Streaming through the blood of people with HIV are cells carrying mutant, incomplete viral genomes—viral DNA sets that researchers have long deemed duds, irrelevant to disease. But a study in PNAS this week refocuses attention on these defective viral tagalongs. The authors report that cells can use them to make abnormal HIV RNA, and possibly even anomalous proteins that could cause ongoing inflammation. Inflammation is a key predictor of death rates in people with HIV, says study author Cliff Lane, director of the division of clinical research at the National Institute of Allergy and Infectious Disease (NIAID) in Bethesda, Maryland.
When HIV infects a cell, it inserts its own DNA into the host’s chromosomes. In people whose disease is well-controlled by medication, the majority of affected cells contain a busted HIV genome, with mutations or deletions, that can’t make any more viruses. These have been considered “junk” by most scientists, says study author Hiromi Imamichi, a virologist at NIAID. Imamichi thinks they’re more like “zombies”—dead, but still able to do damage.
Using blood samples from a repository at the National Institutes of Health Clinical Center in Bethesda, Imamichi checked for HIV DNA and RNA in cells from nine patients. For people whose disease was poorly controlled, with plenty of detectable virus in their blood, most of the HIV genomes in their cells were intact. But in those whose disease was well-managed, most of the HIV genomes were shortened due to missing pieces. Nonetheless, in both one person with detectable virus and four with HIV under control, their cells were producing defective RNAs from the truncated HIV genomes.
Though flawed, those RNAs contained sequences that could, theoretically, be used to make protein. For example, in some cases different HIV genes were glued together, potentially encoding chimeric proteins.
The authors provide “quite convincing evidence” that cells with defective HIV genomes make HIV RNA, says Mathias Lichterfeld, a translational immunologist and infectious disease physician at Brigham and Women’s Hospital in Boston, who was not involved in the study. What remains to be shown is whether those RNAs do then make warped, mismatched HIV proteins. It wasn’t possible to find such proteins in the blood samples, since any amount made by the small cell populations would be undetectable, Lane says. But he and Imamichi are now trying to prove defective HIV genomes make protein both in vitro and in vivo.
If those proteins do exist, Lane believes “they’re probably causing some kind of immune activation.” That would explain why even in people whose HIV is kept in check, antibodies to HIV proteins and inflammation persist. The defective proteins might “distract” the immune system from the truly dangerous viruses, Lichterfeld speculates. The authors plan to study whether the presence of defective HIV RNAs correlates with higher immune activity in patients.
Lichterfeld thinks it might be possible to block production of the defective HIV RNAs. Knocking out these zombies would likely improve the outlook for patients, by eliminating a cause for inflammation, Lichterfeld says, and Lane suspects such a therapeutic could be a key piece of an eventual cure.