Specialized Centers for HIV/AIDS-Related Structural Biology

The Specialized Centers for HIV/AIDS-Related Structural Biology, established in 2007, integrate a variety of techniques from structural biology, biochemistry and cell biology to capture in unprecedented detail the three-dimensional structures of HIV components bound to human cellular components, such as proteins or DNA. This information will help elucidate how the different components interact and reveal new approaches for disrupting those interactions, potentially leading to new targets for HIV therapies.

Two molecules of restriction factor APOBEC3H form a sequence-independent complex with an RNA duplex
Two molecules of restriction factor APOBEC3H form a sequence-independent complex with an RNA duplex. Credit: CRNA

Center for RNA Studies (CRNA) Link to external Web site

Principal investigator: Alice Telesnitsky, Ph.D., University of Michigan

This center studies the structural biology of viral RNA and its interactions with viral and host proteins. Because RNA is less amenable to structural analysis than proteins are, the researchers are developing approaches to overcome this technical challenge. Their work could help identify RNA-based targets for HIV treatments as well as shed light on the multiple biological functions of the viral genome.

Image showing how a budding HIV particle is organized by the viral Gag (gold/tan tones) and Gag-Pol proteins (gold tones plus gr
Image showing how a budding HIV particle is organized by the viral Gag (gold/tan tones) and Gag-Pol proteins (gold tones plus green and yellow) in complex with the viral RNA (blue), and showing how ESCRT-III subunits (turquoise) localize and constrict the bud neck and are recycled by the hexameric VPS4 ATPase (purple) during the budding process. Credit: Illustration by Janet Iwasa, based upon structures of Gag, ESCRT-III and VPS4 structures and domains determined in the CHEETAH Center.

Center for the Structural Biology of Cellular Host Elements in Egress, Trafficking, and Assembly of HIV (CHEETAH) Link to external Web site

Principal investigator: Wesley Sundquist, Ph.D., University of Utah

This center is using computational and experimental methods to analyze HIV molecular complexes and determine how they interact with and commandeer cellular machinery to traffic throughout cells and tissues. By visually reconstructing virus particle assembly and trafficking, the center aims to develop HIV into a leading model for understanding how human viruses interact with cellular hosts, and to provide a platform for designing new therapeutic strategies.

An animated of ESCRT-III. Caption below has additional info.

Animation showing how ESCRT-III subunits (green) are unfolded and recycled by the hexameric VPS4 ATPase (purple) and its LIP5 activator (yellow) during the process of HIV budding. Animation by Janet Iwasa, based upon structures of ESCRT-III and VPS4/LIP5 determined in the CHEETAH Center.

Cryoelectron microscopy structures of Nef and Arf1-bound AP-1 predict a hexagonal assembly (left) whose inner and outer faces bi

Cryoelectron microscopy structures of Nef and Arf1-bound AP-1 predict a hexagonal assembly (left) whose inner and outer faces bind the membrane and clathrin, respectively (right). Credit: HARC Center.

HIV Accessory and Regulatory Complexes (HARC) Center Link to external Web site

Principal investigator: Nevan Krogan, Ph.D., University of California, San Francisco

The HARC Center mission is to elucidate the molecular basis of systems that are essential for, or contribute to, the pathogenesis of HIV/AIDS, including the physical/functional interactions that occur between viral accessory and regulatory proteins and human proteins, membranes, lipids and nucleic acids (DNA/RNA). Through a powerful structure/function pipeline, including genetic approaches, the HARC team is gaining unprecedented insight into HIV biology, new avenues to complex structures, and the potential to fundamentally alter treatment strategies by targeting key cellular processes that contribute to AIDS at interfaces where mutational resistance is highly unlikely. The Center is also developing new technologies to drive forward work in the center and the field in general, including high resolution cryo-EM approaches, a pipeline for recombinant antibody reagents, novel proximity-based and post-translational mass spectrometry approaches and a CRISPR-cas9 based approach for functional study of host genes in T cells.

Illustration of some of the major HIV interactions being targeted by the HIVE Center
Illustration of some of the major HIV interactions being targeted by the HIVE Center. Credit: HIVE Center.

HIV Interaction and Viral Evolution (HIVE) Center Link to external Web site

Principal investigators: Bruce Torbett, Ph.D., The Scripps Research Institute and Stephanos Sarafianos, Ph.D., The University of Missouri

The HIVE Center is characterizing at the atomic level the structural and dynamic relationships among major HIV proteins and their partners, as well as cellular host factors and macromolecules necessary for the HIV life cycle. These interactions are critical for viral replication and characterizing them enables inhibitor targeting and provides a rich base of structural, biological, and evolutionary relationships to explore, which will inform our goals. HIV inhibitor resistance evolution is being studied as a model to help understand the structural interdependencies among interacting macromolecules. The structural and biological insights gained from understanding the interdependence of viral and host mechanisms contributing to viral function may enable future novel therapeutic intervention strategies.

X-ray crystal structure of HIV-1 Vpr (red) in complex with uracil DNA glycosylase 2 (UNG2, green) and the Cul4-DCAF1 E3 ligase,  
X-ray crystal structure of HIV-1 Vpr (red) in complex with uracil DNA glycosylase 2 (UNG2, green) and the Cul4-DCAF1 E3 ligase, comprising DDB1- and CUL4-associated factor 1 (DCAF1, blue), damage-specific DNA binding protein 1 (DDB1, orange), and Cullin4 (CUL4, gray). Credit: Ying Wu, Guillermo Calero, Jinwoo Ahn, and Angela Gronenborn of the Pittsburgh Center for HIV-1 Protein Interactions.

Pittsburgh Center for HIV Protein Interactions (PCHPI) Link to external Web site

Principal investigator: Angela Gronenborn, Ph.D., University of Pittsburgh School of Medicine

The PCHPI is focused on structure determination and imaging of pivotal events that occur during viral particle maturation, post-entry events, nuclear entry and integration. The center applies proteomic approaches to identify novel HIV-interacting host proteins and integrates virological and biochemical approaches in the interrogation of these interactions with structural methodologies for understanding the viral-host interplay. Structural methodologies encompass solution and solid-state NMR spectroscopy, X-ray crystallography, cryo-electron microscopy, and MD simulations, with an emphasis on further developing novel approaches that advance the capabilities of these techniques.