Biology subjects

Permar, S.

Publications and source records attributed to Permar, S..

9 recordsLinked to original sources

bioRxiv2026

Designed nanofiber immunogens prime antibody responsesto diverse conformations of the HIV-1 fusion peptide

Focusing antibody responses towards known neutralizing epitopes is a major strategy for protective immunization. Targeting flexible antigenic regions represents a unique challenge because functional antibodies must be able to bind the epitope of interest in multiple conformations. The fusion peptide (FP) of HIV-1 is a flexible peptide critical to viral entry of host cells for which broadly neutralizing antibodies have been identified. Because elicitation of potent, functional antibodies toward this epitope remains an unmet challenge in HIV-1 vaccination, we introduce a designed immunogen platform capable of raising anti-FP-antibodies with increased conformational tolerance relative to a traditional carrier protein. Antibodies induced by these immunogens bind heterologous FP sequences when elicited in mice and infant non-human primates. This platform shows promise for preclinical development to prime antibody responses toward FP of the HIV-1 envelope and can likely be translated to peptide immunofocusing for other viral pathogens.

bioengineering↗

bioRxiv2024

Assessing the impact of autologous neutralizing antibodies on rebound dynamics in postnatally SHIV-infected ART-treated infant Rhesus macaques

AO_SCPLOWBSTRACTC_SCPLOWThe presence of antibodies against HIV in infected children is associated with a greater capacity to control viremia in the absence of therapy. While the benefits of early antiretroviral treatment (ART) in infants are well documented, early ART may interfere with the development of antibody responses. In contrast to adults, early treated children lack detectable HIV-specific antibodies, suggesting a fundamental difference in HIV pathogenesis. Despite this potential adverse effect, early ART may decrease the size of the latent reservoir established early in infection in infants, which can be beneficial in viral control. Understanding the virologic and immunologic aspects of pediatric HIV is crucial to inform innovative targeted strategies for treating children living with HIV. In this study, we investigate how ART initiation time sets the stage for trade-offs in the latent reservoir establishment and the development of humoral immunity and how these, in turn, affect post-treatment dynamics. We also elucidate the biological function of antibodies in pediatric HIV. We employ mathematical modeling coupled with experimental data from an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT four weeks after birth and started treatment at different times after infection. In addition to viral load measurements, antibody responses and latent reservoir sizes were measured. We estimate model parameters by fitting viral load measurements to the standard HIV viral dynamics model within a nonlinear fixed effects framework. This approach allows us to capture differences between rhesus macaques (RMs) that develop antibody responses or exhibit high latent reservoir sizes compared to those that do not. We find that neutralizing antibody responses are associated with increased viral clearance and decreased viral infectivity but decreased death rate of infected cells. In addition, the presence of detectable latent reservoir is associated with less robust immune responses. These results demonstrate that both immune response and latent reservoir dynamics are needed to understand post-rebound dynamics and point to the necessity of a comprehensive approach in tailoring personalized medical interventions.

immunology↗

bioRxiv2022

Mathematical Modeling of Rhesus Cytomegalovirus (RhCMV) Placental Transmission in Seronegative Rhesus Macaques

