Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission.

Abstract

Despite the wide availability of antiretroviral drugs, more than 250,000 infants are vertically infected with HIV-1 annually, emphasizing the need for additional interventions to eliminate pediatric HIV-1 infections. Here, we aimed to define humoral immune correlates of risk of mother-to-child transmission (MTCT) of HIV-1, including responses associated with protection in the RV144 vaccine trial. Eighty-three untreated, HIV-1-transmitting mothers and 165 propensity score-matched nontransmitting mothers were selected from the Women and Infants Transmission Study (WITS) of US nonbreastfeeding, HIV-1-infected mothers. In a multivariable logistic regression model, the magnitude of the maternal IgG responses specific for the third variable loop (V3) of the HIV-1 envelope was predictive of a reduced risk of MTCT. Neutralizing Ab responses against easy-to-neutralize (tier 1) HIV-1 strains also predicted a reduced risk of peripartum transmission in secondary analyses. Moreover, recombinant maternal V3-specific IgG mAbs mediated neutralization of autologous HIV-1 isolates. Thus, common V3-specific Ab responses in maternal plasma predicted a reduced risk of MTCT and mediated autologous virus neutralization, suggesting that boosting these maternal Ab responses may further reduce HIV-1 MTCT.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1172/JCI81593

Publication Info

Permar, Sallie R, Youyi Fong, Nathan Vandergrift, Genevieve G Fouda, Peter Gilbert, Robert Parks, Frederick H Jaeger, Justin Pollara, et al. (2015). Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission. J Clin Invest, 125(7). pp. 2702–2706. 10.1172/JCI81593 Retrieved from https://hdl.handle.net/10161/12060.

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Scholars@Duke

Permar

Sallie Robey Permar

Adjunct Professor in the Department of Pathology

Dr. Permar's work focuses on the development of vaccines to prevent vertical transmission of neonatal viral pathogens. She has utilized the nonhuman primate model of HIV/AIDS to characterize the virus-specific immune responses and virus evolution in breast milk and develop a maternal vaccine regimen for protection against breast milk transmission of HIV. In addition, Dr. Permar's lab has advanced the understanding of HIV-specific immune responses and virus evolution in vertically-transmitting and nontransmitting HIV-infected women, defining maternal immune responses that may protect against neonatal transmission of HIV. Importantly, Dr. Permar has established a nonhuman primate model of congenital CMV infection adn is using this model to establish the maternal immune responses that are necessary for protection against placental virus transmission. Finally, Dr. Permar is studying the impact and prevention of postnatal CMV transmission in preterm infants.

Pollara

Justin Joseph Pollara

Associate Professor in Surgery

Dr. Justin Pollara is a member of the Duke Human Vaccine Institute and the Duke Center for Human Systems Immunology, and is Associate Director of the Duke Center for AIDS Research (CFAR) Developmental Core. He received his PhD from North Carolina State University and completed his postdoctoral training as a recipient of the Duke NIH Interdisciplinary Research Training Program in AIDS (IRTPA) T32 award in the laboratory of Dr. Guido Ferrari. He joined the faculty of the Duke Department of Surgery in 2016.

A common theme of research performed in Dr. Pollara’s laboratory is a focus on interactions between innate and adaptive immunity. Dr. Pollara’s work has contributed significantly to the understanding of the roles played by non-neutralizing antibodies in limiting HIV-1 disease progression, and in prevention of infection or control of virus replication in preclinical and clinical HIV-1 vaccine trials. Dr. Pollara’s research has also identified specific components of the immune response that reduce the risk of vertical transmission of both HIV-1 and human cytomegalovirus. The Pollara lab characterizes the phenotype and functionality of antibody-interacting innate immune cells and explores how natural genetic variation in antibodies and antibody receptors may contribute to vaccine responsiveness and immune competence. Further, with a strong interdisciplinary and collaborative approach, the Pollara Lab has broadened its scope beyond infectious diseases and is now actively leading studies aimed at understanding how inflammation, antibodies, innate immune cells, and newly described populations of T cells promote allograft injury that underlies rejection of transplanted organs.

