Gladstone Institute of Virology and Immunology -

2011 marked 30 years since the first cases of AIDS appeared in US cities, such as Los Angeles, San Francisco and New York. Since that beginning in the summer of 1981, more than 60 million people have been infected, and 25 million have died due to the collapse of their immune systems. These statistics place HIV/AIDS in league with three other grim infectious reapers, including the bubonic plague of the Middle Ages that killed 75 million, the small pox epidemic of the 18th century that killed an estimated 60 million Europeans, and the great influenza epidemic of 1918–19 that killed roughly 50 million—more than all those who died in World War I. They are the deadliest infectious epidemics in recorded human history.

And yet, 2011 brought encouraging news in the long-standing battle against HIV/AIDS. With the development of more than 30 approved anti-retroviral medications, plus stunning advances in the field of HIV prevention—circumcision, chemoprophylaxis, microbicide treatments as prevention and HIV vaccines—we can, at long last, envision an AIDS-free generation. While we still have far to go, we will soon be well positioned to take a shot at this lofty goal.

Globally, the HIV/AIDS pandemic is slowing. Twenty-two African countries are now reporting declines of more than 25% in HIV infection rates. Anti-retroviral drugs are flowing at an increased pace thanks to the multi-billion dollar investments by the President’s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis and Malaria. These programs promise to save 10 million lives by 2025. Despite this remarkable progress, storm clouds are gathering on the horizon. This year the Global Fund was forced to cancel its current round of grants, citing insufficient funds due to declining contributions from countries within the financially troubled Euro Zone. Our gains are fragile. We as a world must not waver in our commitment to finish this job. Work within the Gladstone Institute of Virology and Immunology continues to address the major three challenges remaining in HIV/AIDS research: 1) effective prevention, 2) a cure for those who are infected, and 3) a better understanding of why HIV-infected individuals on antiretroviral therapy are dying of common diseases 10–15 years sooner than uninfected individuals. Gladstone is providing key insights into HIV prevention through the chemoprophylaxis work of Robert Grant and the HIV vaccine work of Phillip Berman. Gladstone scientists—including Eric Verdin, Melanie Ott, Leor Weinberger and me—are members of the Martin Delaney National Collaboratory, designed to foster public-private partnerships to accelerate progress toward an HIV cure. To address the issue of “accelerated aging” experienced by HIV-infected subjects on treatment, Drs. Verdin, Ott, Shomyseh Sanjabi and Greene have launched studies to determine if chronic low-level inflammation is a major driving factor.

Dr. Grant’s laboratory was the first to demonstrate that chemoprophylaxis works as an HIV preventive—showing that a pill a day can prevent HIV transmission. The iPrEx trial results were heard round the world, and Dr. Grant was recognized by Time as one of the “People Who Mattered” in 2011. He and his colleagues are now conducting the open-label extension of the study fittingly called iPrEx-OLE.

Dr. Verdin’s laboratory is continuing exciting studies on HIV latency, the major problem thwarting a cure for HIV infection. The Verdin lab is exploring how different chromatin-remodeling enzymes are recruited to the integrated HIV LTR. Certain remodeling machines appear to be associated with latency, while others are associated with activation of the latent provirus.

Dr. Ott’s laboratory has been exploring the biology of the hepatitis C virus (HCV) that has infected 170 million people worldwide and is a common co-infection with HIV. Specifically, her laboratory has been investigating the intriguing interplay of HCV with lipid droplets where the virus assembles. They discovered that a triglyceride synthesizing enzyme, DGAT-1, functions as a key cofactor for HCV infection. Inhibition of DGAT-1 activity reduces HCV infection and spread, opening the door to an entirely new strategic approach for attacking this virus that obviates its high mutation rate and development of drug resistance.

Dr. Sanjabi’s laboratory is seeking to understand why neonates and infants mount less effective immune responses than adults. Cytokine profiles of T cells differ in neonate cord blood and peripheral blood from adults, including an increase in interferon-α (IFNα) in adult samples. Most IFNα is produced by plasmacytoid dendritic cells. Dr. Sanjabi and her colleagues found that there are as many plasmacytoid dendritic cells in neonatal as in adult blood, but they are less mature in neonates. IFNα production is greatly decreased when these cells are infected with a rotavirus, a leading cause of dehydrating diarrhea and death in children.

