Two Genes Identified as Potential Drug Targets in Treatment of HIV

Investigators from Johns Hopkins University School of Medicine have uncovered that 2 genes—CMPK2 and BCLG—are selectively activated when a type 1 interferon has been administered, revealing 2 potential drug targets for the treatment of HIV.

Type 1 interferons have been used to treat chronic viral infections and was once used as firstline of treatment against hepatitis C virus. Over 1 million individuals in the United States are infected with HIV and approximately one-quarter of this population also have hepatitis C infections. In the co-infected population, it has been historically difficult to treat hepatitis C with type 1 interferon.

In an effort to understand how the viruses interact with each other and the reason behind why HIV appears to hinder efforts to treat hepatitis C with type 1 interferon, the investigators conducted a small, preliminary study comprised of 29 individuals—15 men and 4 women over the age of 20—who were infected with HIV and hepatitis C.

For the study, investigators administered subcutaneous injections of interferon in participants who were admitted to the Johns Hopkins Hospital Clinical Research Unit. They then collected blood samples every 6 hours from each patient, with each patient discharged 24 hours after the dose. Each patient then returned 48 hours, 72 hours, 7 days, and 14 days after their dose so that investigators could collect blood samples to measure their plasma HIV RNA levels. After 7 days, the patients were found to have, on average, 10 times less HIV in their blood.

“This told us that the interferon we were using to treat hepatitis C was working to control HIV as well, but we needed to investigate how it was accomplishing this,” Ashwin Balagopal, MD, associate professor of medicine at the Johns Hopkins University School of Medicine, explained in a recent statement.

To do this, the investigators studied the CD4 T cells in the participants and measured gene product levels both before and after interferon treatment. The investigators found elevated expression levels in 99 genes following the interferon treatment; these genes included CMPK2 and BCLG which had not been previously linked with HIV.

The investigators then took their research further by initiating a study in lab-grown human cells infected with HIV in an effort to learn more about the interaction between these specific genes and interferon treatment.

First, the cells were modified to be unable to produce the protein made by the CMPK2 gene and then they were treated with interferon. When they tested the cells’ HIV levels, the investigators found that the control cells without CMPK2 function, had 10 times more HIV than cells with functioning CMPK2.

Next, the investigators turned to BCLG, which known to have very low expression levels, and, as such, makes it especially difficult to remove from human cells. They decided to increase the expression of BCLG genes to cells infected with HIV; after doing this, they administered interferon. After 48 hours, the engineered cells were found to have half the amount of HIV compared with the unmodified cells.

“This seems to indicate that CMPK2 and BCLG play a role in interferon’s ability to suppress HIV,” explained Dr. Balagopal. “[The genes] potentially could serve as targets for new drug approaches to HIV treatment, particularly in people who are coinfected.”

The investigators do, however, warn that the level of suppression that was observed in the presence of interferon is not large enough to suggest that interferon be utilized as a sole treatment for patients coinfected with HIV and hepatitis C.

Future research will focus on learning more about the CMPK2 and BCLG genes and determining the role that the genes play in HIV suppression, along with the effect of the genes on the virus’ ability to hide within cells, an ability that has inhibited potential cure efforts.