Approximately 1 in 200 infants is born with congenital cytomegalovirus (CMV), making it the most common congenital infection. About 1 in 5 congenitally-infected babies will suffer long-term sequelae, including sensorineural deafness, intellectual disability, and epilepsy. CMV infection is highly species-dependent, and the Rhesus CMV (RhCMV) infection of rhesus monkey fetuses is the only animal model that replicates essential features of congenital CMV infection in humans, including placental transmission, fetal disease, and fetal loss. To better understand the determinants and dynamics of congenital CMV transmission, we developed a mathematical model for placental transmission, comprising of maternal, placental, and fetal compartments using parameters from literature and experimental data from RhCMV seronegative rhesus macaques inoculated with RhCMV at 7.7-9.0 weeks of pregnancy. The model was then used to study the effect of the timing of inoculation, maternal immune suppression, and hyper-immune globulin infusion on the risk of placental transmission in the context of primary and reactivated chronic maternal CMV infection. Author summaryCongenital cytomegalovirus (CMV) is the most common congenital infection in humans. Congenial CMV affects 1 in 200 infants, and can result in sensorineural deafness, intellectual disability, epilepsy, and death. The Rhesus CMV (RhCMV) model is the only animal model that replicates essential features of congenital CMV infection and fetal sequelae in humans and provides a critical experimental system to develop mechanistic insight. We propose a novel mathematical model for CMV transmission that integrates viral dynamics in the maternal, placental, and fetal compartments. We calibrate the model using data from RhCMV transmission experiments and show that the model can recapitulate experimental observations of primary versus reactivated chronic CMV infection in pregnancy, primary infection at different stages in pregnancy, and infection in the presence of varying degrees of immune suppression and hyper-immune globulin infusion. Our in-silico model provides a means to rapidly explore mechanistic hypotheses for the physical, viral, and immune determinants of CMV transmission to complement and support expensive and difficult experiments on non-human primates.

immunology↗

bioRxiv2020

Different evolutionary pathways of HIV-1 between fetus and mother perinatal transmission pairs indicate unique immune selection pressure in fetuses

Study of evolution and selection pressure on HIV-1 in fetuses will lead to a better understanding of the role of immune responses in shaping virus evolution and vertical transmission. Detailed genetic analyses of HIV-1 env gene from 12 in utero transmission pairs show that most infections (67%) occur within two months from childbirth. In addition, env sequences from long-term infected fetuses were highly divergent and formed separate phylogenetic lineages from their cognate maternal viruses. Host selection sites unique to infant viruses were identified in regions frequently targeted by broadly neutralizing antibodies and T cell immune responses. The identification of unique selection sites in the env gene of fetal viruses indicates that the immune system in fetuses is capable of exerting selection pressure on viral evolution. Studying selection and evolution of HIV-1 or other viruses in fetuses can be an alternative approach to investigate adaptive immunity in fetuses.

microbiology↗

bioRxiv2019

HCMV glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-adjuvanted gB protein immunization

A vaccine to prevent maternal acquisition of human cytomegalovirus (HCMV) during pregnancy is a primary strategy to reduce the incidence of congenital disease. Similarly, vaccination of transplant recipients against HCMV has been proposed to prevent transplant-associated HCMV morbidity. The MF59-adjuvanted glycoprotein B protein subunit vaccine (gB/MF59) is the most efficacious tested to-date for both indications. We previously identified that gB/MF59 vaccination elicited poor neutralizing antibody responses and an immunodominant response against gB antigenic domain 3 (AD-3). Thus, we sought to test novel gB vaccines to improve functional antibody responses and reduce AD-3 immunodominance. Groups of juvenile New Zealand White rabbits were administered 3 sequential doses of full-length gB protein with an MF59-like squalene adjuvant (analogous to clinically-tested vaccine), gB ectodomain protein (lacking AD-3) with squalene adjuvant, or lipid nanoparticle (LNP)-packaged nucleoside-modified mRNA encoding full-length gB. The AD-3 immunodominant IgG response following human gB/MF59 vaccination was closely mimicked in rabbits, with 78% of binding antibodies directed against this region in the full-length gB protein group compared to 1% and 46% in the ectodomain and mRNA-LNP-vaccinated groups, respectively. All vaccines were highly immunogenic with similar kinetics and comparable peak gB-binding and functional antibody responses. Although gB ectodomain subunit vaccination reduced targeting of non-neutralizing epitope AD-3, it did not improve vaccine-elicited neutralizing or non-neutralizing antibody functions. gB nucleoside-modified mRNA-LNP-immunized rabbits exhibited enhanced durability of IgG binding to soluble and cell membrane-associated gB protein as well as HCMV-neutralizing function. Furthermore, the gB mRNA-LNP vaccine enhanced breadth of IgG binding responses against discrete gB peptide residues. Finally, low-magnitude gB-specific T cell activity was observed in the full-length gB protein and mRNA-LNP vaccine groups, though not in ectodomain-vaccinated rabbits. Altogether, these data suggest that the gB mRNA-LNP vaccine candidate, aiming to improve upon the partial efficacy of gB/MF59 vaccination, should be further evaluated in preclinical models.\n\nAuthor summaryHuman cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects, resulting in permanent neurologic disability for one newborn child every hour in the United States. Furthermore, this virus causes significant morbidity and mortality in immune-suppressed transplant recipients. After more than a half century of research and development, we remain without a clinically-licensed vaccine or therapeutic to reduce the burden of HCMV-associated disease. In this study, we sought to improve upon the glycoprotein B protein vaccine (gB/MF59), the most efficacious HCMV vaccine evaluated in clinical trial, via targeted modifications to either the protein structure or vaccine formulation. An attempt to alter the protein structure to focus the immune response on vulnerable epitopes ( gB ectodomain) had little effect on the quality or function of the vaccine-elicited antibodies. However, a novel vaccine platform, nucleoside-modified mRNA formulated in lipid nanoparticles, increased the durability and breadth of vaccine-elicited immune responses. We propose that an mRNA-based gB vaccine may ultimately prove more efficacious than the gB/MF59 vaccine and should be further evaluated for its ability to elicit antiviral immune factors that can prevent both infant and transplant-associated disease caused by HCMV infection.

