Revised February 2015
Your Avant-Garde award—awarded in 2010—was given for the project entitled “Novel Model for HIV Latency in Primary Memory T Cells.” What was your vision for this concept?
The HIV virus persists in a hidden state—called latency—in HIV-infected patients treated with anti-HIV drugs, and when the drugs are stopped, the virus reemerges from these latently infected cells. For this reason, patients need to be treated for life, and latent HIV represents a major barrier to a cure. However, latency has been very difficult to study because cells carrying latent HIV are extremely rare in patients (it has been estimated that less than one cell in 100,000 carries latent HIV). Therefore, the goal of our project was to establish an experimental model system in the laboratory in which latency could be studied and better understood. Our ultimate aim is to identify the mechanism behind latency and to develop a novel treatment to eliminate latent HIV, which we hope could one day be used to develop a cure for HIV infection.
How has the award helped you advance this area of science?
The award was incredibly helpful in allowing us to explore multiple avenues, some of which are very risky. Excitingly, two of these new directions have been successful. First, we developed a new reporter HIV (called HIV-duofluo) that allows us for the first time to identify latently-infected cells. We can now purify latently infected cells, characterize them, and try to understand how they are different from cells that are productively infected (actively making the HIV virus). The second development was a large screen to identify genes that control latent HIV. We used a new approach, called shRNA, to suppress cellular genes one at a time. We then examined the effect of suppressing each of these genes on latent HIV. This screen has been completed, and it has allowed us to identify a well-defined group of cellular proteins that control latent HIV. We hope that this knowledge will help us in developing new drugs to interfere with latent HIV in the future.
Have there been any surprises or unusual challenges along the way?
There were significant challenges in both projects, and both projects have yielded notable surprises. Several of the cellular factors that we identified in our screen were not previously known to be involved in latency, and they are providing us with important new information about the latency process. A significant surprise that arose from the HIV-duofluo virus was the realization that latency is established in activated lymphocytes very early after infection. This is quite different from what was generally assumed to happen in the field and is forcing us to reassess some of our assumptions about the virus.
What advice would you give to others seeking similar awards for bold and innovative science?
This is the best way to do science! Be courageous, be adventurous, explore the unbeaten path, and be sure to submit your ideas as a proposal. I think that this form of grant support is highly likely to yield significant discoveries, and I hope that NIH will consider expanding these programs beyond the Avant-Garde and Pioneer awards.
Where will your vision of HIV/AIDS research take you next?
We are currently using the HIV-duofluo to study HIV latency in different populations of lymphocytes and in monocytes/macrophages. We are also exploring the therapeutic implications for the genes that control latency. While most of the field is focused on trying to reactivate latent HIV, our preliminary results indicate that some unique drugs can suppress the reactivation of latent HIV and could be used as an alternative therapy for a cure.