Research on an AIDS vaccine has been ongoing for years. Very few positive results have been achieved. More recently the focus has been on broadly neutralizing antibodies (bNAbs). Broadly neutralizing antibodies show up naturally in a person infected with HIV only later in the infection. These antibodies have been shown to be effective in neutralizing the HIV virus but only if they appear early in HIV infection.
The idea now is to try to develop a vaccine which elicits bNAbs.
In your investigation of this problem, determine why the vaccines developed in the past have largely been ineffective in prevening AIDS.
Also, answer the following questions.
Why are bNAbs effective?
Why are they more effective in early infection?
Why are they produced later in HIV infection?
Do you think an effective AIDS vaccine will be developed?
Could bNAbs be isolated and purified and used in a passive vaccine?
due DEC 15
bNABs are potentially effective because they work differently than normal antibodies. Most antibodies bind to antigen which leads to the destruction of the antigen. bNABs don't bind to antigen but neutralize it right there, protecting the cells around it. Researchers are attempting to utilize this neutralizing tactic on HIV viruses and are having some success. One major issue with developing bNABs has to do with timing. Research has shown that it may take up to a whole year post infection before the body makes any sort of neutralizing antibodies. By this time, the HIV virus has mutated and learned to evade detection from other immune cells. I think this leads to why making a HIV vaccine is so difficult. Unlike other viruses, HIV not only mutates quickly but is never completely cleaned out of the body. A common influenza virus, once destroyed is forced out of the body, but HIV is not so simple.
ReplyDeleteI think a vaccine is possible to make…. I am just not sure how to make one. If a virus like HIV is ever changing then we need a vaccine or antibody that shows similar dynamics. Either that or somehow speed up adaptive immunity. The second an Ab figures out how to deal with one HIV virus, then that info should be relayed to the rest of the body as soon as possible to prepare for a counter attack, before the HIV has time to change. In other words, somehow match the virus in speed and ability to adapt.
OR, it would be interesting if the body used an APC (cell) as a decoy cell. Let the virus infiltrate the decoy cell then the APC can destroy it from the inside and present it to a nearby T cell, then start developing immunity to it as soon as possible. Whenever the virus mutates there will be more decoying APCs waiting.
Tim, that last point is certainly a cool idea! To my knowledge, I’m not sure that our body currently does this “decoy APC” immunological action. It seems to me that it would be potentially harmful if our body did in fact produce these, as it would either be a large waste (as we never encounter a major strain of HIV, but still produce a number of useless APCs) or a potential backfire (as the HIV strand mutates within the decoy APC, rendering it undetectable). However, an interesting option could be the injection of these decoy APCs into recently diagnosed patients (or even used as a precautionary measure). I’ve no idea the possibility of this procedure, or the potential affects, but it could certainly be an interesting option apart from bNAbs.
DeleteTim, I also think your idea is a really neat one. This idea of APC decoy is super interesting and I wonder if there has been any research done to further investigate the idea. I also can understand Campbell's points of concern in the unaffected person but I definitely can understand APC decoy in a recently diagnosed individual as potentially effective. I still wonder though that, if this procedure were possible, if the viral DNA would still be able to mutate and thus go unrecognized in the body.
DeleteThank you Dewey and Whitney for your inputs. I actually really like your idea what putting the "decoy APC" into a previously diagnosed patient. Then using those immune cells. Of course, there is the issue of an APC backfire. I do not quite know how to solve that... Perhaps place a substrate on all decoy APC cells then everyone once and while inject the patient with the appropriate enzyme. If the substrate reacts, then it will give off a signal to be destroyed.
DeleteThe problem of HIV vaccines can be traced, essentially, to the source: ignorance. While much of science has attempted to replicate the research techniques used to create vaccines for hepatitis and flu, without truly recognizing the difference between these maladies and HIV. Whereas hepatitis is a somewhat stagnant infection that can easily be countered through inoculation, HIV is prone to genetic mutations that prevent a specific antibody being produced by the body to counter it. Furthermore, HIV is very capable of replicating and reproducing, even under extreme circumstances, such as immunological attack. It has the ability to act as a retrovirus as it imbeds its own genome within our own. Finally, even to this day, we are not entirely sure exactly what the immune response is toward HIV infection. All of these factors are combined into an ever-growing pool of ignorance that prevents us from developing an effective vaccination.