Sarzotti-Kelsoe

Marcella Sarzotti-Kelsoe

Research Professor of Integrative Immunobiology

Ongoing Applied Activities 
•I direct a Global Quality Assurance Program, which I developed and pioneered here at Duke University, to oversee compliance with Good Clinical Laboratory Practice Guidelines in three HIV vaccine trial networks (CHAVI, CAVD, Duke HVTN, EQAPOL, Duke VTEU) involving domestic and international laboratory sites.
•I also direct a Global Proficiency Testing Program for laboratories testing for neutralizing antibody function in individuals infected with HIV or vaccinated against HIV. The Program was launched in 2009.
•I provide assistance and oversight for endpoint assay standardization, qualification and validation, as well as for the QSU of the GMP facility at DHVI, which will manufacture HIV vaccine products for first-in-man Phase I trials.

Past Basic Research
•Development of T cell responses in neonates.
•Neonatal T cell receptor Vβ repertoire diversity in the peripheral T cell pool.
•The role of heat shock protein, as a natural adjuvant, at eliciting innate and adaptive immune responses.
•Development of the T cell receptor repertoire in naïve, immunodeficient infants, given bone marrow or thymic transplantation.
•Thymic output, T cell diversity and T cell function in long-term human SCID chimeras.
•Telomere length in T cells from SCID chimeras.


Ferrari

Guido Ferrari

Professor in Surgery

The activities of the Ferrari Laboratory are based on both independent basic research and immune monitoring studies. The research revolves around three main areas of interest: class I-mediated cytotoxic CD8+ T cell responses, antibody-dependent cellular cytotoxicity (ADCC), gene expression in NK and T cellular subsets upon infection with HIV-1. With continuous funding over the last 11 years from the NIH and Bill & Melinda Gates Foundation along with many other productive collaborations within and outside of Duke, the Ferrari Lab has expanded its focus of research to include the ontogeny of HIV-1 specific immune responses that work by eliminating HIV-1 infected cells and how these can be induced by AIDS vaccine candidates.

Alam

S. Munir Alam

Professor in Medicine

Research Interests. 

The Alam laboratory’s primary research is focused on understanding the biophysical properties of antigen-antibody binding and the molecular events of early B cell activation using the HIV-1 broadly neutralizing antibody (bnAb) lineage models. We are studying how HIV-1 Envelope proteins of varying affinities are sensed by B cells expressing HIV-1 bnAbs or their germline antigen receptors and initiate early signaling events for their activation. In the long-term these studies will facilitate design and pre-selection of immunogens for testing in animal models and accelerate HIV-1 vaccine development.
Current research include the following NIAID-funded projects   

Antigen recognition and activation of B cell antigen receptors with the specificity of HIV-1 broadly neutralizing antibodies. This project involves elucidating the early events on the B cell surface following antigen (Ag) engagement of the B cell antigen receptor (BCR) and to provide an assessment of the in vivo potential of an Ag to drive B cell activation. We are performing biophysical interactions analyses and using high-resolution microscopy to define the physico-chemical properties of BCR-Ag interactions that govern signaling and activation thresholds for BCR triggering and the BCR endocytic function in antigen internalization. The overall objective of these studies is to bridge the quantitative biophysical and membrane dynamics measurements of Ag-BCR interactions to ex-vivo and in-vivo B cell activation. This NIAID-funded research is a collaboration with co-investigators Professor Michael Reth (University of Freiburg, Germany) and Dr. Laurent Verkoczy (San Diego Biomedical Research Institute, CA).  

