From the earliest days of Ward 86, the first dedicated HIV clinic in the country, to today’s AI-powered approaches to understanding viral persistence, UCSF has shaped global response to HIV for more than four decades. That legacy continues at the HIV Accessory and Regulatory Complexes (HARC) Center, a multidisciplinary program based in the UCSF School of Pharmacy’s Quantitative Biosciences Institute that unites structural biologists, virologists, computational scientists, and proteomics experts to understand how HIV reprograms human cells.

HARC is driving a shift toward big-data, systems-level HIV science — mapping how viral and host proteins interact, identifying new therapeutic vulnerabilities, and accelerating the path toward interventions that could one day enable a cure.

“The power of HARC lies within its people and its interdisciplinary nature,” said Zelda Love, PhD, associate director at QBI and HARC’s program manager. “Our work remains significant because of the data we produce, and the way we integrate large datasets across disciplines.”

Studying HIV by studying everything at once

“Cells are very complex, and viruses are actually very simple, but somehow a virus can take over a cell, and the virus can hide inside the cell and turn the cell into a factory to just make more viruses,” Love said. "We are studying how something so simple can control something as complex as a cell.”

Instead of studying one protein or pathway at a time, HARC uses quantitative systems biology to map the entire network of interactions inside an infected cell.  

“Systems biology is holistic, high-throughput, and deeply quantitative,” Love said. “We measure a lot of things very carefully, and we let the data guide us to the biology.”

This “data-first” approach lets researchers see how HIV repurposes host machinery at multiple levels at once. Such insights are essential for anticipating viral resistance, discovering new drug targets, or designing therapeutics that hit several viral functions simultaneously.

A dataset that changed HIV science

Much of HARC’s current work builds on a foundational 2011 proteomics study by HARC Director Nevan Krogan, PhD, in collaboration with principal investigators Alan Frankel, PhD, Andrej Sali, PhD, and Charles Craik, PhD, that mapped HIV–human protein complexes at unprecedented depth.

Three major structural discoveries have resulted from the study, forming a roadmap for where antiviral drugs might most effectively intervene:

• Rev/RRE/CRM1/Ran nuclear export complex by Frankel, Yifan Cheng, PhD, and Amber Smith, revealing how HIV moves RNA out of the nucleus
• Vif–APOBEC3G complex by John Gross, PhD, Cheng, and Michael Emerman, PhD, revealing how HIV disables the host’s antiviral APOBEC enzymes
• Tat/UBE2O ubiquitination complex, an emerging finding from HARC PI Natalia Jura, PhD, and Yixin Liu, PhD

“We're integrating proteomics with Cryo-EM and computation, and once we have three-dimensional structures, we can tell exactly where to focus for drug development,” Love said. “It provides mechanistic clarity that cannot be captured by traditional approaches.”

In parallel, a genome-wide CRISPR screen in T cells by the Gladstone Institutes’ Alexander Marson, MD, PhD, identified previously unknown host factors required for HIV replication, work that is also informing HARC’s structural biology studies.

Accelerating drug discovery

HARC’s interdisciplinary flow also moves ideas from data to model to therapeutic hypothesis far faster than traditional methods, and AI is accelerating this pace even further.  

"We have the power to use computation and machine learning to integrate all these data sets and then make inferences on how our findings will actually affect viral-host interactions in patients,” Love said. "It took decades of research to develop [antiretroviral therapy (ART)], and there are millions of people on ART right now who are living full and wonderful lives with HIV.”

“A big misunderstanding about this research boils down to social stigma, which remains a huge obstacle for HIV research,” Love added. “It's important to remember that viruses don't discriminate, but people do. If one person suffers, we all suffer, and funding for HIV research remains very important for the well-being of everyone.”