ReplyDeleteBroadly neutralizing antibodies (bNAbs) have several modified characteristics when compared to normal Abs that allow them to act in a more generally effective capacity. Included in these characteristics are longer loops to increase variability, more mutations that increase its potency, and the ability to “stick” more strongly to lipids or sugars. All of these combine to create an antibody that can neutralize the entire biological effect of the antigenic material. Thus, simply having bNAbs bind to an HIV strain can mitigate most of the negative effects of the disease without needing further assistance from other cells, such as leukocytes.
In early HIV infection, bNAbs are able to latch on to the first strands of HIV, before mutations allow it to infiltrate human cells. This can effectively neutralize the disease before it even takes a hold. However, in the later stages of HIV, the human body, in response to the virus, produces bNAbs. Unfortunately, at this point, the antibodies are too little too late, and are unable to lock down the mutant forms of HIV.
I personally believe we will be able to eventually develop an effective AIDS vaccine. By developing more efficient ways to produces bNAbs to fight this disease, we will be able to inject patients early to combat the virus. I believe we are not too far away from being able to isolate and purify bNAbs, using much the same methods we have today to isolate normal Abs.
I believed that there was already a way that researchers are working toward in making the vaccine. As I have found from an international AIDs conference, they stated that they have found that the V1V2 - Long CD4H3a is the answer to the vaccine, yet there's another way which has left unanswered; it was through CD4bs (highly mutated), which can be achieved in years.
DeleteYour comment and Whitney's comment are all connected to what I also have found. Thus, I believe that the HIV vaccine will be developed soon in the future. Hooray!
I enjoy the optimism in Dewey and Muy, but I think finding this vaccine is more difficult than it seems. The like the idea of VIV2 that Muy, presented but, this is not a for sure combatant. Also, Muy states this can be done within years which I think it amazing but again not very practical. Research, development, and testing is so costly that it may take years just to raise the funds for the project. It does feel nice to create our own vaccines and research many that think they are the answer, but until they are finalized and proven to be effective AIDS will still continue to kill.
DeleteLike Tim, I also feel that it is unlikely that an effective vaccine will be difficult to develop as we're aiming a very small, moving target. That's not to say we will never have a vaccine, I just feel that we are still a ways away from getting it. But I sure hope we find one!
DeleteAccording to Dr. Julie Overbaugh, general neutralizing antibodies are effective in vaccines against pathogens, however she says that it is much harder for those antibodies to be effective against HIV because there are multiple HIV strains with subtly different proteins. Thus, one specific type of epitope that an Ab may recognize could very well be absent from a slightly different strain and the Ab will not recognize the virus. Dr. Overbaugh does state however that bNAbs are effective in passive immunization. bNAbs are able to target diverse epitopes on the HIV glycoprotein envelope (Env) which control the spread of the virus. Essentially, the bNAbs have been most effective when used to target independent epitopes of the HIV Env. Like Campbell, this research definitely makes me optimistic that a vaccine for HIV can very well be derived sometime in my lifetime.
ReplyDeleteWhile HIV has developed a seemingly incurable mentality among the general populous, among the scientific community, there seems to be hope that these new-found bNAbs can provides a potentially powerful cure or treatment f or HIV. I believe that we all can agree that research in this field will obtain (if it hasn’t already) a large amount of funds to help further studies in order to develop the vaccine. However, there are some issues regarding the specifics of these vaccines. There seems to be a bit of non-overlap between animal trials and human trials. This might prevent potential vaccines from coming on market in a timely fashion, as long tests will need to be monitored by the FDA. Much like the HER-2 anti-breast cancer antibody, this HIV vaccine may take many years to fully pass inspection.
