dissertation, we describe the development and preclinical characterization of bispecific antibodies capable of potently and specifically enhancing the elimination of HIV-1-infected CD4+ T cells by cytolytic CTLs and NK cells
DESIGN AND DEVELOPMENT OF BISPECIFIC ANTIBODIES FOR HIV-1 RESERVOIR ELIMINATION
No full textCurrently, there are over 38.4 million people worldwide living human immunodeficiency virus type 1 (HIV-1), and despite advances in HIV-1 prevention, there are still 1.5 million new cases annually. Although antiretroviral therapy (ART) regimens suppress viral replication and prevent immunodeficiency, ART is not curative and cessation of treatment results in viral rebound within weeks. The inability of ART to cure HIV-1 stems from the persistence of a population of resting memory CD4+ T cells that contain integrated and transcriptionally silent HIV-1 proviral DNA. This CD4+ T cell population, referred to as the latent reservoir, eludes the immune system and can resume viral production and disease progression if ART is interrupted. Thus, the latent reservoir represents the major barrier to an HIV-1 cure and novel therapeutics are urgently needed to eliminate the latent reservoir.
Efforts to achieve a cure for HIV-1 infection have largely focused on the strategy known as ‘shock and kill’. In this approach, reversal of HIV latency (‘shock’) would be achieved through treatment with small molecule drugs capable of inducing HIV-1 gene expression without toxic global T cell activation. This latency reversing agent (LRA) would be administered while maintaining ART to prevent new infection events. Renewed expression of HIV-1 gene products would allow for clearance of infected cells (‘kill’) through viral cytopathic effects or immune-mediated clearance, resulting in a reduction in the size of the latent reservoir.
However, despite observations of transient increases in plasma and cell-associated viral RNA, indicative of latency reversal, in some LRA clinical trials, no significant reduction in reservoir size has been achieved to date. Several lines of evidence suggest the lack of reservoir size reduction observed may be partially explained by inefficient immune-mediated elimination of reactivated infected cells. To overcome limitations to CTL- and NK cell-mediated clearance of infected CD4+ T cells after reversal of latency in persons with HIV-1 (PWH), immunotherapies capable of augmenting cell-mediated cytolytic activity may be necessary. In this dissertation, we describe the development and preclinical characterization of bispecific antibodies capable of potently and specifically enhancing the elimination of HIV-1-infected CD4+ T cells by cytolytic CTLs and NK cells
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