Marielle Cavrois’ laboratory is using flow cytometry in the form of a virion-based fusion assay to examine properties of the HIV envelope that promote successful virion transfer across the female reproductive tract. Dr. Cavrois and her colleagues found that envelopes containing shorter V1 loop regions fuse better to target cells than envelopes with longer V1 loop regions. This is the first evidence that transmission may be linked to changes in the fusogenicity of viral envelope protein. My own laboratory is exploring how major proteins present in human semen contribute to HIV transmission. Specifically, he and Nadia Roan showed how the semenogelins are cleaved by prostate specific antigen, to generate smaller peptides that spontaneously form positively charged amyloid fibrils that enhance HIV attachment to target cells. Strikingly, these semenogelin-derived fibrils join SEVI as the second amyloid to be identified in semen. The presence of two such fibrils is unprecedented in a biological fluid and raises the possibility that these fibrils might naturally function in the fertilization process.

During the past year, three new investigators joined the Institute including JJ Miranda, Leor Weinberger and Nevan Krogan. Dr. Miranda completed his PhD in structural biology at Harvard and was a UCSF Fellow before joining GIVI as an assistant investigator. Trained at Berkeley and Princeton in biology, biophysics and computational biology, Dr. Weinberger was an assistant professor at the University of California at San Diego, before joining GIVI as an associate investigator. Dr. Krogan embodies a new type of hybrid appointment between UCSF and Gladstone. He will maintain a laboratory at UCSF in his role as associate professor of cellular and molecular pharmacology while working as an associate investigator at both GIVI and GICD. In 2011, Phillip Berman, a professor of biomolecular engineering at UC Santa Cruz was also appointed as a visiting investigator within GIVI. For many years, his work has focused on developing an effective HIV vaccine. We hope to propel Dr. Berman’s important efforts through increasing interactions with GIVI investigators, as well as individuals within the larger UCSF-GIVI CFAR and HIV research community.

Dr. Miranda’s laboratory is working on the fundamental biological question of how chromosomes are organized. Specifically, he is exploring how the CCCTC-binding factor (CTCF) promotes the formation of chromosomal loops that mediate long-range intra- and inter-chromosomal interactions. He also studying the role of CTCF in establishing and maintaining viral latency in the Epstein-Barr and Kaposi’s sarcoma–associated herpes viruses. These viruses are important co-infections in HIV-positive individuals and can lead to life-threatening cancers.

Dr. Weinberger’s laboratory is exploring the role of spontaneous fluctuations in biological systems (“noise”) and how such noise shapes fate decisions within single cells and biological responses within organisms. Of note, he found that the HIV LTR is one of the noisiest genes thus far characterized. He and his colleagues are exploring the role of such noise in fate decisions, such as latent versus productive HIV infections, and extending these analyses to other viruses, such as the herpes cytomegalovirus.

Dr. Krogan’s laboratory is defining the physical interactome for HIV with host proteins by affinity purification and mass spectrometry approaches. These studies are providing key insights into how HIV efficiently hijacks the CD4 T cell to produce disease. These studies also represent an unbiased assessment of the interplay of HIV’s compendium of 15 proteins with hundreds of cellular polypeptides. Most of these interactions were completely unknown. Importantly, these studies provide new targets for potential drug development.

Dr. Berman’s laboratory has been involved in HIV vaccine-related studies since 1984. He was responsible for the development of AIDSVAX B/E, an envelope subunit vaccine that, when combined with canarypox, produced a vaccine that for the first time showed evidence of partial protection when tested in 16,000 Thai volunteers (the RV144 or Thai trial). His laboratory is now seeking to understand the biological basis for the protective response observed in this vaccine trial. In summary, the Gladstone Institute of Virology and Immunology continues to grow and thrive. Gladstone investigators are making significant progress on multiple fronts in the fight against HIV. The multidisciplinary nature of our work and the collaborations that naturally occur within Gladstone create an environment ripe for discovery.

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