December 2022
How long have you been doing research?
Mavigner: I have been doing biomedical research for over 16 years. I first started as a graduate student in September 2006 in Toulouse, France. After obtaining a PhD in Immunology and Infectious Diseases, I moved in the US in 2011 for a postdoctoral fellowship in Dr. Guido Silvestri’s lab at the Emory National Primate Research Center, then in Dr. Ann Chahroudi’s lab in the Department of Pediatrics followed by an appointment as Instructor and then promotion to Assistant Professor in 2019.
Oliver: My research career began in 2007 as an undergraduate student at Auburn University. While completing a B.S. in Zoology, I worked in various laboratories studying freshwater invertebrate biodiversity, mammalian bone mineral mobilization, and cystic fibrosis (CF)-adapted microbial pathogens. I continued the latter project as an M.S. thesis in Microbiology at Auburn, then moved to the University of Alabama at Birmingham where I completed a Ph.D. in Genetics. My work utilized high-throughput yeast phenomics to identify genetic modifiers of aberrant ABC-C protein biogenesis, and elucidated for the first time effects of ribosomal perturbation on synthesis, trafficking, and function of the CF transmembrane conductance regulator (CFTR). Afterward, I transitioned to a postdoctoral fellowship at Emory, where I focused on evaluating global and CFTR-specific translation kinetics (in vitro and in vivo) following suppression of specific ribosomal components.
What inspired you to get into research? What inspired you to do this particular research?
Mavigner: In my memory there were two major events that triggered my interest for biomedical research. The first one was the HIV epidemic. At a young age, I remember seeing on TV news showing emaciated men dying in hospital beds. I don’t think I fully understood at the time what was going on. While starting to learn biology in middle school, I remember that the scariest thing happening at the time was this virus spreading and killing people with no cure and no great treatment. The second event was seeing on the news a report from a biosafety level 4 laboratory in Europe. I do not recall why this was on TV (maybe an Ebola outbreak?) but it seemed to me that people in this lab wearing suits resembling astronauts were doing critical work. The lab director being interviewed was a woman, and I remember that I very much wanted to become that woman when I grew up.
Oliver: I have always been intrigued by the natural world. Even as an adolescent, I vexed parents, friends, and teachers with seeking a rational explanation for every observation. Enthusiasm for human physiology and genomic science grew, in particular, during my undergraduate and graduate studies through didactic coursework and laboratory training. I pursued research opportunities with a number of different investigators, in order to study a wide variety of scientific inquiries. Shortly after completing my M.S., however, I gave birth to my daughter and learned that she has a rare form of CF. Based on my growing interest in the condition for both personal and professional reasons, I decided to build a career in biomedical research with a distinct emphasis on better understanding cystic fibrosis pathogenesis.
Both my scientific training and experience as parent to a CF child inspires my enthusiasm for this area of research. My daughter encodes an ultra-rare CFTR variant, that to date, has only been reported in seven individuals worldwide. At the time of initial discovery, clinical significance of the mutation was unknown. Recent theratyping investigations have confirmed this variant is disease-causing, as well as hyper-responsive to currently available pharmacologic correctors of CFTR. Conversely, individuals encoding PTCs are largely insensitive to clinically approved CFTR modulators, and these patients often exhibit a severe disease phenotype. My long-term ambition is to discover new therapeutic strategies for this CF population, so that like my child, they may benefit from interventions designed to rescue their CFTR defects.
Tell me about your research
Mavigner: I have always been fascinated by HIV and this is the research topic I chose for my PhD and the problem I have been tackling ever since. People living with HIV who have access to treatment with antiretroviral drugs (ART) present plasma viral loads that are undetectable by standard clinical tests. ART prevents disease progression and HIV transmission, but ART interruption results in viral rebound. It is well known that this rebound in viral load is due to the persistence of latent HIV in a cellular reservoir largely represented by memory CD4+ T cells. My research aims to characterize this viral reservoir by better defining where and how HIV persists in adult and pediatric HIV infection. In my lab, we are also developing and testing new curative approaches using nonhuman primate models of HIV infection. More specifically, currently we are targeting one mechanism of HIV persistence - proliferation of the memory CD4+ T cells - through pharmaceutical modulation of “stemness” signaling pathways such as Wnt or Notch pathways.
