Historically, HIV research has focused on how antiviral proteins block infection. But there remains a lack of understanding in how these proteins behave when the HIV virus has become integrated into the genome but is in its latent, inactive phase.

A new Yale study led by School of Medicine immunobiology scientist Manabu Taura has identified the first gene known to reinforce HIV-1 latency. The research team discovered that this gene, known as Apobec3A, acts as a silencer that suppresses gene expression and HIV virus production.

“While there are many host proteins known to block the initial infection with HIV, how host immune proteins control latency of HIV remains less clear,” said molecular, cellular and developmental biology professor and senior author Akiko Iwasaki.

With no current cure for HIV/AIDs, patients are typically treated with antiretroviral drugs. HIV-1 can become integrated into the genome without being expressed, Taura explained, but the normally functioning immune system can activate HIV. Patients therefore need to take antiretroviral drugs to repress the normal immune response and avoid the risk of reactivation.

These medications are prescribed to be consumed daily throughout a person’s lifetime. Though available antiretroviral drugs strongly suppress virus production, they are expensive, often making the drugs inaccessible to those in developing countries. And the drugs have caused harmful side effects, including Type 2 diabetes.

With a new understanding that Apobec3A serves as a gene silencer, scientists can work toward a cure for HIV. One possible therapeutic strategy, “block and lock,” involves preventing reactivation of HIV by permanently expressing the gene in latently infected cells. Since the cells would be latent forever, the body would no longer produce HIV viruses.

It is difficult, however, to insure expression in all latently infected cells. Another approach, known as “kick and kill,” is to block A3A function in infected cells, which immune cells can then target and kill.

“Either way, our study provides a possible switch to turning on or off HIV genome within the infected cells,” Iwasaki said.

Future research will investigate whether A3A affects genomic DNA, and if so, how A3A regulates those genes, according to Taura.

In addition, Iwasaki said that the researchers will continue investigating the function of A3A.

This paper was the first of Iwasaki’s lab to study the HIV virus.

Katherine Du | katherine.du@yale.edu .