immunology↗

bioRxiv2019

Pharyngeal motor cortex grey matter abnormalities and retinal photoreceptor layer dysfunction in macaques exposed to Zika virus in utero

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.

microbiology↗

bioRxiv2019

Maternal antibodies provide partial protection from postnatal Zika viremia in nonhuman primates

Zika virus (ZIKV) will remain a public health threat until effective vaccines and therapeutics are made available in the hardest hit areas of the world. Recent data in a nonhuman primate model showed that infants postnatally infected with ZIKV were acutely susceptible to high viremia and neurological damage, suggesting the window of vulnerability extends beyond gestation. We addressed the susceptibility of two infant rhesus macaques born healthy to dams infected with Zika virus during pregnancy. Passively acquired neutralizing antibody titers dropped below detection limits between 2 and 3 months of age, while binding, possibly non-neutralizing antibodies remained detectable until viral infection at 5 months of age. Post-infection acute serum viremia was substantially reduced relative to adults infected with the same dose of the same stock of a Brazilian isolate of ZIKV (n=11 pregnant females) and another stock of the same isolate (n=4 males and 4 non-pregnant females). Virus was never detected in cerebrospinal fluid nor in neural tissues at necropsy two weeks after infection, suggesting reduced viral burden relative to adults and published data from infants. However, viral RNA was detected in lymph nodes, confirming some tissue dissemination. Though protection was not absolute, our data suggest infants born healthy to infected mothers may harbor a modest but important level of protection from postnatally acquired ZIKV for several months after birth, an encouraging result given the potentially severe infection outcomes of this population.

microbiology↗

bioRxiv2019

Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques.

