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Dive into the research topics where Lara E. Pereira is active.

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Featured researches published by Lara E. Pereira.


Journal of Clinical Investigation | 2008

Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys

Nichole R. Klatt; Francois Villinger; Pavel Bostik; Shari N. Gordon; Lara E. Pereira; Jessica C. Engram; Ann E. Mayne; Richard M. Dunham; Benton Lawson; Sarah J. Ratcliffe; Donald L. Sodora; James G. Else; Keith A. Reimann; Silvija I. Staprans; Ashley T. Haase; Jacob D. Estes; Guido Silvestri; Aftab A. Ansari

Naturally SIV-infected sooty mangabeys (SMs) remain asymptomatic despite high virus replication. Elucidating the mechanisms underlying AIDS resistance of SIV-infected SMs may provide crucial information to better understand AIDS pathogenesis. In this study, we assessed the determinants of set-point viremia in naturally SIV-infected SMs, i.e., immune control of SIV replication versus target cell limitation. We depleted CD4+ T cells in 6 naturally SIV-infected SMs by treating with humanized anti-CD4 mAb (Cdr-OKT4A-huIgG1). CD4+ T cells were depleted almost completely in blood and BM and at variable levels in mucosal tissues and LNs. No marked depletion of CD14+ monocytes was observed. Importantly, CD4+ T cell depletion was associated with a rapid, significant decline in viral load, which returned to baseline level at day 30-45, coincident with an increased fraction of proliferating and activated CD4+ T cells. Throughout the study, virus replication correlated with the level of proliferating CD4+ T cells. CD4+ T cell depletion did not induce any changes in the fraction of Tregs or the level of SIV-specific CD8+ T cells. Our results suggest that the availability of activated CD4+ T cells, rather than immune control of SIV replication, is the main determinant of set-point viral load during natural SIV infection of SMs.


Cellular Immunology | 2008

Sooty mangabeys and rhesus macaques exhibit significant divergent natural killer cell responses during both acute and chronic phases of SIV infection

Lara E. Pereira; R.P. Johnson; Aftab A. Ansari

A correlation between NK cells and rate of disease progression in HIV-1-infected individuals has been documented. The role NK cells play in disease outcome can optimally be studied in SIV-infected disease susceptible rhesus macaques (RM) and SIV-infected disease resistant sooty mangabeys (SM). In this study, three main subsets of CD16(+)CD56(-), CD16(-/dim)CD56(+) and CD16(-)CD56(-) NK cells have been identified with the predominant CD16(+)CD56(-) subset being primarily responsible for cytolytic activity in both species. Cross-sectional studies revealed a significant decline in the frequency and function of this cytolytic subset in SIV-infected RM while an increase occurred in SIV-infected SM. Longitudinal studies revealed that an earlier NK response during acute infection occurred in all SIV-infected SM and in select SIV-infected RM that eventually controlled viral load set point during chronic infection, suggesting that early NK activity and continued maintenance of this cell lineage may indirectly contribute to disease resistance.


Journal of Immunology | 2009

Decreased NK cell frequency and function is associated with increased risk of KIR3DL allele polymorphism in simian immunodeficiency virus-infected rhesus macaques with high viral loads.

Pavel Bostik; Jaruda Kobkitjaroen; Weining Tang; Francois Villinger; Lara E. Pereira; Dawn M. Little; Susan T. Stephenson; Mark Bouzyk; Aftab A. Ansari

NK cells have been established as an important effector of innate immunity in a variety of viral infections. In HIV-1 infection in humans, alterations of NK cell function, frequency, and expression of various NK receptors have been reported to be associated with differential dynamics of disease progression. Expression of certain alleles of KIR3DL and KIR3DS receptors on NK cells was shown to correlate with levels of virus replication. In the SIV-infected rhesus macaque (RM) model of AIDS, several families of killer inhibitory Ig-related receptors (KIR receptors) corresponding to their human counterparts have been characterized, but only at the level of individual sequence variants. Here we define 14 different alleles of KIR3DL expressed among 38 SIV-infected RM, characterized by either high or low levels of SIV replication, by analyzing multiple sequences from individual animals and show an unequal distribution of certain alleles in these cohorts. High levels of SIV replication were associated with significant increases in KIR3DL mRNA levels in addition to decreases in both the frequency and function of NK cells in these animals. The higher frequency of inheritance of two KIR3DL alleles characterized by a single nucleotide polymorphism 159 H/Q was associated with RM that exhibited high plasma viral load. This data for the first time defines multiple alleles of KIR3DL in RM and shows an association between virus control, NK cell function and genetic polymorphisms of KIR receptors.


