Taking aim at a moving target

Microbiologist Hillel Haim believes the key to developing a vaccine for HIV is through mathematical models used to predict the volatility of the stock market, specifically the ups and downs, the highs and lows of individual stock prices. Like stock prices that fluctuate, a protein on the surface of HIV mutates frequently, making it hard to create a vaccine to match the virus over time.

Could stock market math inspire an HIV vaccine?

By Jennifer Brown

What do particle diffusion in liquids and stock price prediction have to do with building a better HIV vaccine? According to University of Iowa microbiologist Hillel Haim, you can apply concepts from the first two to predict the evolution of HIV surface proteins—information that then can be used to design better vaccines.

Human immunodeficiency virus type-1 (HIV- 1) is the cause of the worldwide AIDS pandemic. According to the World Health Organization, more than 70 million people have been infected since the epidemic began in the 1970s, and about 35 million people have died of HIV.

“HIV is a highly dynamic virus. It continuously changes, both in an infected individual and, as a consequence of that, in the greater population,” says Haim, MD, PhD, assistant professor of microbiology and immunology in the UI Carver College of Medicine and senior author of a study published April 6, 2017, in the journal PLOS Biology. “When we make a vaccine, we are essentially trying to mimic the virus so that the immune system will learn how to recognize and attack the real virus. The problem we are trying to solve for HIV is how can you design a vaccine to hit a moving and continuously changing target?”

The moving target that Haim is referring to is the envelope glycoprotein (Env), which sits on the surface of HIV. This protein mutates frequently, leading to an increasing number of Env variants in the population. This diversity has limited the success of HIV vaccines tested to date. In order to make a vaccine that will continue to match the virus over time, vaccine makers need to know what Env variants are currently circulating in the patient population and be able to predict how these proteins will change.

Using computational tools and approaches inspired by mathematical models developed to predict changes in stock prices, Haim and his team were able to accurately predict how different properties of the Env protein evolved in the population of Iowa over the course of 30 years.

Key to the work was a unique resource available at the UI. In the 1980s, Jack Stapleton, MD, UI professor of internal medicine, established an HIV clinic in Iowa City. Over the decades, the clinic collected blood samples from several hundred patients.

Haim and his colleagues painstakingly isolated and analyzed hundreds of HIV Envs from these samples.

They examined the changes in structural properties of the Env protein that occurred in the HIV-infected population of Iowa over the last 30 years. The patterns of change reminded Haim of his graduate research on the random motion (diffusion) of viruses through liquids.

“Studying the physical process of virus particle diffusion, I became familiar with that (math),” he says. “Zoom forward 10 years and looking at the patterns of change in virus properties, I said, ‘Wow, this is diffusion!’”

They proceeded to investigate properties of Env to find clues that could predict the observed patterns of change. When they compared the Envs of different viruses derived from the same blood sample, they found that some properties are relatively similar, whereas others are highly variable. They called this characteristic variance “volatility.” The volatility of each property was very similar among patients.

Another system where volatility is measured and diffusion models are used to make predictions is the stock market. Small fluctuations in stock price are often quite characteristic for a particular stock.

In both HIV evolution and the stock market, randomness itself has a defined and frequently predictable structure that can be used to predict how the system will evolve. The diffusion-based model the UI team used efficiently describes evolution of HIV Env proteins.

“We found that volatilities of Env properties measured from a few patient samples from the 1980s allowed us to accurately predict how these properties of the virus evolved in the Iowa population over the course of 30 years,” Haim says.

The ability to accurately predict future changes by testing a small number of patients could potentially allow tailoring of vaccines to the specific forms of HIV present in different populations worldwide.

“Fortunately, relative to the financial market models that inspired this work, our predictions of changes in HIV are remarkably accurate due to the highly conserved nature of randomness in this virus,” Haim adds.

Pioneering clinic into third decade serving Iowans

By Sara Epstein Moninger

Jack Stapleton

Six months before World AIDS Day was observed for the first time, University of Iowa Hospitals and Clinics launched its HIV/AIDS clinic.

It was the summer of 1988, and the new clinic was expected to draw an initial cohort of about 20 patients. Instead, nearly 80 people sought care in the first few months, and by the end of the clinic’s first two years, it was treating some 200 patients. The UI clinic was the state’s first clinic to treat HIV infection and AIDS, and it remains the state’s largest such clinic, says founding director Jack Stapleton, MD.

“A patient today with a new diagnosis of HIV has as good a life expectancy as someone newly diagnosed with diabetes or hypertension,” says Stapleton, professor of internal medicine, and microbiology and immunology, in the UI Carver College of Medicine.

Considering that AIDS had become the leading cause of death for Americans ages 25 to 44 in 1994, that’s significant progress. Though the disease has no cure, advances in antiviral drug treatment have helped slow the progression of HIV to full-blown AIDS. Now, people who are HIV-positive and who receive prompt, consistent medical treatment can live long, healthy, and productive lives.

