A research team led by GAO Guangxia of the Institute of Biophysics of the Chinese Academy of Sciences (CAS) published important findings on the interaction between HIV and host cells in Cell Host & Microbe on July 23. The study, “HIV Exploits the Host Factor RuvB-like 2 to Balance Viral Protein Expression,” discovered that RuvB-like 2 (RVB2) inhibits Gag expression. 

The study has implications for the development of drugs that can potentially eliminate HIV from cells rather than just slow the progression of AIDS. 

As of 2014, about 36.9 million people worldwide were infected with HIV. In the same year, over a million people died of AIDS. The current strategy for treating HIV is to use drugs that interfere with various stages of the HIV life cycle. This treatment – highly active antiretroviral therapy (HAART) – controls the replication of the virus, thus slowing the development of symptoms. However, it is not a cure. 

In order to lay the foundation for more effective drugs, GAO’s research team has been devoted to studying the interaction between HIV and host-cell proteins. They have carried out thorough and systematic research on how the Zinc-Finger Antiviral Protein (ZAP) inhibits HIV replication. They have found that ZAP inhibits viral infection through promoting target viral mRNA degradation. ZAP-mediated target mRNA degradation is caused by specifically binding to viral mRNA elements to induce translation repression. ZAP also recruits host RNA-decay factors to facilitate the degradation of target RNA.

By Interacting with both the 5’ untranslated region of target mRNA and newly translated proteins, RVB2 induces ribosome pausing and realizes the inhibition of Gag protein expression. Interestingly, by competing with RVB2 to bind to Gag proteins, HIV-encoded envelope proteins can antagonize RVB2 from inhibiting Gag expression.

According to more precise analysis, the amount of envelope proteins is very low at early stages of viral gene expression. Since Gag proteins can form viral particles by themselves, the viruses produced are free from infection since they lack adequate envelope proteins. The amount of envelope proteins at this stage is unable to antagonize RVB2. With the help of endogenous RVB2, the number of viral particles decreases. Thus, the possibility of producing non-infected viruses without envelope proteins is decreased. As time goes by, the amount of envelope proteins in cells increases, thus meeting the needs of virus production and being capable of antagonizing RVB2, following that Gag expression will not be inhibited by RVB2. Thus, virus production can proceed smoothly. By making use of one inhibitory factor of host cells, HIV replicates effectively and reduces the risk of being attacked by the immune system due to producing too many non-infected particles. Prof. SHANG Hong’s group, from the First Affiliated Hospital of China Medical University in Shenyang collaborated with Prof. GAO’s group. They found a positive correlation between the RVB2 expression level and pathogenic progression of HIV, which provided strong proof for their findings.

Taking advantage of its own properties and the internal environment of host cells, these viruses replicate effectively and precisely, just like controlling an assembly line, whose quantity and quality are strictly monitored and controlled. These findings extend our knowledge of HIV and broaden our understanding of the interaction between host and viruses. GAO’s group will continue research in this area.