Pioneering HIV Researcher at CU Anschutz Drives Development of Long-Acting Therapies, Eyes Once-a-Year Injectable
Key Insights
Mamuka Kvaratskhelia, PhD, at CU Anschutz has spent 25 years unraveling HIV's molecular mechanisms to develop longer-lasting treatments that address poor adherence to daily antiretroviral therapy.
His team's research on the HIV capsid (search) protein led to the landmark 2020 Science publication explaining how lenacapavir binds the capsid, contributing to its 2022 approval as a twice-yearly treatment.
Kvaratskhelia pioneered a new drug class called allosteric HIV-1 integrase (search) inhibitors (ALLINIs), with first-in-class pirmitegravir now advancing through U.S. clinical trials.
In the quarter-century that Mamuka Kvaratskhelia, PhD, has been studying HIV, he has arrived at a sobering conclusion about the virus. "HIV is smarter than us," says Kvaratskhelia, a professor in the University of Colorado Anschutz Department of Medicine's Division of Infectious Diseases. "It's a tiny, tiny virus, but it's very complex. We're still trying to figure it out and develop new drugs against it, because this tiny virus has evaded vaccines and developed resistance to amazing drugs we have been using against it."
Kvaratskhelia's basic-science research has helped expand understanding of how currently used antiretroviral therapies work and how resistance to them emerges. More critically, his work has pioneered entirely new drug classes now advancing through clinical trials, with the ultimate goal of developing a once-a-year injectable that could dramatically improve adherence and reduce HIV transmission rates.
The Adherence Challenge Driving Long-Acting Innovation
Antiretroviral therapies (ART) do not cure HIV, but when taken consistently as prescribed, they can reduce the amount of virus in a person's blood below detectable levels, enabling long, healthy lives and effectively preventing sexual transmission. Yet studies show that only 65% of people living with HIV in the U.S. today have the virus controlled by ART.
"Daily pills work amazingly well in suppressing HIV replication and maintaining normal immune function," Kvaratskhelia says, but adherence to ART prescriptions "remains a major problem." Sub-optimal drug concentrations can lead to the emergence of drug-resistant strains, and many factors contribute to poor adherence, including behavioral and psychosocial barriers as well as inconsistent access to medications and care for financial reasons.
This is why, Kvaratskhelia explains, "the field is focused on developing long-acting therapies that last six months or possibly a year."
Decoding the Capsid: The Lenacapavir Breakthrough
A large portion of Kvaratskhelia's research involves HIV's capsid, the protein protective shell that surrounds the virus's genetic material. When HIV fuses with a human cell, the capsid carries genetic material to the cell's nucleus, then releases viral DNA to infect the cell.
His team's work on lenacapavir, an experimental drug developed by Gilead Sciences, led to a landmark 2020 publication in the journal Science. Kvaratskhelia and his colleagues explained how the drug binds to the HIV capsid (search) and renders the virus non-infectious, while also identifying ways that viral variants develop resistance to the drug. Following that research and other studies, lenacapavir was approved in 2022 as an HIV treatment administered once every six months.
Since then, Kvaratskhelia's team has been working on potential designs for second-generation capsid inhibitor therapies.
The Hunt for Companion Drugs
As important as lenacapavir is, "it's not enough" on its own for treatment of infection, Kvaratskhelia cautions. "We need a companion drug to go along with it, because people with HIV can develop resistance to it. We've described in several papers how the virus is very skilled at evolving resistance to lenacapavir."
At present, no companion drug exists that would last six months. "To overcome that resistance, we need at least two long-acting therapies, if both drugs are really good, or a triple therapy. Triple therapy works really well," he says.
ALLINIs: A New Class of Antiretrovirals
Kvaratskhelia and his colleagues have also done pioneering work on an entirely new class of antiretrovirals called allosteric HIV-1 integrase (search) inhibitors (ALLINIs). These compounds work like a "molecular glue" to bind a viral protein, integrase, into a clump, disrupting its ability to infect new cells.
The mechanistic studies with ALLINIs led Kvaratskhelia and his collaborators to uncover a previously unknown function of HIV-1 integrase (search): directly binding and positioning the viral RNA genome inside the capsid, which is essential for the formation of infectious viruses. These seminal studies were published in 2016 in Cell.
Continued efforts from Kvaratskhelia helped develop the first-in-class ALLINI pirmitegravir, which has been successfully advancing through clinical trials in the U.S.
Uncovering HIV's Cellular Navigation
In parallel, Kvaratskhelia's lab discovered that a human protein called Sec24C (search) binds to HIV's capsid, thereby helping the invading virus to infect the cell. That research was published in 2021 in Nature Microbiology, adding another layer to the understanding of how HIV navigates through a human cell's defenses to reach the nucleus.
The Once-a-Year Vision
While the search continues for additional once-every-six-months drugs, Kvaratskhelia is looking ahead at even longer-lasting therapies. "The goal is a once-a-year injectable, which could address adherence challenges, and HIV rates could go down very significantly," he says.
Wendy Armstrong, MD, FIDSA, head of the Division of Infectious Diseases and president-elect of the Infectious Diseases Society of America, underscores the clinical significance. "Mamuka is incredible. He is an important figure in scientific discovery in HIV, and what he is doing is so important clinically for patients. It's huge."
Armstrong also highlights the broader public health context: an estimated 1.2 million people in the U.S. have HIV, with about 38,000 new diagnoses in 2022 alone. Worldwide, HIV infection is estimated at 41 million people, with deaths from AIDS (search)-related illnesses in 2024 estimated at 490,000 to 820,000.
"HIV is a disease of disparities," Armstrong says. "There are many people, globally and in the U.S., who don't get to benefit from a lot of these advances. That's why the advent of long-lasting therapies the last few years is so important. Having that available for folks who have so many social and other barriers to care, for folks who have struggled to control their HIV, has brought remarkable results."