“We recognized early on that we needed a multidisciplinary approach to care in our clinic, and the hospital administration came through with the resources we asked for,” Stapleton explains. “We were able to hire a nurse and set up a patient database to help us track the disease.”

The UI team has grown to include as many as 24 experts in infectious diseases, social work, psychiatry, pharmacy, and nursing. They also make referrals to health care professionals who have experience treating patients with HIV—from dentists to obstetricians to ophthalmologists— and operate a satellite clinic in Waterloo, Iowa, twice a month. About 2,200 patients have been treated at the UI clinic, with more than 700 patients seen in 2017.

“Our staff provides an amazing amount of care. We will arrange rides or provide gas cards, if patients need transportation—and our pharmacists call two weeks after appointments just to check in,” he says. “The part I enjoy most is meeting patients and taking care of them. Some of them I have taken care of for nearly 30 years. I’m like their family practitioner.”

Throughout his nearly three decades of running the clinic, Stapleton has seen firsthand the progress made in the fight against AIDS. The clinic has participated in numerous clinical trials that have led to advances in AIDS treatments.

“In the past three to five years, we’ve seen multiple drug treatment regimens that are less toxic and better tolerated,” he says. “Patients are living longer and enjoying a higher quality of life.”

That noted, Stapleton says he does not anticipate a cure to be found in the near future. The ability of HIV to duplicate quickly makes it a formidable foe—and underscores the importance of research.

“Finding the molecules that the virus needs to have in order to multiply led to the discovery of drugs that can interfere with that process. The key is to inhibit replication,” says Stapleton, who studies antiviral therapy and the effect of co-infection of HIV, HCV, and GB virus type C.

Since HIV has a latent stage where its genetic material is inserted into an infected patient’s chromosome, today’s treatments can’t eradicate it, Stapleton says. Because of this, he thinks the cure will take an entirely new approach.

“A lot of things are being tried to cure HIV, and we’re learning important information about the virus and its treatment,” he says. “However, I believe that the current approaches are unlikely to lead to a cure, and it will instead take a totally unexpected angle to get to a cure. Most great advances in science are not planned—they’re serendipitous.”

As treatments and tech advance, HIV care adjusts

Pharmacist Angela Hoth (left) videoconferences with a “patient”—Seth Owens of Johnson County Public Health—to demonstrate how the TelePrEP program communicates with clients across Iowa.

By Dawn Goodlove

With timely diagnosis and appropriate treatment, people who are HIV-positive can live with a chronic condition, much like patients with diabetes or coronary artery disease whose care is managed by primary care providers and specialists.

“Times have changed since Jack (Stapleton) started the HIV clinic here 30 years ago,” says Michael Ohl, MD, a University of Iowa Health Care infectious disease specialist. “In general, people with HIV are doing well on one pill once a day, and HIV is in the background. Our jobs have really become primary care of an aging population, so we need new models where we re-engage with primary care.”

A regular dose of the medication Truvada has been a long-established treatment for people testing positive for HIV. Just five years ago, the Food and Drug Administration also approved Truvada to prevent HIV infection, and large clinical trials have shown Truvada to be more than 90 percent effective at reducing HIV transmission if taken consistently. UI Health Care provides this pre-exposure prophylaxis (PrEP) to at-risk patients without HIV who visit the PrEP Clinic at UI Health Care–Iowa River Landing in Coralville, Iowa, or through a new telemedicine program known as TelePrEP.

Ohl is medical director of the TelePrEP program, which is a collaboration of the Iowa Department of Public Health, the Signal Center for Health Innovation, and UI Health Care’s infectious diseases division and pharmaceutical care department. Through TelePrEP, adults all across Iowa who are at higher risk of getting HIV, through sexual contact or intravenous drug use, can videoconference from home with a UI Health Care pharmacist over a HIPAA-compliant channel, obtain required lab work by visiting a local outpatient lab site or public health provider, and then receive PrEP medication by mail.

Angela Hoth, PharmD, and Dena Dillon, PharmD, completed videoconference visits with 40 individuals during the TelePrEP pilot phase, which began in February 2017.

The process for obtaining medication through TelePrEP includes counseling about risk reduction and condom use, testing for other sexually transmitted infections, monitoring adherence to the medication, and follow-up lab work after several months of PrEP. National health organizations suggest primary care providers should supervise PrEP usage.

“In rural Iowa, that is a difficult model to follow, partly because of the physician shortage. We advise people to go to a provider because we want people to have primary care, but if seeing their provider presents a barrier—due to stigma or travel distance—then it’s better to have TelePrEP than no PrEP,” Ohl says.

While Iowa has a low incidence of HIV compared to other states, the number of new HIV diagnoses increased 11 percent from 2015 to 2016, according to the Iowa Department of Public Health. In addition, there is a statewide increase in sexually transmitted infections, such as chlamydia, gonorrhea, and syphilis.

The goals of the TelePrEP program are to reduce the number of new HIV infections and sexually transmitted infections over the next five years.