Study offers guidance for targeting HIV’s viral reservoir

After decades of progress, people with HIV now have access to drugs that keep the virus undetectable and thus under control with simple one-pill-a-day treatments of antiretroviral therapy (ART).   

These treatments suppress the virus, preventing progression of HIV infection to AIDS and eliminating potential transmission of the virus to others.  

But the virus can persist during treatment, even over many years. If ART is stopped, the virus typically resumes replicating, a “viral rebound” of high levels of virus in the blood, which can cause disease progression. This persistent virus is the major obstacle to more definitive treatment or even cure of HIV infection. 

Understanding this persistent virus—the Rebound Competent Viral Reservoir (RCVR)—is a key area of current HIV research. But for many reasons it is extraordinarily difficult to study the RCVR in people living with HIV.  

New research from the AIDS and Cancer Virus Program employed a novel nonhuman primate model using a barcoded virus that allows detailed tracking and dynamics of the biology of the RCVR, from its establishment to the process of viral rebound when treatment is stopped. 

"We sought to advance two key objectives of HIV cure research," reported the group from the Frederick National Laboratory for Cancer Research, Oregon Health & Science University, and University of New South Wales in the journal PLOS Pathogens.  

According to the study, the first objective sought to better understand the way RCVR is established and maintained, defining how these dynamics influence post-ART viral rebound. The second goal was to develop a research model that could test and evaluate potential new treatments. 

In the experiments reported in this study, 35 specially bred rhesus macaques were infected intravenously with barcoded SIVmac239M, a virus model developed at the Frederick National Laboratory’s AIDS and Cancer Virus Program that behaves like HIV in monkeys but with a genetic barcode that allows scientists to track individual viral lineages over time.  

Groups of five animals were treated with daily ART starting at 3, 4, 5, 6, 7, 9, or 12 days post-infection. Viral RNA in the blood plasma, indicative of viral replication, increased rapidly in the animals during primary infection then declined sharply following initiation of ART. 

Use of the barcoded virus model enabled tracking of how the individual barcode variant viruses contributed to viral rebound, enabling calculation of reactivation rates for viruses when ART was discontinued, a powerful approach for analyzing the RCVR.  

Analyses showed that when ART was started within the first four days after infection, and continued for one year, an initial infection was established but the virus was not capable of persisting through the year of ART and rebounding when ART was stopped—a RCVR was not established. 

When ART was started from days 5 to 7 of infection, the level of infection established increased exponentially with each day’s delay of ART initiation and an increasing level of RCVR was established, resulting in enhanced and rapid viral reactivation and rebound when ART was stopped after a year of treatment. But when ART was started from day 7 to 12 post-infection, the level of infection kept expanding exponentially until ART was started, but the level of RCVR and viral reactivation and rebound when ART was stopped no longer increased proportionally. 

The barcoded virus nonhuman primate model established in this this study makes it possible to detect even small changes to the RCVR which could be useful for fine-tuning and retesting new treatment options that might be developed, individually or in combinations.  

A reduction in the viral reservoir might have therapeutic benefits, but the scientists noted that eradication of the virus may not be possible if a treatment makes only minor changes to the reservoir. 

Information from this study may be particularly relevant to patients who began ART immediately after being infected.  

“These individuals often retain a greater intact immune capacity and have a smaller RCVR, making them the most likely candidates to respond to RCVR-reducing treatments,” the scientists wrote. 

The research was part of an ongoing collaboration between Jeffrey Lifson, M.D., of the FNL’s AIDS and Cancer Virus Program, and Louis Picker, M.D., of the Vaccine and Gene Therapy Institute and Oregon National Primate Research Center. First author on the paper, Brandon Keele, Ph.D., of the AIDS and Cancer Virus Program, pioneered the development and application of the barcoded virus model that enabled the study.