DeleteWhitney, I think this is a really interesting concept of trying to define one specific epitope in the AIDs Ab that would help us to determine a conserved DNA sequence. Although it seems that this conserved DNA may be missing from most strains that we have analyzed thus far, there has to be genetic similarities in the virus that categorize it as AIDs and illicit similar autoimmune responses. I believe that genetic sequencing of all the different strains of HIV could be the key to making a vaccine.
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ReplyDeleteBroadly neutralizing antibodies (bNAbs) are able to inhibit multiple strains of HIV by blocking viral receptors. Non-bNAns are specific for individual strains. Neutralizing antibodies, in general, defend a cell against an antigen by inhibiting or neutralizing its effects rather than binding to the antigen and flagging them for the immune system to recognize. The difference between neutralizing Abs and binding Abs has to do with IFN-β. Antibodies can simply bind to IFN-β with no subsequent effect on function or they can block or neutralize the virus’s biological activity. In order to acquire the strains of bNAbs, an HIV infected person’s B cells must be isolated.
ReplyDeleteHuman immunodeficiency virus infection (HIV) begins with influenza-like symptoms, a period of no symptoms, susceptibility to infections, and then the late symptoms present as AIDS (acquired immune deficiency syndrome). Antiretroviral treatments can slow down the course of the disease, but there is no cure. Research has shown the prevention of the virus, through inhibition, can improve T cell count and the overall immune system. There is a possibility, like all viruses, that HIV can become resistant to the antiretroviral treatments.
Although the bNAbs that have been identified are effective in primate models of HIV, they show limited potency against non-clade B viruses, which are responsible for most HIV infections outside Europe and North America. An idea for an HIV vaccine using bNAbs could be to use a second generation of antibodies used in the passive immunity of individuals. The antibody would be optimized and modified to achieve the result of protecting the individual from diverse strains of HIV.
ReplyDeleteThe vaccines that were developed in the past have been ineffective in preventing AIDS because the virus is not responding to regular vaccines. It’s probably because the vaccines were not targeting the right receptors where the virus could have developed, or otherwise because of the form of vaccines which were from virus instead of developing antibodies against the virus itself. In recent research of BNAbs (antibodies used to neutralizing multiple HIV-1 viral strains) as vaccine, researchers have tried to find the UCA (unmutated common ancestor) of the BNAbs and where it was brought about. Some infected persons do have BNAbs and some do not. So what produced these antibodies? They started by isolating the monoclonal anti-HIV antibodies and sequencing them to identify the viral vulnerabilities. Based on the research, they were able to distinguished two antibodies that might be the pathway of creating the BNAbs, first is the V2/glycan that has long CDRH3 which penetrates glycan shield and protects the virus to reach through that shield and touch the content of the base, second is the CD4bs, the heavily mutated (30%) and do not have such long CDRH3.
ReplyDeleteIn a paper, CD4bs was said to be a gradually formed antibody which takes time to develop. But is the V2 also a gradually formed antibody as well? After sequencing, they found that the UCA had a 35 amino acid CDR H3 fully formed through VDJ recombination. So V2 is not a maturation process but an already formed CDR H3, which allows it to be formed faster than CD4bs. It is suggest that V1V2 – Long CDH3 requires the engagement of a BCR with a long CDR H3 – these B cells are very rare. Once stimulated, V1V2 BNAbs can develop within months. Unlike CD4bs which takes years, but it doesn’t require for long CDRH3, only that Ig allele skewing may limit viable BCRs. It may need high levels of affinity maturation which take years – hard to achieve through vaccination.
I would say developing V1V2 – Long CDRH3a NBAbs for vaccination would be the best choice. Even though, the type of B cells that is required to engage to the antibody is very rare, once B cell is found, we can just grow that specific B cells for more cells. CD4bs takes too long to develop which costing too much.
