Dr. Alon Herschhorn is an Assistant Professor of Medicine in the Division of Infectious Diseases and International Medicine at the University of Minnesota. He has previously held a faculty position and conducted research at the Dana-Farber Cancer Institute and Harvard Medical School, and is the recipient of a Rothschild Fellowship and an amfAR Mathilde Krim Fellowship in Basic Biomedical Research. Dr. Herschhorn has now won a 2019 Avenir Award for HIV/AIDS Research for a project investigating the pathways used by HIV to escape broadly neutralizing antibodies. He is also building a platform to bioengineer a vaccine able to more precisely target the HIV envelope proteins (Env) for elicitation of broadly neutralizing antibodies. Dr. Herschhorn hopes that his in vitro and in vivo studies will lead the way to new therapeutic and preventive strategies against HIV.
amfAR: How did you become interested in HIV research?
Dr. Herschhorn: When I started my undergraduate studies, I was looking for a challenging research direction that would be both important and have an impact on human health. At that time, there were only a few FDA-approved drugs for antiretroviral therapy, and HIV quasispecies—“swarms” of mutated viruses—in patients were rapidly developing resistance to these drugs. The HIV pandemic was spreading at an alarming rate and there were emerging efforts to prevent transmission.
These were difficult times and I thought that understanding the complex biological processes involved in the HIV life cycle would provide insights and tools for developing new strategies for interventions. I started working on two HIV enzymes: reverse transcriptase and integrase, which are main targets of antiretroviral drugs. Then, during my postdoctoral studies, I focused on the molecular mechanisms of Env function, which is key to the development of an effective HIV vaccine.
I would like to add that I was lucky to be able to do what I love through my career and encourage researchers starting their scientific journeys to trust their hearts to do what they really love. Everything else will follow.
amfAR: It is often difficult for early career scientists to find funding. How did our Mathilde Krim Fellowship help to advance your research career?
Dr. Herschhorn: I will always be grateful to the Mathilde Krim Fellowship for advancing my research career. The prestigious fellowship was not only an acknowledgment of my past scientific achievements and vision for the future, but it was the first time that I learned how to responsibly manage a budget for a scientific project, how to interact with a program administrator, and how to apply for NIH funding after participating in a workshop on the NIH grant mechanisms.
The second phase of the Krim Fellowship was critical. At that time, funding in our laboratory was rapidly decreasing and my visa status depended on a sponsor. Without the support of amfAR funds, I probably would have had to leave the U.S. and start over. Luckily, the second phase of funding provided me extra time and support to continue my studies and I laid new groundwork for understanding HIV Env function and inhibition. These concepts opened new opportunities for research and were the basis of my successful application for the Avenir Award (NIH Director's New Innovator Award mechanism) from the National Institute on Drug Abuse. I would like to personally thank Jonathan Miller and Dr. Marcella Flores for their help during the grant period.
amfAR: Can you summarize your work since completing the Mathilde Krim Fellowship?
Dr. Herschhorn: The Krim Fellowship provided me with the time and support to establish a new platform for dissecting HIV Env function. After completing the fellowship, I used these tools to study the molecular mechanisms of HIV entry into the cell. In collaboration with the groups of Dr. Walther Mothes of the Yale School of Medicine and Dr. Peter Kwong of the NIH, we identified a switch that regulates changes in the structure of HIV Env during cell entry. We showed that the regulatory switch controls opening of HIV Env from a closed to a more open conformation during the interactions with the CD4 cellular receptor.
I have also developed a new system to monitor HIV latency and replication at single cell and population levels. The system, which is based on concepts published by the group of Dr. Eric Verdin of the University of California, San Francisco, was distributed to more than ten laboratories around the world and is now being used as part of scientific collaborations to understand the alternative outcomes (viral latency or active replication) of HIV infection in target cells.
Since my appointment as Assistant Professor at the University of Minnesota, I have been applying the knowledge and tools that I developed during and after the Krim Fellowship to bioengineer new Env-based immunogens for HIV vaccine development, to delineate the pathways used by HIV to escape broadly neutralizing antibodies—specialized antibodies able to inactivate diverse types of HIV—and to elucidate the network of HIV-host interactions during HIV infection.
amfAR: What are your hopes for the HIV research field in the next five years?
Dr. Herschhorn: There are several exciting research directions that may lead to insights into the interactions of HIV with the immune system and HIV pathogenesis.
Multiple clinical trials are now testing the effect of administration of broadly neutralizing antibodies to people who live with HIV. Evidence from a minority of patients suggests that, in a few cases, HIV may be suppressed for a long period of time. I hope that in the next five years we will understand why these antibodies have long-lasting effects in some patients, how long HIV can be suppressed, and the limitations of the ability of HIV to develop resistance in vivo.
Several vaccine trials have begun. One design will test the ability of a germline-targeting immunogen to elicit broadly neutralizing antibodies specific to the CD4 binding site of HIV Env. I hope that the results of this trial will guide new strategies to elicit broadly neutralizing antibodies in humans.
We need a method for robust measurement of the latent, replication competent reservoir (of HIV with all the components needed to assemble virions) in infected individuals. I hope that advances in next generation technologies will lead to a simple assay capable of measuring the size of the replication competent HIV reservoir in patients.
As a final comment, I would like to say that I am grateful to many people that helped me along the way: Drs. Ashley Haase, Timothy Schacker, and Reuben Harris, who provided endless support since my arrival to the University of Minnesota; Dr. Joseph Sodroski, my postdoctoral mentor at Harvard Medical School and Dana-Farber Cancer Institute; Dr. Alan Engelman, who offered me a short-term position when I most needed one, Dr. Walther Mothes for the continuous support, and Dr. Amnon Hizi, my adviser during my graduate studies.