No. 8 How evil was Ramsey, or “Can HIV be eradicated?”

Blue 4 Overlayed on a Red X

 
Welcome back sweet summer children! Sorry I have been away so long. I had planned to blog about the mysterious illness, Sarcoidosis, but at the last minute my plan was foiled. I need the scientists whose work I’m highlighting to cough up a little more data in order to make the blog particularly useful. I’m still waiting for them to reply to my raven. Don’t worry though there is plenty to Blog about. A stellar presentation by Dr Jason Baker of Hennepin County Hospital at CROI 2018 will show up on the blog for sure. First though I need to update you on House QVOA + and explain why it is so hard to pin down how many of these traitors exist. Let’s start at the beginning.
House QVOA + represents those CD4 cells that are not only infected by HIV, but are silently waiting to activate and start creating havoc. QVOA stands for Quantitative Viral Outgrowth Assay, which is an important concept in the field pioneered by Drs Bob and Janet Siliciano. QVOA essentially means if we take cells out of the body can we provoke them to make infectious HIV virus (outgrowth) and measure how much they make? The term is sometime used almost synonymously with the HIV reservoir, but they are not the same for some important reasons that I’ll get into later. QVOA+ cells and the reservoir are much closer to being the same though than any other measurement of the reservoir from the blood system for reasons that I’ll explain now.
It is relatively easy to measure how many CD4 T cells have been infected and have viral DNA inserted (integrated) into the T cells. They can be detected by various HIV DNA nucleic acid tests. Only a small percentage of these infected cells though will be truly evil and infectious like House QVOA+. Likely in some patients less than 1 in 100 of those integrations are “error free” and productive enough for the virus to make it back out. In severely infected individuals who maybe unusually immunologically vulnerable to HIV or started therapy very late it might be more than 1% but the % of infected cells that can make viable virus is still less than 5% even in these individuals. Hence most HIV infection events count towards House Infected but not Infectious. I will admit this House doesn’t have the “snappiest” name. If any of you devoted readers have suggestions I’m eager for change. The sigil though I think was a cool inspiration from Alec Winzenried, the first webmaster of our site. You Thrones afficionados will know the character “cold hands”, aka Benjin Stark in the show has been clearly “messed up” by some evil stuff. Still he somehow remains on the “good side”, even coming the aid of some major characters just as their “plot armor” appeared to be pierced. Well we at Game of T cells (Alec really), thought this was reminiscent of T cells infected but who somehow managed to keep the the viral DNA locked away and silenced, never to come out. Silencing is actually a genetic term referring to both naturally occurring and laboratory methods of making sure a gene is either not transcribed to RNA or if the gene is transcribed, the RNA is not translated. Most of the integrated HIV in these cells is “silenced” in this case due to mutations that occurred in the integration process that are so problematic that no viable virus is produced even if transcription occurs.
Ok, now we are done with the introduction of both Houses. Despite the fact that the QVOA+ cells are very rare, on the order of only 1 in a million CD4+ cells (infected and uninfected) the havoc they can create is considerable. A study by Shacker et al1 took 12 HIV+ patients all of which had been virally undetectable for years with wonderful immune recovery and examined how fast HIV would appear in the blood and be infectious if they briefly stopped their medication. Extensive biopsies and other procedures were done during this brief medication break to gain information from this study (ie don’t try this at home, you won’t learn anything). This study was published in 2015, and two of the subjects were on the newest intergrase inhibitor therapy and all had CD4 cells of over 500 so there was some hope that some patients wouldn’t relapse right away. Unfortunately, all had rebound viremia within one month, many within just 2 weeks, suggesting that even patients that have been well controlled for many years are not significantly closer to being cured than they were several years earlier. While disappointing (and some would say predictable) not all hope was dashed. The subject who started therapy very early after infection (within 6 months), did relapse a little later than rest of the patients. More convincing was that patients who started without ever having developed actual AIDS (such as never having Pneumocystis pneumonia) also relapsed later than those that had more immune damage prior to starting therapy. These differences were small though and by themselves do not present an obvious plan for future victorious battles.

One more important caveat before we return to battle. Earlier I mentioned the HIV reservoir was not necessarily identical to House QVOA+. The true strength of the enemy is currently “hidden” in lymph nodes (which Dr Shacker biopsied in the paper discussed above) The lymphatic tissue probably contains ~50 fold the QVOA+ cells at any one time than does the blood. If House QVOA+ which is sampled from the blood “weakens” in parallel with reduction in the reservoir in the lymph nodes then the distinction between House QVOA+ and the true “reservoir” is largely one of scale and fairly semantic. If though an attack on House QVOA+ is effective in the blood and ineffective in the lymph nodes or some other unknown factor is at play then a catastrophic plot twist is likely.

To conclude for this episode while every HIV infected patient has at least a few QVOA+ cells waiting for a chance to create havoc, how many of these cells each person has is still hard to pinpoint. New research is demonstrating that certain characteristics are associated with fewer QVOA + cells and lower reservoirs. What those characteristics are will have to wait for another blog. Perhaps with enough maester knowledge eventually Ramsey will be truly defanged.

1. Rothenberger, MK and Schacker, TW et al, “Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption” PNAS 2015. http://www.pnas.org/content/112/10/E1126

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