Science Topics – 151

HIV uses the host (human) RNA modification for viral replication.

Hiroyuki Fukuda (Takeshi Chujo & Kazuhito Tomizawa)

Virus uses the host system for viral replication. For example, many viruses with RNA genomes use RNA modifications to evade host immune recognition of the viral genomic RNA. Humans also use RNA modification in mRNA vaccines against SARS-CoV-2. The RNA modification enables the mRNA vaccines to evade immune recognition.
In the current paper, we showed two ways that HIV-1 makes use of human transfer RNA (tRNA) modification machinery for HIV-1 replication. First, we showed that during HIV-1 replication, methylations at human lysine tRNA (tRNA^Lys) positions 58 and 54 are necessary for HIV-1 to stop reverse transcription at appropriate positions. Second, we discovered that human tRNA methylation at tRNA position 58 is pivotal for HIV-1 protein accumulation and HIV-1 virion production.
Progression of acquired immune deficiency syndrome (AIDS) can be mostly suppressed by appropriate medications. However, HIV-1 can easily mutate, and drug resistance can become a problem. Our study illuminated the importance of human tRNA methylation for HIV-1 replication. Thus, targeting of this human tRNA methylation may lead to the development of anti-AIDS drugs that do not easily allow HIV-1 to become resistant.

Fukuda, H., Chujo, T., Wei, F.-Y., Shi, S.-L., Hirayama, M., Kaitsuka, T., Yamamoto, T., Oshiumi, H., and Tomizawa, K. Cooperative methylation of human tRNA₃^Lys at positions A58 and U54 drives the early and late steps of HIV-1 replication. Nucleic Acids Research (2021) gkab879, doi: 10.1093/nar/gkab879.

The cellular tRNA position 58 methylase gene was mutated to inactivate much of the methylation activity. We then used the mutant cell lines to monitor HIV-1 reverse transcription activity and virion production activity, and demonstrated that human tRNA methylation at tRNA^Lys position 58 is required to stop reverse transcription at appropriate position (Figure, the red letters in the top half). In addition, the importance of methylation at position 54 as a second RT-stop site was supported by conservation of retroviral genome-tRNA^Lys sequence-complementarity (Figure, the blue and green letters in the top half). Moreover, unexpectedly, we discovered that the human tRNA position 58 methylase is required for HIV-1 protein accumulation and HIV-1 virion production (Figure, bottom half).

Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Japan