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Search Results: 1 - 10 of 15402 matches for " Javier Martinez-Picado "
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Optimal Antiviral Switching to Minimize Resistance Risk in HIV Therapy
Rutao Luo, Michael J. Piovoso, Javier Martinez-Picado, Ryan Zurakowski
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027047
Abstract: The development of resistant strains of HIV is the most significant barrier to effective long-term treatment of HIV infection. The most common causes of resistance development are patient noncompliance and pre-existence of resistant strains. In this paper, methods of antiviral regimen switching are developed that minimize the risk of pre-existing resistant virus emerging during therapy switches necessitated by virological failure. Two distinct cases are considered; a single previous virological failure and multiple virological failures. These methods use optimal control approaches on experimentally verified mathematical models of HIV strain competition and statistical models of resistance risk. It is shown that, theoretically, order-of-magnitude reduction in risk can be achieved, and multiple previous virological failures enable greater success of these methods in reducing the risk of subsequent treatment failures.
HIV Model Parameter Estimates from Interruption Trial Data including Drug Efficacy and Reservoir Dynamics
Rutao Luo, Michael J. Piovoso, Javier Martinez-Picado, Ryan Zurakowski
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040198
Abstract: Mathematical models based on ordinary differential equations (ODE) have had significant impact on understanding HIV disease dynamics and optimizing patient treatment. A model that characterizes the essential disease dynamics can be used for prediction only if the model parameters are identifiable from clinical data. Most previous parameter identification studies for HIV have used sparsely sampled data from the decay phase following the introduction of therapy. In this paper, model parameters are identified from frequently sampled viral-load data taken from ten patients enrolled in the previously published AutoVac HAART interruption study, providing between 69 and 114 viral load measurements from 3–5 phases of viral decay and rebound for each patient. This dataset is considerably larger than those used in previously published parameter estimation studies. Furthermore, the measurements come from two separate experimental conditions, which allows for the direct estimation of drug efficacy and reservoir contribution rates, two parameters that cannot be identified from decay-phase data alone. A Markov-Chain Monte-Carlo method is used to estimate the model parameter values, with initial estimates obtained using nonlinear least-squares methods. The posterior distributions of the parameter estimates are reported and compared for all patients.
HIV-1 Capture and Transmission by Dendritic Cells: The Role of Viral Glycolipids and the Cellular Receptor Siglec-1
Nuria Izquierdo-Useros ,Maier Lorizate,Paul J. McLaren,Amalio Telenti,Hans-Georg Kr?usslich ? ,Javier Martinez-Picado
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004146
Abstract: Dendritic cells (DCs) are essential in order to combat invading viruses and trigger antiviral responses. Paradoxically, in the case of HIV-1, DCs might contribute to viral pathogenesis through trans-infection, a mechanism that promotes viral capture and transmission to target cells, especially after DC maturation. In this review, we highlight recent evidence identifying sialyllactose-containing gangliosides in the viral membrane and the cellular lectin Siglec-1 as critical determinants for HIV-1 capture and storage by mature DCs and for DC-mediated trans-infection of T cells. In contrast, DC-SIGN, long considered to be the main receptor for DC capture of HIV-1, plays a minor role in mature DC-mediated HIV-1 capture and trans-infection.
HIV and Mature Dendritic Cells: Trojan Exosomes Riding the Trojan Horse?
Nuria Izquierdo-Useros,Mar Naranjo-Gómez,Itziar Erkizia,Maria Carmen Puertas,Francesc E. Borràs,Julià Blanco,Javier Martinez-Picado
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000740
Abstract: Exosomes are secreted cellular vesicles that can induce specific CD4+ T cell responses in vivo when they interact with competent antigen-presenting cells like mature dendritic cells (mDCs). The Trojan exosome hypothesis proposes that retroviruses can take advantage of the cell-encoded intercellular vesicle traffic and exosome exchange pathway, moving between cells in the absence of fusion events in search of adequate target cells. Here, we discuss recent data supporting this hypothesis, which further explains how DCs can capture and internalize retroviruses like HIV-1 in the absence of fusion events, leading to the productive infection of interacting CD4+ T cells and contributing to viral spread through a mechanism known as trans-infection. We suggest that HIV-1 can exploit an exosome antigen-dissemination pathway intrinsic to mDCs, allowing viral internalization and final trans-infection of CD4+ T cells. In contrast to previous reports that focus on the ability of immature DCs to capture HIV in the mucosa, this review emphasizes the outstanding role that mature DCs could have promoting trans-infection in the lymph node, underscoring a new potential viral dissemination pathway.
