6 ms·
I read through the original paper (https://dx.doi.org/10.1016/j.immuni.2016.10.027 https://dx.doi.org/10.1016/j.immuni.2016.10.027, paywalled). In essence, an
by nneonneo 10y ago
I read through the original paper (https://dx.doi.org/10.1016/j.immuni.2016.10.027 https://dx.doi.org/10.1016/j.immuni.2016.10.027, paywalled).
In essence, an antibody called N6 was extracted from an HIV patient. The patient is a long-term nonprogressor who has had HIV for 21 years, but an exceptionally low viral load of <1000/mL and normal CD4 T-cell count. This indicates that his immune system has kept the virus at bay for all these years with essentially no ill effect.
HIV viruses have a surface protein complex called Env, which binds to the CD4 surface protein to gain entry to T-cells (part of the immune system). HIV cannot transmit without this protein complex, and so certain parts of the complex are very well conserved across different HIV strains.
N6 binds to this part of Env, in some sense "simulating" CD4. However, because it's just an antibody and not a cell, once Env is bound it cannot infect anything. This is what makes N6 a neutralizing antibody.
The thing that makes N6 special (more potent and more broadly applicable) is that it is able to avoid the parts of Env that HIV doesn't need for replication. Imagine Env as a wrench. The head of the wrench is a specific hex shape to mate with CD4 and can't change. Antibodies can grab on to the wrench handle to prevent infection. But the handle can change, and HIV regularly mutates this part to avoid being caught - adding side branches, changing the shape, and so forth. N6 is cleverly arranged so that it can strongly bind to the wrench without grabbing the handle too strongly - in other words, it tightly binds the head of the wrench like a person wrapping a thumb and index finger around it (this hand analogy appears in the paper). The result is that HIV has a much harder time getting out from under the antibody, since mutating itself to alter the head shape would also affect infectivity.
Now that larger HIV screening trials are done, and the technology has advanced to better detect such super-antibodies, more of these clever antibodies may be discovered. We may yet have a good shot at defeating this tricky virus!
- errantspark 10y agoReminds me of Shapely from William Gibson's Bridge Trilogy "He was discovered by the AIDS industry when he had already been HIV-positive for twelve years. His strain of HIV was notpathogenic but was able to kill the lethal strain of HIV. By isolating his mutant strain of HIV it was possible to develop an AIDS vaccine."
- waterhouse 10y agoHmm, I wonder how well that would work. I believe HIV mutates a lot, and so if you infected yourself with a "nonpathogenic" version, I'm not sure it would remain so forever. (Though it says "develop", so perhaps they could find or introduce some other weaknesses in that strain, and let it kill all the existing HIV, then flood the patient's body with something that kills the new strain before it can mutate.)
- sanj 10y agoIt makes me wonder if patient Z258 is gay and if that'll have implications on who uses this therapy.
- sanj 10y agoThose down-voting may want to read Gibson's work for context.
- j_m_b 10y agoThank you for this elegant summary!
- kylehotchkiss 10y agoThe scientists who discover these solutions are my heroes. They spend their lives tangled in these complexities and save actual lives with their work. That's admirable!
- hollander 10y agoAnd may those scientists who devote their life to stuff like this, but who will never find a solution, be (y)our heroes as well! It's a game of big numbers, much (very smart) trial and error I suppose, and never finding something meaningful may result in much frustration. Still this has to be done because you simply don't know which path will lead to the solution.
- jaimehrubiks 10y agoYou are so right
- TeMPOraL 10y agoThey're too are my heroes. Those who never find a solution still did the work, traversed the other paths - which is a necessary part of figuring out which path is the correct one - and quite often, what they saw on those paths may lead someone else to solve some other problem in the future!
- zouhair 10y agoThis is why big time negative results that lead to closing a big path that may have wasted humanity huge research time should also get rewards and grants. Now if you only do negative research you cannot publish and you if you don;t publish you die.
- collyw 10y agoAgreed. I wonder how many negative results get repeated because they don't get published. It could save a lot of effort and money publishing negative results.
- deleted 10y ago[deleted]
- Twirrim 10y agoJust to check I understand this correctly, as a layman: It stops HIV from progressing in the body, holding it at bay. Someone with HIV would need to take this medicine for the rest of their lives. It doesn't actually cure it. (not denying that holding it at bay is a significant step forward)
- carbocation 10y ago(NB: I don't do HIV research.) You are correct. Obviously, curing HIV is an open research question, but also the way to go about curing this retroviral infection is still unknown. When there is sustained virologic response, we know that the virus will come back if drugs are withdrawn. Exactly which niche of cells have integrated HIV into their genome, and how to identify them, is an active area of research at least as of about a year ago when I last looked into it (hint: probably macrophages and T cells). The Berlin patient shows that cure is possible via treatments that also eradicate the bone marrow, but these are not generalizable across populations due to the high morbidity and mortality. For prevention, vaccination that can generate antibodies such as the one in the article would be highly valuable. Less valuable but still very beneficial would be a long-lasting monoclonal antibody injection that can be given once a month (or ideally less often) to reduce the likelihood that high-risk individuals become infected. For cure, I suspect that an approach which pairs replication suppression with genome editing tools, such as CRISPR, may ultimately prove successful in curing individuals of HIV.
- ekianjo 10y ago> The Berlin patient shows that cure is possible via treatments that also eradicate the bone marrow, but these are not generalizable across populations due to the high morbidity and mortality. Correct me if I'm wrong but I thought that patient got HIV back a year or two after the bone marrow transplant?
- carbocation 10y agoWe're actually both right: there are two patients referred to as "The Berlin patient." The first one is a man who was given an unusual ART regimen and has been able to stay off of it for an indefinite time, with low circulating levels of HIV. But this isn't the person that most physicians think of when we talk about the Berlin patient. Rather, we're thinking of the man who had a bone marrow transplant and has been truly cured.
- otm_shank 10y agoThe full paper is available on researchgate: https://www.researchgate.net/publication/310327204_Identification_of_a_CD4-Binding-Site_Antibody_to_HIV_that_Evolved_Near-Pan_Neutralization_Breadth https://www.researchgate.net/publication/310327204_Identific...
- astockwell 10y agoGreat summary! Is there any discussion of how these antibodies would affect transmission/communicability to others?
- djsumdog 10y agoDid the study indicate if the long-term nonprogressor on any anti-viral drugs? I think the most interesting nonprogressors to look at are the ones who refuse treatment. Many of them die within 5 ~ 10 years, but the ones who don't could potentially have a natural resistance to HIV.
- nneonneo 10y agoThe patient was not on any antivirals at the time his sample was taken.
- erikb 10y agoGreat summary that can be understood without any technical knowledge about the topic. Thanks.
- aswanson 10y agoCan you recommend any introductory texts regarding protein complex binding dynamics?
- zamalek 10y agoThe article indicates that this could be used to create a vaccine. How would that work? So far as I understand the medicine for vaccines, they are used to train your immune system to create new antibodies by exposing it to the virus. What process would be used to train the immune system from an existing antibody?
- ufo 10y agoI don't think it would help to create a vaccine directly but it could help vaccine research.
- judahmeek 10y agoNice post, but there's an awful lot of anthropomorphizing there. As far as I know, viruses don't purposely mutate. Rather, their design has evolved to encourage beneficial (to them anyway) mutations.