Experimental Biology and Medicine | 2007

Pharmacokinetics, Toxicity, and Functional Studies of the Selective Kv1.3 Channel Blocker 5-(4-Phenoxybutoxy)Psoralen in Rhesus Macaques

Lara E. Pereira; Francois Villinger; Heike Wulff; A. Sankaranarayanan; Girija Raman; Aftab A. Ansari

The small molecule 5-(4-phenoxybutoxy)psoralen (PAP-1) is a selective blocker of the voltage-gated potassium channel Kv1.3 that is highly expressed in cell membranes of activated effector memory T cells (TEMs). The blockade of Kv1.3 results in membrane depolarization and inhibition of TEM proliferation and function. In this study, the in vitro effects of PAP-1 on T cells and the in vivo toxicity and pharmacokinetics (PK) were examined in rhesus macaques (RM) with the ultimate aim of utilizing PAP-1 to define the role of TEMs in RM infected with simian immunodeficiency virus (SIV). Electrophysiologic studies on T cells in RM revealed a Kv1.3 expression pattern similar to that in human T cells. Thus, PAP-1 effectively suppressed TEM proliferation in RM. When administered intravenously, PAP-1 showed a half-life of 6.4 hrs; the volume of distribution suggested extensive distribution into extravascular compartments. When orally administered, PAP-1 was efficiently absorbed. Plasma concentrations in RM undergoing a 30-day, chronic dosing study indicated that PAP-1 levels suppressive to TEMs in vitro can be achieved and maintained in vivo at a non-toxic dose. PAP-1 selectively inhibited the TEM function in vivo, as indicated by a modest reactivation of cytomegalovirus (CMV) replication. Immunization of these chronically treated RM with the live influenza A/PR8 (flu) virus suggested that the development of an in vivo, flu-specific, central memory response was unaffected by PAP-1. These RM remained disease-free during the entire course of the PAP-1 study. Collectively, these data provide a rational basis for future studies with PAP-1 in SIV-infected RM.


Microbiology | 2009

Helicobacter pylori FlhB processing-deficient variants affect flagellar assembly but not flagellar gene expression

Todd G. Smith; Lara E. Pereira; Timothy R. Hoover

Regulation of the Helicobacter pylori flagellar gene cascade involves the transcription factors sigma(54) (RpoN), employed for expression of genes required midway through flagellar assembly, and sigma(28) (FliA), required for expression of late genes. Previous studies revealed that mutations in genes encoding components of the flagellar protein export apparatus block expression of the H. pylori RpoN and FliA regulons. FlhB is a membrane-bound component of the export apparatus that possesses a large cytoplasmic domain (FlhB(C)). The hook length control protein FliK interacts with FlhB(C) to modulate the substrate specificity of the export apparatus. FlhB(C) undergoes autocleavage as part of the switch in substrate specificity. Consistent with previous reports, deletion of flhB in H. pylori interfered with expression of RpoN-dependent reporter genes, while deletion of fliK stimulated expression of these reporter genes. In the DeltaflhB mutant, disrupting fliK did not restore expression of RpoN-dependent reporter genes, suggesting that the inhibitory effect of the DeltaflhB mutation is not due to the inability to export FliK. Amino acid substitutions (N265A and P266G) at the putative autocleavage site of H. pylori FlhB prevented processing of FlhB and export of filament-type substrates. The FlhB variants supported wild-type expression of RpoN- and FliA-dependent reporter genes. In the strain producing FlhB(N265A), expression of RpoN- and FliA-dependent reporter genes was inhibited when fliK was disrupted. In contrast, expression of these reporter genes was unaffected or slightly stimulated when fliK was disrupted in the strain producing FlhB(P266G). H. pylori HP1575 (FlhX) shares homology with the C-terminal portion of FlhB(C) (FlhB(CC)) and can substitute for FlhB(CC) in flagellar assembly. Disrupting flhX inhibited expression of a flaB reporter gene in the wild-type but not in the DeltafliK mutant or strains producing FlhB variants, suggesting a role for FlhX or FlhB(CC) in normal expression of the RpoN regulon. Taken together, these data indicate that the mechanism by which the flagellar protein export apparatus exerts control over the H. pylori RpoN regulon is complex and involves more than simply switching substrate specificity of the flagellar protein export apparatus.