In–Depth Characterization of Viral Isolates from Plasma and Cells Compared with Plasma Circulating Quasispecies in Early HIV-1 Infection
Judith Dalmau, Francisco M. Codo?er, Itziar Erkizia, Maria Pino, Christian Pou, Roger Paredes, Bonaventura Clotet, Javier Martinez-Picado, Julia G. Prado
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032714
Abstract: Background The use of in vitro models to unravel the phenotypic characteristics of circulating viral variants is key to understanding HIV-1 pathogenesis but limited by the availability of primary viral isolates from biological samples. However, overall in vivo genetic variability of HIV-1 within a subject may not be reflected in the viable viral population obtained after isolation. Although several studies have tried to determine whether viral populations expanded in vitro are representative of in vivo findings, the answer remains unclear due to the reduced number of clonal sequences analyzed or samples compared. In order to overcome previous experimental limitations, here we applied Deep Pyrosequencing (DPS) technology in combination with phenotypic experiments to analyze and compare with unprecedented detail the composition of viral isolates and in vivo quasispecies. Methodology/Principal Findings We amplified by DPS HIV-1 genomic regions covering gag, protease, integrase and env-V3 to characterize paired isolates from plasma and peripheral blood mononuclear cells and compare them with total plasma viral RNA in four recently HIV-1 infected subjects. Our study demonstrated the presence of unique haplotypes scattered between sample types with conservation of major variants. In addition, no differences in intra- and inter-population encoded protein variability were found between the different types of isolates or when these were compared to plasma viral RNA within subjects. Additionally, in vitro experiments demonstrated phenotypic similarities in terms of replicative capacity and co-receptor usage between viral isolates and plasma viral RNA. Conclusion This study is the first in-depth comparison and characterization of viral isolates from different sources and plasma circulating quasispecies using DPS in recently HIV-1 infected subjects. Our data supports the use of primary isolates regardless of their plasma or cellular origin to define genetic variability and biological traits of circulating HIV-1 quasispecies.
HIV transfer between CD4 T cells does not require LFA-1 binding to ICAM-1 and is governed by the interaction of HIV envelope glycoprotein with CD4
Isabel Puigdomènech, Marta Massanella, Nuria Izquierdo-Useros, Raul Ruiz-Hernandez, Marta Curriu, Margarita Bofill, Javier Martinez-Picado, Manel Juan, Bonaventura Clotet, Julià Blanco
Retrovirology , 2008, DOI: 10.1186/1742-4690-5-32
Abstract: The formation of cellular conjugates and subsequent HIV transmission between productively infected MOLT cell lines and primary CD4 T cells was not inhibited by a panel of blocking antibodies against ICAM-1, ICAM-3 and α and β chains of LFA-1. Complete abrogation of HIV transmission and formation of cellular conjugates was only observed when gp120/CD4 interactions were blocked. The dispensable role of LFA-1 in HIV transmission was confirmed using non-lymphoid 293T cells, lacking the expression of adhesion molecules, as HIV producing cells. Moreover, HIV transmission between infected and uninfected primary CD4 T cells was abrogated by inhibitors of gp120 binding to CD4 but was not inhibited by blocking LFA-1 binding to ICAM-1 or ICAM-3. Rather, LFA-1 and ICAM-3 mAbs enhanced HIV transfer. All HIV producing cells (including 293T cells) transferred HIV particles more efficiently to memory than to naive CD4 T cells.In contrast to other mechanisms of viral spread, HIV transmission between infected and uninfected T cells efficiently occurs in the absence of adhesion molecules. Thus, gp120/CD4 interactions are the main driving force of the formation of cellular contacts between infected and uninfected CD4 T cells whereby HIV transmission occurs.Cell-to-cell HIV transmission is a major determinant of HIV spread in vivo [1] and is required for efficient HIV replication in vitro [2]. Although free HIV particles are infectious, they show a short lifespan at 37°C [3] and lower infectivity than cell-to-cell HIV transmission [4]. Cell-to-cell virus transmission occurs through the formation of stable cellular contacts defined as virological synapses [5], that can be formed between a target CD4 T cell and either a dendritic cell (DC) or a productively HIV infected cell. Although both synapses share the common function of transmitting HIV to CD4 T cells, their structures appreciably differ: DC-T cell synapses concentrate TCR/MHC complexes in the central supramolecular activation clus
Sialyllactose in Viral Membrane Gangliosides Is a Novel Molecular Recognition Pattern for Mature Dendritic Cell Capture of HIV-1
Nuria Izquierdo-Useros,Maier Lorizate,F.-Xabier Contreras,Maria T. Rodriguez-Plata,B?rbel Glass,Itziar Erkizia,Julia G. Prado,Josefina Casas,Gemma Fabriàs,Hans-Georg Kr?usslich,Javier Martinez-Picado
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001315
Abstract: HIV-1 is internalized into mature dendritic cells (mDCs) via an as yet undefined mechanism with subsequent transfer of stored, infectious virus to CD4+ T lymphocytes. Thus, HIV-1 subverts a DC antigen capture mechanism to promote viral spread. Here, we show that gangliosides in the HIV-1 membrane are the key molecules for mDC uptake. HIV-1 virus-like particles and liposomes mimicking the HIV-1 lipid composition were shown to use a common internalization pathway and the same trafficking route within mDCs. Hence, these results demonstrate that gangliosides can act as viral attachment factors, in addition to their well known function as cellular receptors for certain viruses. Furthermore, the sialyllactose molecule present in specific gangliosides was identified as the determinant moiety for mDC HIV-1 uptake. Thus, sialyllactose represents a novel molecular recognition pattern for mDC capture, and may be crucial both for antigen presentation leading to immunity against pathogens and for succumbing to subversion by HIV-1.
