Angela Wahl, Ph.D.Angela Wahl, Ph.D., recently completed an amfAR Mathilde Krim Fellowship, which funded her study that found that breast milk of HIV-positive mothers has potent HIV-inhibitory activity and that it can prevent multiple routes of infection. She did her research as a postdoctoral associate at the University of North Carolina (UNC) at Chapel Hill, under the mentorship of J. Victor Garcia, Ph.D. Dr. Wahl has published 22 journal articles, including three that resulted from her Krim Fellowship.
Now a Research Assistant Professor in UNC’s Department of Medicine, Dr. Wahl was recently awarded a Research Project Grant (R01) from the National Institutes of Health (NIH) to study how human gut microbiota affects rectal acquisition and development of HIV. The coveted R01 grant establishes a scientist’s independence, as it provides significant research dollars and allows the principal investigator to hire junior scientists as research staff. It is very unusual for a researcher just completing a postdoctoral program to receive the R01. amfAR spoke to Dr. Wahl about her planned research and the role of her Krim Fellowship in advancing her career.
amfAR: Your R01 project will focus on a different route of HIV acquisition from the area you studied during your Krim Fellowship. Why did you want to investigate how the human gut microbiota affects rectal acquisition of HIV? (The gut microbiota is the community of microorganisms that live in our intestines.)
Dr. Wahl: The microbiota stimulates gut immunity and protects the gut from infection. However, gut microbiota may also help transmit certain viruses that target the gut as well as increase the ability of those viruses to cause disease. It’s well known that the composition of the gut microbiome is altered in HIV-infected patients, because the gut is a major site of HIV replication and CD4 T-cell depletion. However, the role of the gut microbiota in HIV acquisition, replication and disease development is unknown.
In the future we’d also like to study the oral microbiome with our new model. The oral cavity and the gut are potential sites of HIV transmission in infants who acquire HIV through breastfeeding, which was the focus of the work I did under my Krim fellowship.
amfAR: What preliminary data did you generate to submit to the NIH in your R01 application?
Because the Krim fellowship is viewed in the HIV field as a highly selective and prestigious award, I was specifically advised by the NIH program officer to highlight that I was a recipient of a Krim award.
Dr. Wahl: In my R01 application, I proposed to use a new humanized mouse model that we developed to study the microbiota’s role in HIV infection. Humanized mice are mice that have been given a human immune system possessing all of the human immune cells that are targeted by HIV. Humanized mice can be infected with HIV by the same routes that humans are infected. Although humanized mice have been extensively used to study HIV infection, the microbiota in their gut is very different from humans. Therefore, we created germ-free humanized mice that can be colonized with the gut microbiota of different human donors. We first had to validate the model for our proposed study. We demonstrated that the composition of the gut microbiome in our model reflected the composition of the human donor sample that we used to colonize the gut and that it was maintained over time. We also showed the presence of human HIV target cells in their gut. In addition, we demonstrated that the model is susceptible to rectal HIV acquisition. Then we also showed that the presence of human gut microbiota increases the susceptibility of mice to rectal HIV transmission, in comparison to our humanized mice colonized with mouse gut microbiota.
amfAR: What was innovative about your application?
Dr. Wahl: Our model will allow us to selectively colonize, manipulate, and analyze the gut microbiome prior to HIV exposure. This isn’t possible to do in humans or any other model system that doesn’t begin with germ-free animals, as ours does. Our humanized mouse model will allow us to evaluate, for the first time, how the composition of the gut microbiome prior to HIV exposure, and the microbial diversity that’s observed between humans, affects HIV acquisition, replication, and disease development. In addition, since we know the exact timing of HIV exposure, we’ll be able to closely monitor the composition of the microbiome after HIV infection.
amfAR: What clues could your research findings give about HIV transmission?
Dr. Wahl: We think the results will show whether the composition of an individual’s microbiome and the diversity between humans could affect the risk of rectal HIV acquisition, as well as the course of infection. The findings could also have significant implications for the design and evaluation of future clinical prevention and therapeutic interventions.
amfAR: So, the differences in people’s gut microbiota can affect whether or not they acquire HIV?
Dr. Wahl: It’s possible. It’s well known that the composition of the gut microbiome affects gut immunity. So it’s possible that it could affect the frequency of HIV target cells in the gut, or activation of the target cells, making them more susceptible to HIV infection.
amfAR: Are there environmental factors that can affect an individual human’s microbiome, such as diet, and could those factors have any effect on whether or not someone is more susceptible to HIV?
Dr. Wahl: Yes. The composition of someone’s microbiome heavily relies on diet, as well as antibiotic use, disease, and stress. There are a lot of factors that influence the composition of the microbiome.
amfAR: You will be performing your study in mice. How can we translate the findings to humans?
I feel there is a concerted effort across the US and globally to find a cure for HIV. There is a lot of hope and excitement in the field. It’s really nice to see the camaraderie.
Dr. Wahl: Because our model possesses both human target cells for HIV and human gut microbiota, I think we’ll be able to translate our findings to humans. If we do identify categories of microbes that are associated with an increased or decreased risk of rectal HIV transmission, our next step will be to determine how they promote or inhibit HIV transmission; and then we’d also like to confirm our observations in humans.
amfAR: What role did the Krim Fellowship play in your securing an independent position?
Dr. Wahl: The research funded by my Krim award resulted in the publication of three manuscripts, and I had the opportunity to present my findings locally and internationally. This allowed me to establish collaborations with other investigators in the field. The Krim award also has a strong career development focus, which helped me gain the skills to become a successful independently funded investigator. So, in addition to performing research, I assisted Dr. Garcia, my mentor for the Krim award, in preparing grant applications and reviewing manuscripts. I’ve also been able to mentor and directly supervise research technicians, graduate students, and postdoctoral fellows. I think all these experiences contributed to my securing an independent faculty position.
amfAR: What role did the Krim Fellowship play in obtaining your RO1?
Dr. Wahl: Because the Krim fellowship is viewed in the HIV field as a highly selective and prestigious award, I was specifically advised by the NIH program officer to highlight that I was a recipient of a Krim award. The career development component of the Krim award allowed me to focus on my grant writing skills. In addition to assisting Dr. Garcia with grant applications, I attended grant writing workshops and seminars. I was also able to work closely with the grant proposal development team at UNC to develop my RO1 application.
amfAR: How optimistic are you that we will find a cure for HIV?
Dr. Wahl: I think we’ll see a cure for HIV in our lifetime. There’s a tremendous amount of cure research, both basic science and clinical research, being conducted at UNC by investigators in the UNC HIV Cure Center, and by Qura Therapeutics, a joint venture of UNC and GSK (GlaxoSmithKline).
More broadly, I feel there is a concerted effort across the US and globally to find a cure for HIV. There is a lot of hope and excitement in the field. It’s really nice to see the camaraderie.