Cellular Immunology | 2009

Preliminary in vivo efficacy studies of a recombinant rhesus anti-α4β7 monoclonal antibody

Lara E. Pereira; Nattawat Onlamoon; X. Wang; Rijian Wang; J. Li; Keith A. Reimann; Francois Villinger; Kovit Pattanapanyasat; Kazuyasu Mori; Aftab A. Ansari

Recent findings established that primary targets of HIV/SIV are lymphoid cells within the gastrointestinal (GI) tract. Focus has therefore shifted to T-cells expressing alpha(4)beta(7) integrin which facilitates trafficking to the GI tract via binding to MAdCAM-1. Approaches to better understand the role of alpha(4)beta(7)+ T-cells in HIV/SIV pathogenesis include their depletion or blockade of their synthesis, binding and/or homing capabilities in vivo. Such studies can ideally be conducted in rhesus macaques (RM), the non-human primate model of AIDS. Characterization of alpha(4)beta(7) expression on cell lineages in RM blood and GI tissues reveal low densities of expression by NK cells, B-cells, naïve and TEM (effector memory) T-cells. High densities were observed on TCM (central memory) T-cells. Intravenous administration of a single 50mg/kg dose of recombinant rhesus alpha(4)beta(7) antibody resulted in significant initial decline of alpha(4)beta(7)+ lymphocytes and sustained coating of the alpha(4)beta(7) receptor in both the periphery and GI tissues.


Clinical & Developmental Immunology | 2005

The development of mouse APECED models provides new insight into the role of AIRE in immune regulation.

Lara E. Pereira; Pavel Bostik; Aftab A. Ansari

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed.


Current HIV Research | 2009

A Case for Innate Immune Effector Mechanisms as Contributors to Disease Resistance in SIV-Infected Sooty Mangabeys

Lara E. Pereira; Aftab A. Ansari

Natural or experimental infection of the African sooty mangabey (SM) with the simian immunodeficiency virus (SIV) results in chronic high levels of virus replication but is associated with none of the debilitating immunopathology, including the marked CD4 T-cell depletion, persistent cell activation and acquired immunodeficiency, that afflicts non-natural hosts such as SIV-infected Asian rhesus macaques (RM) and HIV-infected humans. Although SIV-infected RM have served as important models of AIDS given their remarkably similar course of disease to HIV-infected humans, deciphering the immune mechanisms that enable SIV-infected SM to resist disease development despite high viremia has yet to be defined. Intense studies for the past two decades using these nonhuman primate models have been conducted with the hope that this will yield better insight into the pathogenesis of AIDS, translating into the development of therapeutic strategies for HIV-infected individuals such as but not limited to identifying correlates of protective immunity that can be harnessed for the preparation of effective vaccines. Although much has been reported about SIV-specific adaptive immune responses in both the natural and unnatural hosts of SIV, we submit that innate immunity may play a larger than previously appreciated role in SIV pathogenesis, in particular during the period of acute infection. The purpose of this review is to therefore highlight the recent advances that have been made in understanding innate immune responses in SIV-infected SM and to discuss the role(s) of the major innate immune cell lineages that potentially contribute to disease resistance in this non-human primate species.


Drug Development and Industrial Pharmacy | 2010

Formulation-based approach to support early drug discovery and development efforts: a case study with enteric microencapsulation dosage form development for a triarylmethane derivative TRAM-34; a novel potential immunosuppressant.

Abeer M. Al-Ghananeem; Maggie Abbassi; Srishti Shrestha; Girija Raman; Heike Wulff; Lara E. Pereira; Aftab A. Ansari

Background: Enteric microencapsulation of the potential immunosuppressant TRAM-34 was investigated as a means of enhancing oral drug delivery and minimizing or eliminating hydrolysis of pyrazole-substituted triarylmethane to the respective alcohol. Method: TRAM-34 was successfully enteric microencapsulated by a coacervation method using the pH-sensitive Eudragit L 100 polymer. In this study, we utilized water‐miscible organic solvents such as acetone and ethanol, which are considered safe class 3 solvents according to the ICH guideline. We deemed such an approach suitable for safe scale up and for enteric coating application to other compounds of a similar lipophilicity. Results: The resulting microparticles were spherical and uniform with an average particle size of 460 μm at 15% theoretical loading. The encapsulation efficiency was 90 ± 1.9% and the percentage yield was found to be 91.5 ± 0.3%. The oral administration in rhesus macaques of TRAM-34-loaded enteric-coated microparticles illustrated six times enhancement in its oral bioavailability. However, the TRAM-34 plasma concentration was less than the therapeutic effective level. Conclusion: The low oral bioavailability, even after enteric coating, could be attributed to the compounds inherent absorption characteristics and high lipophilicity.


Hepatology Research | 2007

Autoimmunity and HIV/simian immunodeficiency virus infection: A two edged sword.

Aftab A. Ansari; Kovit Pattanapanyasat; Lara E. Pereira

The purpose of this review is to provide an overview of the spectrum of autoimmune responses that we have so far characterized in the simian immunodeficiency virus (SIV)‐infected disease susceptible rhesus macaques, the potential role of the lymphopenic state for the generation of the autoimmune response and the important new finding that such autoimmune response in fact can serve to provide both clinical benefit and clinical disease depending on the stage of the disease and the nature of the host proteins that are recognized during this process.

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Girija Raman

University of California

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Heike Wulff

University of California

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