Zika virus (ZIKV) and dengue virus (DENV) are genetically and antigenically related flaviviruses that now co-circulate in much of the tropical and subtropical world. The rapid emergence of ZIKV in the Americas in 2015 and 2016, and its recent associations with Guillain-Barre syndrome, birth defects, and fetal loss have led to the hypothesis that DENV infection induces cross-reactive antibodies that influence the severity of secondary ZIKV infections. It has also been proposed that pre-existing ZIKV immunity could affect DENV pathogenesis. We examined outcomes of secondary ZIKV infections in three rhesus and fifteen cynomolgus macaques, as well as secondary DENV-2 infections in three additional rhesus macaques up to a year post-primary ZIKV infection. Although cross-binding antibodies were detected prior to secondary infection for all animals and cross-neutralizing antibodies were detected for some animals, previous DENV or ZIKV infection had no apparent effect on the clinical course of heterotypic secondary infections in these animals. All animals had asymptomatic infections and, when compared to controls, did not have significantly perturbed hematological parameters. Rhesus macaques infected with DENV-2 approximately one year after primary ZIKV infection had higher vRNA loads in plasma when compared with serum vRNA loads from ZIKV-naive animals infected with DENV-2, but a differential effect of sample type could not be ruled out. In cynomolgus macaques, the serotype of primary DENV infection did not affect the outcome of secondary ZIKV infection.\n\nAuthor summaryPre-existing immunity to one of the four DENV serotypes is known to increase the risk of severe disease upon secondary infection with a different serotype. Due to the antigenic similarities between ZIKV and DENV, it has been proposed that these viruses could interact in a similar fashion. Data from in vitro experiments and murine models suggests that pre-existing immunity to one virus could either enhance or protect against infection with the other. These somewhat contradictory findings highlight the need for immune competent animal models for understanding the role of cross-reactive antibodies in flavivirus pathogenesis. We examined secondary ZIKV or DENV infections in rhesus and cynomolgus macaques that had previously been infected with the other virus. We assessed the outcomes of secondary ZIKV or DENV infections by quantifying vRNA loads, clinical and laboratory parameters, body temperature, and weight for each cohort of animals and compared them with control animals. These comparisons demonstrated that within a year of primary infection, secondary infections with either ZIKV or DENV were similar to primary infections and were not associated with enhancement or reduction in severity of disease based on the outcomes that we assessed.

pathology↗

bioRxiv2018

IgG is differentially and selectively transferred across the placenta in HIV-infected women

SUMMARY\n\nThe transplacental transfer of maternal IgG to the developing fetus is critical for infant protection against infectious pathogens in the first year of life. However, factors that modulate the transplacental transfer efficiency of maternal IgG that could be harnessed for maternal vaccine design remain largely undefined. HIV-infected women have impaired placental IgG transfer, yet the mechanism underlying this impaired transfer is unknown, presenting an opportunity to explore factors that contribute to the efficiency of placental IgG transfer. We measured the transplacental transfer efficiency of maternal HIV and other pathogen-specific IgG in historical U.S. (n=120) and Malawian (n=47) cohorts of HIV-infected mothers and their HIV- exposed uninfected and HIV-infected infants. We then examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, and IgG Fc region subclass and glycan signatures and their association with transplacental transfer efficiency of maternal antigen-specific IgG. We established 3 distinct phenotypes of placental IgG transfer efficiency in HIV-infected women, including: 1) efficient transfer of the majority of antigen-specific IgG populations; 2) generally poor IgG transfer phenotype that was strongly associated with maternal CD4+ T cell counts, hypergammaglobulinemia, and frequently yielded non-protective levels of vaccine-specific IgG; and 3) variable transfer of IgG across distinct antigen specificities. Interestingly, maternal IgG characteristics, such as binding to placentally expressed Fc receptors Fc{gamma}RIIa and Fc{gamma}RIIIa, IgG subclass frequency, and Fc region glycan profiles were associated with placental IgG transfer efficiency. These maternal IgG transplacental transfer determinants were distinct among different antigen-specific IgG populations. Our findings suggest that in HIV-infected women, both maternal disease progression and Fc region characteristics modulate the selective placental transfer of distinct IgG subpopulations, with implications for both the health of HIV-exposed uninfected infants and maternal vaccine design.\n\nHighlightsO_LILow peripheral blood CD4 + T cell count and hypergammaglobulinemia are associated with inefficient transplacental IgG transfer in HIV-infected women\nC_LIO_LIAntigen-specific IgG binding strength to placentally-expressed Fc receptors, but not placental Fc receptor expression levels, mediates selective placental IgG transfer\nC_LIO_LIAntigen-specific IgG Fc region glycan profiles also contribute to the selective placental IgG transfer of maternal IgG populations in HIV-infected women\nC_LI

microbiology↗