Recently, the latest issue of science published an important study on AIDS. By analyzing the structure of HIV RNA, a team of researchers led by the University of Maryland not only explains a peculiar phenomenon of the virus, but also helps us better understand the mechanisms in which RNA works in cells.
Whether it’s for the development of anti-HIV drugs or for basic science, the study is important.
Fifteen undergraduates and two high school students participated in the study (Photo: Resources 1)
Scientists have long found that the RNA structure of HIV-1 virus is somewhat different. In its promoter region, there are three consecutive otolysine nucleosides (G), which can be the starting point for transcription. As a result, the HIV genome produces three different transcription products, starting with one, two, and three oguanine nucleosides (hereinafter 1G, 2G and 3G, of which 1G and 3G account for 90%, the vast majority).
Depending on the number of “Gs” at the beginning, HIV-1 can produce 3 different transcription products (Photo: Resources)
Interestingly, these transcripts have very different fates. Scientists have found that 1G transcription products form a bipolymer in vitro and are selectively encased in the newly formed virus as the virus’s genomic RNA (gRNA). 2G and 3G transcription products, on the other hand, perform mRNA functions and guide protein synthesis.
Why do the differences in 1-2 nucleosides in the region bring very different fates to the genetic material of HIV? To answer this question, the scientists used the HIV-1 strain common lying in humans to take their first 368 nucleosides to infect the cell lines used in the experiment. The study found that only 1G and 3G transcription products existed in these cells, and that 1G products were mainly present in newly generated viruses, while 3G products remained mainly in cells. In addition, 1G products tend to form dipolymers. These results show that the original conditions of the HIV-1 strain of more than 300 nucleoside gRNA and mRNA selection, as previously reported, are consistent and have reference value.
The 1G transcription product prevents eIF4E from starting the translation process, and it also becomes gRNA (Image Source: Resources
Then, using a variety of techniques to analyze RNA structures, the researchers found the reasons why the two transcription products showed different fates — for 1G transcription products, their RNAs form a dipoly “dimeric multihair” structure, making it impossible for the eukaryotic starting factor 4E (eIF4E) to recognize the 5′ cap end of RNA and thus to initiate the translation process.
The formation of several G-C base pairs has created a completely new structure for 3G transcription products into mRNA (Photo: Resources 1)
In contrast, 3G transcription products use a completely different structure, and their 5′ cap ends are easier to touch, starting a subsequent translation process. The researchers note that changes in several nucleosides in the region can make a huge difference to the entire 9kb-long viral RNA structure through the formation of G-C base pairs.
“For decades, scientists have known that THERE are two different structures in HIV RNA, but they don’t know what balance is in between,” said Dr. Joshua Brown, lead author of the study. This is a paradigm change in understanding how HIV works. “
This work may also have special value in understanding the function of RNA (Image Source: Resources 1)
The researchers say this could make a huge difference in the treatment of AIDS. Theoretically, if we can develop a drug that “locks” the transcription products of the HIV-1 virus into a particular structure, either to lose the gRNA or the virus to lose mRNA, it could prevent further infection of the virus.
The authors also conclude with a previous pan-genome study that found that there were similar “double transcription start sites” in mammalian starters. In the future, we deserve further research on these regulatory transcription sites, which may give us a deeper understanding of the function of RNA.