Oliver: My present research program employs interdisciplinary approaches in functional genomics, biochemistry, and cellular physiology to delineate genetic factors that influence severity of rare CFTR variants. Attention is placed on premature termination codons (PTCs) in CFTR, which not only interrupt protein synthesis, but also decrease mRNA expression. With support from the NIH (K99/R00) and CF Foundation (NIH K-Boost Award), we recently performed genome-wide yeast phenomic screens and revealed novel contributors to CFTR PTC biogenesis. Emerging targets include factors involved in mRNA decay, translation initiation, and tRNA processing, as well as constituents of the proteasome, peroxisome, and ribosome. In multiple mammalian airway models tested, results indicate siRNA-mediated depletion of two specific ribosomal components markedly improves functional expression of CFTR PTCs. Based on these findings, an immediate objective of my research is to elucidate mechanism(s) by which suppression of ribosomal proteins influences CFTR PTC processing in vitro and in vivo. An overarching hypothesis is that ribosomal silencing alters mRNA utilization, translation velocity, and/or ribosome fidelity to promote synthesis and functional assembly of otherwise defective CFTR.
What are your goals for this research?
Mavigner: The ultimate goal of my research is to contribute to the development of a HIV cure available to all people, ideally reaching viral eradication, but at least achieving sustained viral remission in the absence of ART. Regarding my ongoing projects, our goals are to demonstrate that modulation of “stemness” pathways can be safely performed in vivo and represents a new approach that can alter HIV persistence over time by inhibiting the proliferation of the latently infected cells and/or by facilitating latency reversal.
Oliver: My near-term goals are to: (1) furnish novel quantitative information with regard to translational coupling, as well as mechanisms by which modulating ribosome fidelity – or other aspects of protein synthesis – impact CF pathophysiology, and (2) uncover new ways in which we can counteract molecular effect(s) of CFTR PTCs. Regarding therapeutics development, I recently established a collaboration with Ionis Pharmaceuticals to design antisense oligonucleotides directed against a ribosomal protein of interest – i.e. studies that are currently undergoing pre-clinical validation with funding from the Atlanta Pediatric Research Alliance.
What’s the research process like?
Mavigner: The process might seem slow with many steps from the formulation of a hypothesis and obtaining funding to support to the data collection and analysis, and ultimately sharing these results through oral presentations and publications. In the case of nonhuman primate studies of HIV persistence, the in vivo work itself can often take close to 2 years. However, within the lab we work at a fast pace. I don’t think it is possible to get bored in a biomedical research lab. The research process also involves a lot of collaborative work. In recent years we have seen a lot more of large multidisciplinary collaboratories for HIV cure research.
Oliver: Conducting patient-centered, basic/translational scientific research is a high-intensity and reiterative process that requires multidisciplinary, team-based approaches. Mechanistic and therapeutic hypotheses are systematically interrogated using mutually reinforcing experimental systems, such as yeast, mice, and human-derived cell models employed by my laboratory and colleagues. Our studies incorporate sophisticated techniques required for quantification of changes to CFTR maturation and activity (western blot, pulse-chase, electrophysiology), together with global and transcript-specific alterations in the translatome (qRT-PCR, sucrose gradient fractionation, Ribo-Seq). This type of work is equally challenging and rewarding. Motivations are easily maintained, however, as we are uniformly guided by the desire to improve quality and quantity of life for individuals living with CF. Knowing that our work contributes to this enterprise – even if it equates to laying a single brick on a long stretch of road – is well worth the effort.
Why is this research important to you?
Mavigner: I want to see the day that we can achieve a cure for HIV - importantly, for all children and adults living with HIV, of course, but also for the rest of the population not to have to live in fear of an incurable infection that requires lifelong treatment. Eliminating the stigma and discrimination associated with HIV that particularly affect women and gay men is also a strong motivation for me to pursue HIV cure research.
Oliver: Rare CFTR variants are prevalent among Black, Indigenous, and People of Color (BIPOC) with CF, who represent a significantly underserved patient community. This includes my daughter, who possesses genomic admixture with African and Latin ancestry. My scientific objectives are focused on advancing basic understanding of CFTR biogenesis and providing new ideas relevant to CF clinical intervention, giving particular attention to BIPOC populations with the disease. I also intend to utilize my findings as a model for similar investigations of additional proteins and genetic conditions in the future.