Welcome back dear readers! If you remember our last blog we highlighted recent evidence that there might be patterns to who has a “big” HIV reservoir and who has a “small” reservoir. Now we’ve known for a long-time reservoirs vary in size, but even “medium to small” reservoir, lead to viremia within a couple (usually 2) weeks of stopping therapy (Digression: my partner is adamant that a couple can only be two, but I’ve been known to eat a “couple” of cookies, and that has only rarely meant two). Whether a very small reservoir would predictably allow a Person Living with HIV to go off medications without becoming viremic is uncertain. Certainly, there are People Living with HIV who have small reservoirs and go off medications without becoming viremic (so called Post Treatment Controllers), but these people are unusual, only a little more common than so called Elite Controllers (who are ~1 in 200) so there is probably something else needed besides a very small reservoir)
This issue we want to highlight an intriguing paper about the HIV reservoir that suggests another possible “pattern” to who tends to have a large vs small reservoir. The paper traveled much further than your run of the mill paper in Proceedings of the National Academy of Science (PNAS) by Biswajit Das, Jonathan Karn1 and co-workers and needs validation in larger cohorts, nevertheless it rings true. This paper started as many molecular studies do now a days with a fishing expedition. The authors did a screen with small interfering RNAs of ~15,000 genes in a male T cell line called Jurkats for genes that were related to the maintenance of HIV latency. They came up with a handful of genes that seem to be required to maintain HIV latency and the second most strongly associated of gene was the Estrogen Receptor 1 (ESR-1). Some genes that were expected such as one that interacts with the HIV tat gene were also associated suggesting the screen worked as expected, but ESR-1 was a surprise. Like a lot of surprises though, once revealed a lot of things came into focus.
The authors follow-up on this result by doing some cell experiments using both ESR-1 agonists, as well as antagonists, in part because this is relatively easy to do with at least some medications that are fairly safe such as tamoxifen. These cell culture results supported the idea that enhancing or blocking estrogen receptor signaling pharmacologically would alter latency. There is some interesting virology in the paper but for the purposes of this blog we want to focus on the final few people experiments that make up this publication. First the authors obtained large blood volume samples from 6 men and 6 women who were fairly well matched for the duration of therapy and the pretreatment viral load. This is a very small study. One might quibble some that the subjects were not perfectly matched. Although the age is statistically similar, the average age of the males (37) was a little younger then the women (44) and the women had been infected a little longer on average (11 vs 8 years) but perfectly matching on all of these variables would have been very difficult. The results of this comparison was that the HIV reservoir from women was ~1/3 lower then that of the men. They did further experiments with cells from both males and females living with HIV to suggest that sex of the chromosome correlated with how the reservoir from those cells responded to different latency activation agents. In broad strokes some reactivation agents worked better in male cells than female cells, presumably because there was more virus there to reactivate. Now we have to remember there are many unanswered questions about how to shrink reservoirs to a degree that is clinically meaningful. At the end of the day even if this work is validated independently, it might be that these differences between men and women are not relevant to how we attempt to eradicate reservoirs. For today though any clue on how to even recognize meaningful reservoir shrinkage is important. The fact that shrinkage might be different in men and women certainly opens up new areas of investigation.
I just want to end with a Shout out and Thanks to the authors (B. Das, R. Johnston, N. Chomont, J. Karn and coworkers) and @AMFAR for funding this innovative work. (Clarification AMFAR doesn’t fund this blog). I do want to make a half-hearted apology for the title which I just couldn’t resist. Obviously both Theon and Yara have tremendous courage in their own way. I don’t think it is particular instructive to compare the “size of their courage”. When it comes to the HIV reservoir though….I do think size matters.
- Das et al PNAS, 2018 (pnas.org/cgi/doi/10.1073/pnas.1803468115)