The Case of the Sugars that “Strike Back” Against HIV

[Electromicrograph of an HIV-infected T-cell via NIAID & CC2.0] 

“Pitch Imperfect” is a series of blog posts where I highlight stories that I pitched but didn’t quite sell and discuss why it was tough to sell them. The goal is to share both interesting research stories and some of the obstacles in getting them into the news cycle.

Proposed Headline:

Sugar signals force HIV out of hiding

Proposed Dek:

And the same sugar signalling pathway “poisons the virus on the way out”

The Pitch:

Anti-retroviral therapies can block HIV’s attempts to infect new cells in patients but do nothing to get rid of HIV sleeper cells that are already in the patient’s blood stream. The immune system can’t spot infected cells unless the HIV is actively building viruses.

However, a paper in PLOS Pathogens may have revealed an unexpected ally in the fight against HIV–the sugar coatings on immune cells. Having sugars on the surface of a cell isn’t unusual; surface-sugars serve as ID-badges that allow immune cells to tell self from not-self. But they’re usually thought of as relatively passive in cell-to-cell communications. This study indicates that yanking on a certain class of surface sugar can start a chain reaction that forces HIV into the open.

“Even though it seems kind of counter-intuitive to wake up the HIV, it really boils down to: the infected cells will die if we wake them up,” says the study’s senior co-author Satish Pillai of the Blood Systems Research Institute in San Francisco.

The paper came out on Thursday, but a Google News search turned up zero hits.

Sugars, in general, are relatively underused in next-gen medicine strategies–while genes, proteins, and RNAs hog all the glory–but they may have been potential allies ambushing HIV, hiding in plain sight.

Why It Didn’t Quite Land:

(A) Like I said in the tegu lizard post, I need to work on coming up with stronger endings for my pitches. Pointing out that no one else is covering a story can help convince editors that this story is unique, but it might also make them think, “Well, if no one else is on this story, is it really important?”

In marketing emails, you want to end with a clear “call to action”, something that says to people “Now that I’ve convinced you I’m awesome, I want you to [sign up for my newsletter/ email me back with times we could meet / read my blog/ pay me to write more about this thing!]”  And like it or not, when you’re a freelance writer, pitching to editors means that you’re basically sending super-specific marketing emails about a story you want to tell. 

(B) However, I think the main reason the pitch didn’t quite land was that in spite of the “Sugars don’t get enough credit, dude” angle I’m pushing, the paper is about an interesting protein–GAL-9–that does something to cells that looks like it might potentially help us fight a scary disease, but we don’t know whether it’ll work in people. 

(The fact that they gathered the HIV infected cells from actual patients who are currently on anti-retroviral therapies and living with HIV helps them, but since those cells were isolated into petri dishes for the experiments, at this point, they’re still making an educated guess about what would happen with a whole immune system in play.) 

Loads of papers pointing to a promising molecule that might cure a disease come out every week, prompting some editors to label pitches off of those studies as too “Gene of the Week” or “Too Protein of the Week.”  Editors need the story to have an obvious hook that makes it stand out from the crowd. Researchers with interesting backstories,  studies that mark the “first time scientists ever did [X]”, papers that challenge the public’s ideas, cute animals, well-executed metaphors, and interesting comparisons are just a few of the most common “hooks” in science news stories.

The “Sugars-are-Underrated” approach was my way of attempting to get around the blending-into-the-crowd problem, but general readers are not necessarily going to care that sugars get less attention than proteins.  They probably don’t think about proteins in the 1st place when they think about HIV, so the whole “Surprise! You thought this was all about the proteins, but the sugars can actually fight back too!” probably wouldn’t work outside of a fairly scientist-heavy audience.

Also, truth be told, I have a tendency to lean on the “[Science Thing X] is so under-rated in [Scientific Field Y]” a lot.  I’m always trying to convince editors editors that they need to pay me to write microbiology stories on fungi (“They’re literally still underground, dude!), neuroscience stories about the neurons outside of your brain (“People just don’t realize how profoundly influential the somatosensory neurons are…”), and “explainer” stories about molecular biology (“Hey, I bet your readers haven’t even heard of Alternative Splicing yet…. )

Yeah. I blame my Alma Mater for my hipster tendencies.  (Christopher “It-goes-to-eleven” Guest went to Bard…Also, Steely Dan is kind of Bard’s fault.)

At the same time,  editors always want to highlight the stories that no one else is telling, so the “[Science Thing X] is so under-rated in [Scientific Field Y]” is often a good angle to use, once you’ve made sure the facts back it up.

It just also helps to have other angle strategies in your repertoire, too.

Stuff That Didn’t Make the Pitch:
  • Observant readers may recognize Satish Pillai’s name from this previous post on HIV.  Like many science journalists, I usually tell my scientist sources to let me know if their lab has exciting papers coming out in the future, and most of the time, the scientists don’t do that. But in this case, Pillai actually did email me about the upcoming paper about one day before it was coming out. Not much time to read a 28-page paper, but being the source who actually does volunteer information about interesting upcoming source is a good way to stand out to journalists.
  • This particular project was a collaboration between 

    Lishomwa C. Ndhlovu‘s group at University of Hawai’i and Pillai’s group at The Blood Systems Research Institute in SF.  The study’s first author is a staff scientist with Pillai’s group named Mohamed Abdel-Mohsen. He did a lot of the reading up on sugar chemistry and figuring out how to isolate effects of particular surface sugars (which is really, really hard.)

