Though the makers of the sixth Harry Potter movie downplayed it, the young wizard’s mysterious invisibility cloak gave him vitally important passage and power. The same holds true for the herpes simplex virus (HSV), other herpesviruses, and the human immunodeficiency virus (HIV), all of which can hide indefinitely inside cells in a dormant state. Safely cloaked, these viruses remain protected from antiviral medications yet at the same time poised to erupt back into infection.
It is not clear yet how the cloak forms—whether viruses mask themselves or if this latent state is part of an imperfect defense mounted by cells—but new work from David Knipe, the Higgins professor of microbiology and molecular genetics, has determined precisely which viral genes are responsible for weaving this molecular veil. The work may eventually lead to strategies that make latent viruses vulnerable to antiviral drugs by preventing latency or knocking viruses out of latency.
Though this study focused on herpes, new strategies may apply directly to HIV, which, according to an earlier report, uses a molecularly similar cloaking device. It may be even more feasible for HIV, said Knipe, because HIV viruses become latent in immune cells rather than in the less dispensable sensory neurons that herpes hides inside.
When herpes viruses infect epithelial cells, they cause infection by mimicking cellular genes and replicating alongside them. A spool-like chromatin structure forms in the nucleus to assist in viral DNA replication. But when these viruses enter sensory neurons, they become latent. Rather than replicating, all of the viral DNA save an exclusive set of active latency-associated transcripts lurks quietly inside the cell. The chromatin structure that forms with the viral DNA contains modifications—changes to underlying proteins called histones—that make the assembly more compact. This tighter structure makes it impossible for the transcription factors that read genetic instructions to access the genes.
Knipe and first author Anna Cliffe, HMS research associate, discovered the exact histone modification that cloaks the DNA, trimethylation of the residue number 27 (lysine) on histone H3, or H3K27me3. They also found that this modification only emerges along with the latency-associated transcripts, suggesting that these bits of noncoding RNA promote this gene-silencing modification. The researchers, who will next try to understand how these molecules interact to weave the cloak, described this work in the August Journal of Virology.
Students may contact David Knipe at david_knipe@hms.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The National Institutes of Health; the content of the work is the responsibility solely of the authors.