Immunogen Design for Induction of HIV gp41 Broadly Neutralizing Antibodies. This research project addresses the critical problem of vaccine induction of disfavored HIV-1 antibody lineages, like those that target the membrane proximal external region (MPER) of HIV Env gp41. This program combines structure and lineage-based vaccine development strategies to design immunogens that will induce bnAb lineages that are not polyreactive and therefore easier to induce. The overall objective of this program grant is to develop and test sequential immunogens that will initiate and induce HIV-1 bnAb lineages like the potent MPER bnAb DH511. Using a germline-targeting (GT) epitope scaffold design and a prime/boost strategy, we are testing induction of DH511-like bnAbs in knock-in (KI) mice models expressing the DH511 germline receptors. This P01 research program is in collaboration with Dr. William Schief (The Scripps Research Institute, CA), who leads the team that are designing germline targeting (GT)-scaffold prime and boost immunogens and Dr. Ming Tian at Harvard University who developed relevant knock-mice models for the study.
Montefiori

David Charles Montefiori

Professor in Surgery

Dr. Montefiori is Professor and Director of the Laboratory for HIV and COVID-19 Vaccine Research & Development in the Department of Surgery, Division of Surgical Sciences at Duke University Medical Center. His major research interests are viral immunology and HIV and COVID-19 vaccine development, with a special emphasis on neutralizing antibodies.

Multiple aspects of HIV-1 neutralizing antibodies are studied in his laboratory, including mechanisms of neutralization and escape, epitope diversity among the different genetic subtypes and geographic distributions of the virus, neutralizing epitopes, requirements to elicit protective neutralizing antibodies by vaccination, optimal combinations of neutralizing antibodies for immunoprophylaxis, and novel vaccine designs for HIV-1. Dr. Montefiori also directs large vaccine immune monitoring programs funded by the NIH and the Bill & Melinda Gates Foundation that operate in compliance with Good Clinical Laboratory Practices and has served as a national and international resource for standardized assessments of neutralizing antibody responses in preclinical and clinical trials of candidate HIV vaccines since 1988.

At the onset of the COVID-19 pandemic he turned his attention to SARS-CoV-2, with a special interest in emerging variants and how they might impact transmission, vaccines and immunotherapeutics. His rapid response to emerging SARS-CoV-2 variants of concern provided some of the earliest evidence of the potential risk the variants pose to vaccines. In May 2020, his laboratory was recruited by the US Government to lead the national neutralizing antibody laboratory program for COVID-19 vaccines.

His laboratory utilizes FDA approved validated assay criteria to facilitate regulatory approvals of COVID-19 vaccines. He has published over 750 original research papers that have helped shape the scientific rationale for antibody-based vaccines.

Moody

Michael Anthony Moody

Professor of Pediatrics

Tony Moody, MD is a Professor in the Department of Pediatrics, Division of Infectious Diseases and Professor in the Department of Integrative Immunobiology at Duke University Medical Center. Research in the Moody lab is focused on understanding the B cell responses during infection, vaccination, and disease. The lab has become a resource for human phenotyping, flow characterization, staining and analysis at the Duke Human Vaccine Institute (DHVI). The Moody lab is currently funded to study influenza, syphilis, HIV-1, and emerging infectious diseases.

Dr. Moody is the director of the Duke CIVICs Vaccine Center (DCVC) at (DHVI) and co-director of the Centers for Research of Emerging Infectious Disease Coordinating Center (CREID-CC). Dr. Moody is mPI of a U01 program to develop a syphilis vaccine; this program is a collaboration with mPI Dr. Justin Radolf at the University of Connecticut. Dr. Moody is also the director of the DHVI Accessioning Unit, a biorepository that provides support for work occurring at DHVI and with its many collaborators around the world by providing processing, shipping, and inventory support for a wide array of projects.

Dr. Moody and his team are involved in many networks studying vaccine response including the Collaborative Influenza Vaccine Innovation Centers (CIVICs) and the COVID-19 Prevention Network (CoVPN).

Gao

Feng Gao

Professor Emeritus in Medicine

Dr. Feng Gao is Professor of Medicine at Duke University. The Gao laboratory has a long-standing interest in elucidating the origins and evolution of human and simian inmmunodeficiency viruses (HIV and SIV), and in studying HIV/SIV gene function and pathogenic mechanisms from the evolutionary perspective. These studies have led to new strategies to better understand HIV origins,  biology, pathogenesis and drug resistance, and to design new AIDS vaccines.


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