  • The “sugars are under-rated” arc isn’t my invention, or even specific to this paper. I first heard about the relative neglect of sugars in molecular biology from Lara Mahal, an NYU chemist who makes sugar-detecting devices. Her spiel on that stuck in my head long enough for me to connect it with a study where a different team of chemical engineers tweaked an antibiotic such that it could kill drug-resistant bacteria.  A lot of drug molecules have a sugar component, so some chemists are looking into inventing new drugs simply by peeling off the drug’s default sugar and replacing it with a slightly different one. (Kind of like changing the hats on Lego people…) Anyway, that turned into my fall feature project at MIT SciWrite,  which would have been awesome if I were faster at writing about chemistry. Instead, I ended up with interview upon interview with chemists who all said sugars are understudied, an overdue feature project draft, and an anvil hanging over the head of my grad-student-status. The anvil fell. My MIT grad-student-status is in a potentially permanent coma.  I still want to write about the “understudied sugars” narrative (“It’s so 300-level biochemistry, even most of the science wonks have no idea about it yet.”), but what happened at MIT has made me leery of approaching sugar stories, but you never get over your fear unless you face it head-on, right?
  • I wrote back to Pillai saying that sugar biochemistry–aka glycobiology–is often a tough field to sell. I threw in a link to one of the few people to ever write a mainstream magazine feature that involves glycobiology talking about how tough it is conceptually (among other things).  I get this email back:
  • OK this is going to blow your mind:I haven't seen that feature before, but Seth Mnookin and I were best friends all through grade school - like from 2nd grade all through high school!  We even went on Grateful Dead tours together!  Small world…

    Yeah. Small world…Seth also happens to be a prof at MIT SciWrite, but he didn’t teach in the grad student seminar this past fall, nor was he involved in my feature project at all.  (Which was frustrating, but working with grad students just wasn’t his priority that fall.) 

    But the funny thing is: Pillai told me at one point that he almost became a science writer instead of a virologist, and I also have a friend from high school who is sometimes a science writer but now studying virology on the West Coast. Her name is Katherine, and she studies flu viruses. (Granted, HIV and flu viruses are just about as different as two human-infecting viruses could be, but it’s still kinda funny.) 

  • But back to the viruses: Hopefully, the researchers will be able to use Gal-9 as part of a strategy called “Shock-and-Kill”, where a medicine “shocks” dormant HIV into action. Churning out viruses is toxic for cells, but since HIV is a retrovirus, it can simply slip its genetic code into our cells’ genomes. The whirligig outer shell of the HIV [pictured below] disintegrates, and for all intents and purposes, the latent HIV looks like just another gene. 
    9576597766_afeb072db3_o

[Diagram of an HIV capsid (or virus shell). The stuff inside the blue circle is the virus’s genetic material. Image via AJcann & CC 2.0] 

Immune cells in HIV-infected people are looking for a needle buried deep in a hay stack…Except the needle can also hijack and destroy their comrades’ bodies from the inside out. And could be lurking in any one of the immune cells.

Whether this strategy would actually work in practice depends on how quickly the infected immune cells die after the viral genes “wake up”.  Figuring that out requires lots of math and computer simulations that focuses on what factors allow HIV genes to hide for a long time and how quickly they’ll burn through immune cells once active.

(Oddly enough, I know an HIV “fancy math” researcher from a science writing workshopping group called Neuwrite.  Her name is Alison, and as far as I know she did not secretly go to high school with any well-known science writers….But she did just email me about these two new anti-HIV antibody papers out in Cell. This one is about a hybrid antibody that combines the binding abilities from two natural ones, and this one is about a different synthetic antibody that has a hinge so it can shapeshift and kill more different HIV strains…

I’m not sure if this is just a string of coincidences or evidence that virology is turning into one of my beats…) 

  • While the antibody research aims to prevent new people from contracting HIV, the “shock-and-kill” research is for individuals who are already infected.  
  • We don’t know the details of the chain reaction Gal-9 sets off when it binds to surface sugars, but in addition to forcing the HIV to replicate, it also amps up production of a virus-sabotaging protein called APOBEC3G.  Its name is terrible, but it attacks the base pairs in viral RNA and DNA and changes the “G” nucleotides into “A” nucleotides.  In other words, it goes around just adding typos to copies of HIV’s genetic code, so many that the virus can’t assemble new copies of itself.  Our cells make APOBEC3G naturally, but HIV carries a protein called Vif for the sole purpose of destroying APOBEC3G and its kin.

20160621_143243

[A very scientific dramatization of APOBEC3G’s job.  It doesn’t have hands or eyes in real life. Vif’s resemblance to a shark is exaggerated for comic effect. Drawn by me. ] 

When Pillai and company dosed infected cells with Gal-9–the sugar-binder, the cells started making more 4 or 5 times as many APOBECG3s as cells in the control group. (A few their cell samples  actually started making 10-20 times as many APOBECG3s with the Gal-9 boost. ) There’s a solid chance those APOBECG3 numbers are large enough to overwhelm any Vifs the virus makes.

Best case scenario: When Gal-9 sets off a signal cascade in the sugars, the hidden HIV starts building, the infected cell dies, and the virus copies it makes will be so full of typos that they won’t be able to infect any new cells. 

Worst case scenario: You wake up all the HIV and accidentally poison the healthy immune cells by overdosing them with Gal-9.

Obviously, more experiments and lots of simulations are needed before anyone can try this in people.

  • When I asked Pillai whether sugar research was “A Thing” in HIV research, this is what he said: “”Sugars are part of HIV virology, but it’s always from the perspective of sugars on the surface of the virus. For decades we’ve known that one of the ways HIV avoids the immune system is by coating itself with lots and lots of host sugars…There’s been very, very little attention paid to how the sugar coating on the surface affects the fate of the virus.”

 

TL;DR:

Researchers found evidence that hidden HIV can be (partially) thwarted by manipulating the sugars in immune cells.

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