Deep Molecular Characterization of HIV-1 Dynamics under Suppressive HAART
Maria J. Buzón equal contributor,Francisco M. Codo?er equal contributor,Simon D. W. Frost,Christian Pou,Maria C. Puertas,Marta Massanella,Judith Dalmau,Josep M. Llibre,Mario Stevenson,Julià Blanco,Bonaventura Clotet,Roger Paredes,Javier Martinez-Picado
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002314
Abstract: In order to design strategies for eradication of HIV-1 from infected individuals, detailed insight into the HIV-1 reservoirs that persist in patients on suppressive antiretroviral therapy (ART) is required. In this regard, most studies have focused on integrated (proviral) HIV-1 DNA forms in cells circulating in blood. However, the majority of proviral DNA is replication-defective and archival, and as such, has limited ability to reveal the dynamics of the viral population that persists in patients on suppressive ART. In contrast, extrachromosomal (episomal) viral DNA is labile and as a consequence is a better surrogate for recent infection events and is able to inform on the extent to which residual replication contributes to viral reservoir maintenance. To gain insight into the diversity and compartmentalization of HIV-1 under suppressive ART, we extensively analyzed longitudinal peripheral blood mononuclear cells (PBMC) samples by deep sequencing of episomal and integrated HIV-1 DNA from patients undergoing raltegravir intensification. Reverse-transcriptase genes selectively amplified from episomal and proviral HIV-1 DNA were analyzed by deep sequencing 0, 2, 4, 12, 24 and 48 weeks after raltegravir intensification. We used maximum likelihood phylogenies and statistical tests (AMOVA and Slatkin-Maddison (SM)) in order to determine molecular compartmentalization. We observed low molecular variance (mean variability ≤0.042). Although phylogenies showed that both DNA forms were intermingled within the phylogenetic tree, we found a statistically significant compartmentalization between episomal and proviral DNA samples (P<10?6 AMOVA test; P = 0.001 SM test), suggesting that they belong to different viral populations. In addition, longitudinal analysis of episomal and proviral DNA by phylogeny and AMOVA showed signs of non-chronological temporal compartmentalization (all comparisons P<10?6) suggesting that episomal and proviral DNA forms originated from different anatomical compartments. Collectively, this suggests the presence of a chronic viral reservoir in which there is stochastic release of infectious virus and in which there are limited rounds of de novo infection. This could be explained by the existence of different reservoirs with unique pharmacological accessibility properties, which will require strategies that improve drug penetration/retention within these reservoirs in order to minimise maintenance of the viral reservoir by de novo infection.
New Macrocyclic Amines Showing Activity as HIV Entry Inhibitors Against Wild Type and Multi-Drug Resistant Viruses
Stefano Rusconi,Mirko Lo Cicero,Ottavia Viganò,Francesca Sirianni,Elisabetta Bulgheroni,Stefania Ferramosca,Andrea Bencini,Antonio Bianchi,Lidia Ruiz,Cecilia Cabrera,Javier Martinez-Picado,Claudiu T. Supuran,Massimo Galli
Molecules , 2009, DOI: 10.3390/molecules14051927
Abstract: Considering as a lead molecule the chemokine CXCR4 receptor antagonist AMD-3100, which shows significant anti-HIV activity in vitro and in vivo, we investigated a series of structurally related macrocyclic polyamines incorporating o,o’-phenanthroline or 2,2’-bipyridyl scaffolds as potential antiviral agents with lower toxicity and increased activity against both wild type X4-tropic and dual tropic HIV strains. The antiviral activity of these compounds was evaluated by susceptibility assays in PBMC (Peripheral Blood Mononuclear Cells) and compared to that of AMD-3100. The newly investigated compounds showed IC50s values in the low micromolar range and significantly inhibited the viral replication of wild type X4-tropic isolate and dual tropic strains. These macrocyclic polyamines constitute a promising class of HIV entry inhibitors.
Copy Number Variation of KIR Genes Influences HIV-1 Control
Kimberly Pelak,Anna C. Need,Jacques Fellay,Kevin V. Shianna,Sheng Feng,Thomas J. Urban,Dongliang Ge,Andrea De Luca,Javier Martinez-Picado,Steven M. Wolinsky,Jeremy J. Martinson,Beth D. Jamieson,Jay H. Bream,Maureen P. Martin,Persephone Borrow,Norman L. Letvin,Andrew J. McMichael,Barton F. Haynes,Amalio Telenti,Mary Carrington,David B. Goldstein,Galit Alter
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001208
Abstract: A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.
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