Gladstone Institute of Virology and Immunology -

Director's Greeting

Warner C. Greene, MD, PhD
Director
Gladstone Institute of Virology & Immunology

Welcome to the Gladstone Institute of Virology & Immunology, a basic science center dedicated to the studies of contemporary topics in human virology and immunology with a focus on HIV and AIDS. Now more than 25 years into the global pandemic, HIV/AIDS remains one of the defining health challenges of our time. The ongoing battle against this retrovirus has yielded both good and bad news. The good news includes the finding that circumcision reduces HIV transmission from infected women to men by 50-60%, HIV infection rates seem to be declining in a few African countries, and two new classes of antiretroviral drugs were approved for clinical use (Maraviroc, a CCR5 entry inhibitor, and raltegravir, an HIV integrase inhibitor). The bad news included the failure of the Merck Ad5 HIV gag-pol-nef vaccine candidate in the STEP and Phambili trials, the inability of diaphragm use to reduce new HIV infections, and the finding that a second microbicide candidate, cellulose sulfate, enhances rather than inhibits HIV transmission. Using more accurate survey results, UNAIDS now estimates that 33.2 million people are infected with HIV worldwide and 2.5 million were newly infected in 2007. Approximately 2.1 million people succumbed to HIV/AIDS this past year.

Against this backdrop, investigators within the Gladstone Institute of Virology and Immunology continue their important work. The year included several notable events for us. We recently recruited Dr. Melanie Ott as an associate investigator and Dr. Ya-Lin Chiu as an assistant investigator. I could not be more pleased with these recruitments: each is among the brightest young scientists working on HIV. My own professional life took an exciting turn with my appointment as President of the Accordia Global Health Foundation, an organization dedicated to creating alliances to fight infectious disease in Africa. We also launched two significant corporate-sponsored research collaborations with Gilead Sciences and JT Pharma. Both are companies with outstanding track records for drug development in the HIV arena.

Below, I summarize aspects of the science from each of the GIVI laboratories.

Ya-Lin Chiu – APOBEC3G (A3G) functions as a potent post-entry restriction factor for HIV in resting CD4 T cells, monocytes, and dendritic cells. This function involves a low-molecular-mass (LMM) form of A3G. However, when T cells are activated or monocytes induced to differentiate into macrophages, A3G is recruited into high-molecular-mass (HMM) RNA-protein complexes. Strikingly, these complexes contain Alu and hY retroelement RNAs that are specifically recruited by A3G. Chiu and colleagues now show that Alu and hY retroelement RNAs function as the driving force for nucleation of HMM A3G complexes. The introduction of Alu or hY retroelement RNAs into resting CD4 T cells is sufficient to render these cells permissive for HIV infection. These findings highlight the distinct external and internal protective functions of A3G.

Robert Grant – Dr. Robert Grant and his colleagues enrolled their first volunteers in an international preexposure prophylaxis trial designed to determine whether potent antiretroviral therapy can be use to prevent HIV infection in high-risk individuals. This work has garnered supported from both the National Institutes of Health and the Bill and Melinda Gates Foundation. I believe this is one of the most important clinical HIV prevention trials underway. The Grant lab also focused on the remarkable but vexing ability of HIV to rapidly mutate. Their studies identified a new player, APOBEC3C, that enhances this mutation frequency. Unlike its cousin, APOBEC3G, the 3C protein exerts little or no anti-HIV activity, but instead mediates non-lethal mutations that may speed immune escape or the acquisition of drug resistance.

Eric Verdin – Dr. Dwayne Bisgrove in the Verdin laboratory performed fascinating studies showing how HIV Tat usurps a key cellular kinase complex termed P-TEFb to promote HIV replication. Tat brings this kinase to the HIV LTR where it modifies bound polymerase resulting in extremely high-level production of viral RNAs. These studies illustrate how Tat recruits P-TEFb out of an inactive complex and further prevents the docking of this potentially active kinase with a second cellular protein called BRD4. The insights gleaned from these basic studies could ultimately provide new approaches for blocking Tat action.

Melanie Ott – Dr. Hye-Sook Kwon in the Ott laboratory has produced exciting data detailing a new mechanism through which HIV promotes a state of chronic immune activation. Such activation is now thought to play a central role in HIV disease progression. Drs. Kwon and Ott have found that the HIV Tat protein blocks a cellular pathway responsible for the inactivation of the NF-kB transcription factor. These effects of Tat result in a prolonged NF-kB–driven transcriptional response and a sustained state of immune activation.

Warner Greene – Dr. Marielle Cavrois and Jason Neidleman explored the fundamental mechanism underlying the ability of dendritic cells to surreptitiously transfer intact HIV virions to interacting CD4 T cells without themselves becoming productively infected with the virus. The widely accepted model for this process termed trans-infection posited that these virions were taken up and hidden in internal vesicles within the dendritic cells prior to exocytic transfer to CD4 T cells. This mechanism was dubbed the “Trojan Horse” model of HIV trans-infection. However, our studies reveal that virions on the cell surface are the principal mediators of trans-infection. These findings argue that HIV virions “surf” along the external plasma membrane to the site of T cell contact before CD4 T cell transfer. As such, attachment inhibitors and neutralizing antibodies could greatly curb HIV trans-infection.

In summary, investigations within GIVI continue to be exciting and productive. I could not be more proud of the many investigators, postdoctoral fellows, research associates, and students who day-in and day-out are diligently exploring the biology of HIV while at the same time creating a unique environment ripe for discovery and collaboration.

Warner C. Greene, MD, PhD
Director, Gladstone Institute of Virology and Immunology