If youll recall one of my first posts on SciBlogs, I urged everyone not to give up on an HIV-1 vaccine. Ya, we are sucking right now, but if we can get over our 'AAAAAAAAAAAAHHHHH!!!!!' response to HIV-1, refocus on the basic virology of HIV-1, we can get this mo-fo.
The first step in the right direction was a paper published a couple days ago in PNAS:
If youre wondering about who the gawds are in HIV-1 research, just look at the last three names on this paper: Bette Korber, Beatrice Hahn, George Shaw.
Heh. What they focused on was a really hard thing to study in the lab-- what happens right after someone is infected with HIV-1. What happens right then? Are you infected with one virus? Is there a huge breech of a mucosal barrier, and lots of viruses get through? What are the molecular characteristics of the viruses that get through? Those first few moments are The Key for making an effective HIV-1 vaccine.
But these questions are nearly impossible to answer, because who the hell just happens to be collecting their own blood right before and right after they get infected with HIV?
Well, the gawds of HIV research know where to look for such samples-- plasma donation banks. They got samples from 102 people who donated plasma often enough that they caught a donation right after infection. They isolated and sequenced lots of envelope genes (next 'Intro to ERVs' entry!), and tried to elucidate the relationship between the envelope sequences. If there was lots of diversity, that means that there were lots of different kinds of HIV-1 that established infection. Not a lot of diversity, fewer kinds of viruses got through. So what did they see?
What they found--
Of the 102 patients, 78 were initially infected by one genotype of virus. This is a point I was annoyed with the authors-- they write 'evidence of productive clinical infection by a single virus'-- thats not what their data says. Their data says that these patients were infected with one type of envelope sequence. Not that it was 'one virus'. There could be more diversity in other areas of the genome that they arent seeing, but because infection (viral entry) is mediated by the envelope proteins, that is the important sequence. Just want to clarify that point for ERV readers, since the paper is open for everyone to read ;)
What this means--
There might be molecular determinants of HIV-1 transmission. Only one 'kind' of virus gets through. Is this random? Or is it a predictable, biochemical process that only certain variants of HIV-1 are good at? If its the former, were screwed. If its the latter, we can make vaccines that prevent transmission.
Im crossing my fingers for the latter, and hoping this cherub can get her act together to help out the gawds ;)
Spelling correction: it's "breach", not "breech", at least in the context you've used it.
Their data says that these patients were infected with one type of envelope sequence. Not that it was 'one virus'. There could be more diversity in other areas of the genome that they arent seeing,
I've just skimmed through the paper so if I missed it tell me, but it seems like don't address that possibility at all which seems to have some pretty big implications.
If there's variability in other parts of the genome but not the env protein then that would lend even more weight to the idea that some feature is making that variant of env more able to infect. On the other hand if everything shows the same kind of bottleneck it seems more consistent with the idea that some subpopulation just gets in first and takes over, which might be more likely to be the random mechanism.
Abbie, assuming it is a "predictable, biochemical process that only certain variants of HIV-1 are good at," how long do you think it would take to understand these processes, and, realistically, how far away do you think a vaccine might be?
On top of Optimus Primate's question I'd like to add one.
Following the same assumptions, once a vaccine is made do you see research down this path also possibly leading to a cure for HIV in infected people?
I'd guess not myself, but since you have immeasurably more experience in this field I thought I'd ask for your view. Still, a vaccine that can stop it spreading is already an impressive result if this research leads to one.
For some reason I can't seem to get the PNAS site to pop up, but do the authors address the route of infection at all? I've seen a lot of SIV work recently (some for instance from Ashley Haase, who shows some great pictures) of what happens even MORE immediately in the vaginal tissue than what you would get in the plasma. This could have implications as to where bottlenecks may occur or what populations may cause the spread of the virus, and I would assume that an infected needle could potentially cause a significantly different signature than a sexual transmission if you have tissue specific founder populations.
I'd assume you'd be right about the needle Max since the virus would not need to go through any mucous membranes and instead is put straight into the blood stream. Any variation of HIV that gets stopped at the membrane would be home free if it gets transfered by a needle. I haven't had a chance to look at the article since I'm technically at work (I can somehow justify blogs, but not science publications to the boss) but from what has been covered here the vaccine would only really protect against sexually transmitted HIV from this work. On the other hand, if the work does lead to a cure for HIV I believe it would also be able to lead to a complete vaccine, as long as it doesn't out-evolve our barriers and treatments for it.
What I really wanna know is -
Where's Phlegming? I'm sure he'd have a lot to contribute here.
Don't let your readers, or yourself, get confused here. Of the 102 patients it was NOT that 78 of them were infected with one "strain". They were infected with 78 different strains, one EACH. In most cases (78 of 102 in this study), it seems that one or a very few viruses contribute to the initial viremia, there is an "evolutionary bottleneck" at the time of transmission.
However, it is not easy to find one particular thing that these viruses that survive the bottleneck share in common. In one patient the competition at the time of transmission might be between an AZT resistant strain (the donor was taking AZT so most of the virions in his blood were AZT resistant) that replicates slowly and an AZT sensitive strain that replicates quickly. In the recipient who is not taking any AZT, the faster replicating virus wins. This has nothing to do with envelope, except that envelope is linked to pol in each genome. In another patient, the main factor might be an antibody and or CTL response in the donor, that is then not present in the recipient.
At any rate, it is not simply that we can look at the 78 transmitted viruses, see one thing that they all have in common, and build a vaccine against that.
Brian, I think that's a good clarification, but I also think that regardless of the variety between the patients, the main point that everyone has been discussing still relates directly to the variety within patients, which is essentially zero for env in 78 of the 102 patients. Furthermore, I think your last sentence may stray slightly from the rest of your comment because if there really is one thing that all 78 have in common, would that not be a potentially very powerful therapeutic target? Even if there are other things about the env that the 78 do not share? The one "thing" does not have to be the actual strain of env, it could be either a common motif which could possibly lead to a vaccine target, or it could be a common evasion strategy that could point to an important infection mechanism, which could then lead to a different type of drug altogether.
The one "thing" in common doesn't really even matter so long as it exists at all and can be targeted in some effective way. 78 out of 102 have the same env, that's great, it's a big target for treatment if we can find something that hits that env or causes the body to naturally lock on and destroy it before HIV can do any damage. Find some more points of commonality among the rest of the 102 viruses and even if it doesn't result in a vaccine we could still come up with new and better treatments as well as possibly a medicine, even if it has to be like a 1 per day thing, that will prevent the transmission of HIV. Granted, I think we'll need a bigger sampling than even 102 different virus strains to get one that's properly effective, but even so, I think this is one of the biggest steps towards treatment/vaccination/cure that Erv has covered since I started reading.
Bleh, should've proofread a little more.
Should say "that can prevent the transmission" instead of "that will prevent..."
Naturally with something that shifts and rapidly evolves new forms of itself nothing can really be guaranteed short of managing to completely eradicate somehow. That'd probably take both vaccinations and an actual cure, as well as a worldwide campaign to get them to everyone.
Since we're talking about things in common, what's the most highly conserved element in the HIV genome? (whether it's targetable or not)
Hey FTK? Look! Science!
Dang it, now where did she go?
She may have rushed to change her envelope.
Maybe she will come back as FTK-2?
Great Qs and comments, folks! Ill try to address them in an upcoming post about Env!
(Its good to know there is a LANL person reading this blog to correct me when Im wrong/not clear-- Thanks Brian!! (he works with one of the Gods ;) hehe!)