The John H. Tietze Foundation

YOUR GIFTS IN ACTION AT THE UNIVERSITY OF COLORADO ANSCHUTZ MEDICAL CAMPUS

The John H. Tietze Foundation December 2020

Dear Eileen, Judy, Larry and Tyler: Thank you all very much for the Tietze Foundation’s generosity in funding our work. Your support makes our research possible, and I am pleased to share our progress with you.

While still making great strides in our work on HIV-1 related to combating latent viruses, in the early months of 2020 we pivoted our efforts to focus on a fundamental topic related to SARS-CoV-2: bats are the animal reservoir for SARS, SARS-CoV-2 and several other lethal viruses. My colleague, James Morrison, and I were very pleased to see our additional work with bats pay off in discovery, and we published our research in September.

We have been working on drugs to impact viral life cycles, including viral latency. Latency underlies both the inability to cure HIV-1 and the problem of reactivating latent herpes simplex virus type 1 (HSV-1), which virtually all of us have but in an unfortunate few, such as Mrs. Tietze, reactivates into the brain. Both of these viruses are massively pandemic and the latent DNA state is central for both.

In collaboration with colleagues that include Drs. James Morrison, Mamuka Kvaratskhelia and others, we published a paper in the worldleading journal Science regarding our work on HIV-1. It describes an amazing new drug that behaves in an entirely new way against HIV. It acts on the incoming virus just after it enters a cell and before it integrates into the genome to establish latency, and it targets the viral capsid shell. This groundbreaking drug heralds an entirely new kind of treatment for clinicians to employ against HIV and illuminates key, relatively mysterious features of the HIV-1 life cycle. Science is one of the top two scientific journals in the world, and we are proud to see this major paper published, and the accrual of this and similar knowledge helps for all latent viruses.

Your support was a key part of these discoveries. I hope you enjoy reading about the impact you have had on our work and on infectious diseases research in greater detail in the following pages. We are truly grateful to have you on our team in the effort to better understand – and better treat – infectious diseases.

With gratitude,

Eric M. Poeschla, MD Chief, Division of Infectious Diseases Tim Gill Endowed Chair for AIDS Research

Senolytic drugs and HIV latency Our screen for the senolytic drugs on viral latency of integrated HIV turned up initial effects that were promising in immortalized human T-cell lines. When we looked at primary human T cells (cells fresh from blood), we did not see effects that were potent enough to take forward to further clinical development.

We are now waiting to see what further senolytic drugs are developed and if they have strong effects. However, as we have concentrated on drug effects on the virus, the offshoots described below have led to several major successes. In regards to the HIV-1 capsid inhibitor, HSV-1 also has a capsid so we can begin to think about targeting its capsid, too.

Figure. Both HSV-1 and HIV-1 are viruses that generate persistent latent DNA forms, and both have capsid shells that are wrapped inside an outer lipid envelope.

A radically new type of ultra-potent, long-acting antiviral drug As we engage with the COVID-19 pandemic, we know that additional viral pandemics are certain to occur when more viruses cross species barriers from animals to humans. In addition to SARS-CoV-2, no virus illustrates this risk better than HIV-1, for which the proximate source was chimpanzees. It has caused 35 million deaths, and there are 40 million people presently living with HIV. It affects Americans of all walks of life – in fact, the largest single provider of HIV care in the United States is the Veterans Administration.

James Morrison and I were part of a team of researchers in seven American laboratories that made a key discovery about a strikingly innovative addition to the HIV therapeutic armamentarium. The new antiviral drug, a first-in-class capsid inhibitor named GS-6207, is ultrapotent and effective at concentrations a thousand-fold lower than most antiviral drugs.

Combining molecular biology, virology, structural biology, high-resolution imaging of HIV-1 in cells and an array of biochemical and biophysical methods, we found that GS-6207 blocks HIV’s ability to infect cells by hyper-stabilizing the virion protein shell as it tries to cross the cytoplasm to enter the nucleus and establish the latent state. The drug’s remarkable potency and other advantageous features are being tested in clinical trials now, with dosing only every six months. This work gets us closer to a “functional cure” for HIV, as we can simply administer drugs like this once or twice a year. Pursuing more high-tech, elaborate or even toxic approaches like gene therapy and bone marrow transplantation will start to become irrelevant.

Why bats keep giving us lethal viruses The Tietze Foundation’s support has played an integral role in helping us react to the COVID-19 pandemic and understand a key question that has risen to the top of the world’s attention this year: why are bats are often the primary reservoirs for multiple, highly lethal human viruses that have caused major destructive outbreaks? Such dangerous viruses include Ebola, Nipah, Hendra, Rabies, SARS-CoV, MERS and, most recently, SARS-CoV-2, the cause of COVID-19. These epidemics appear to have accelerated over the past twenty years, and it is virtually certain that further destructive human viral diseases will cross from bats to humans, likely within the next decade.

Bats seem to have very different ways of dealing with viruses, but how they do this is largely mysterious. Especially in light of SARS-CoV-2, this concept is woefully understudied relative to the high medical importance of these animals, and your support is instrumental in helping us bridge the gap.

With colleagues in Singapore and Australia, we studied the large bat Pteropus alecto, which is the reservoir species for Nipah virus (the virus that inspired the scientifically-realistic movie Contagion). This species is also closely related to the Rhinolophus bats that are the source of SARS-CoV and SARS-CoV-2. We started with the striking core observation that the bats’ cells potently restrict HIV-1 from infecting them. This is quite specific in that they do not block non-primate animal viruses in the HIV class. Bats have evolved very interesting antiviral defenses that could shed light on how to block HIV and other viruses as well.

Our goal now is to apply this to understanding not just retroviruses but also coronaviruses like SARS-CoV-2, and we now have this virus in the lab and approval to work with it. We will also study other bats, including Rhinolophus bats. This is fascinating work and puts us on the leading edge of basic science.

The Tietze Foundation’s support has played a key role in helping us understand why bats are often primary reservoirs for multiple highly lethal human viruses that have caused major outbreaks‌ Our goal now is to apply this to understanding not just retroviruses but also coronaviruses like SARS-CoV-2, and we now have this virus in the lab and have approval to work with it.

James Morrison, PhD

Dear Eileen, Judy, Larry, and Tyler: The partnership between the John H. Tietze Foundation and the University of Colorado Anschutz Medical Campus is transforming our understanding of infectious diseases and producing tangible results. With support from your foundation, we are on the leading edge of research and innovation that will ultimately reduce suffering and improve lives.

Your investments in the Division of Infectious Diseases have helped deepen our understanding of viruses that cross from animals into humans. We are applying that knowledge during the current pandemic, and we expect that we will be able to better prepare for - and possibly even prevent - major outbreaks in the future. Thanks to your generosity, patients with HIV and other life-altering infectious diseases can find hope in our discoveries of new and improved treatment options.

Your support has been essential. Thank you for your dedication to improving lives and advancing research in infectious diseases.

Sincerely,

John J. Reilly, Jr., MD Vice Chancellor for Health Affairs Dean, CU School of Medicine Richard D. Krugman Endowed Chair