The fact that bNABs don't appear until much later after a patient has been infected with HIV, combined with the fact that it only appears in such a small percentage of the population, I would say that this is not the best way to make an Ab to the disease. Again, I would say that the best way to go about this is genetic sequencing of as many different HIV viruses that we can find. This would enable researchers to narrow down the possibilities for conserved gene regions. The body has to be recognizing some of the same gene regions even in different strains of the HIV virus, because all HIV responses are generally the same: autoimmune issues. Therefore, if we could isolate a gene region and make an Ab for that region, our Ab could recognize it on theoretically on any different strain of HIV virus. I think the difficult part of this research would be testing all sorts of strains and making sure that you had the majority of the different strains in your possession to do the genetic sequencing on. Maybe because it mutates too fast, it is impossible to genetically sequence the virus. It could be altering its genome with every cell it comes into contact with. But right now I think its a viable option.
ReplyDeleteShannon, I see why you are skeptical about bNABs being the best way to make an Ab to the disease, especially in light of the small production of them and delayed response. However, there has been much success regarding them. There has even been research that has shown some isolated B cells that were able to stop 90% from establishing an infection. Read about it here: http://www.nature.com/nchembio/journal/v10/n12/full/nchembio.1685.html To my knowledge, there are not any other treatments that have been so successful. So that’s why I think that we have a very legitimate shot at developing a HIV vaccine with bNABs.
DeleteWhen it comes to tackling HIV, I think that the key will be developing a vaccine that keeps the virus from being able to infect, rather than developing a cure after it was established an infection in the body. I say this because, as was stated earlier, HIV is a very quickly adapting virus. Once it is established and multiplying in the body, it is able to adapt very quickly to handle the natural immune response, as well as outside attacks from antivirals. So in essence, we need to attack it early in the game.
Broadly Neutralizing Antibodies (bNabs) prove to be very effective because of their ability to respond to a wide range of antigens, whereas normal antibodies are specific for one viral strain. The HIV virus only has about 10 trimers a very small amount when compared to the influenza virus, which has about 450 trimeres with which to bind to. Despite this, bNabs unique structure allows it to bind to the lipids that make up the viral membrane.
ReplyDeletebNabs are more effective in the early stages of the infection as they would be able attach to the first strains and prevent the virus’ mutagenic processes from taking hold of the patient. However, if they come about later in the process, as they seem to always do, the virus has already caused the damage, making it very difficult to fight back from that point.
bNabs are only found in a very small number of HIV patients and can take years to develop. A proposed reason for this is that B cells may need to come in contact with the virus for years in order to develop the changes and mutations needed in order to bind to the various epitopes on the virus.
I wont necessarily rule out the possibility of developing a vaccine, as the continued efforts may very well pay off. However, I think that it is likely really difficult to be able to develop a vaccination that will work consistently for a pathogen that is ever changing. I think it’s a lot like the flu vaccine in that there are always new ones coming out as the virus mutates. The major difference being that a patient that gets the flu will be fine and will fully recover with the proper medication, whereas a patient that contracts the HIV virus will have little to no chance of removing it from his or her system.
Theoretically, the isolation of bNabs would work very well in a vaccine. However, we would then need to deal with the problem of the patient rejecting the infused antibody. But it is definitely an interesting idea, one worth investigating.
bNAbs are very interesting because they not only bind to the virus and flag it for other immune cells to come in and attack, but they also neutralize the biological effects of the antigen simultaneously. They have proven to be very successful in treating bacterial infections but also have been successful in HIV treatment trials. It is difficult for these as well as other treatment options to be successful against HIV because, among other reasons, they have an incredible variety of protein epitopes that are expressed, sometimes even on the same HIV strain, but many different bNAbs have been found that have been moderately successful in treatment of HIV in recent studies. It is even being considered that maybe a patient can be given multiple bNAbs at the same time, or in a single inoculation; ones that match and bind to the most common HIV epitomes.
ReplyDeleteThe one thing that makes HIV so very difficult to treat or generate a vaccine for is constant adaptation upon reproduction. If a vaccine is going to be created, this one aspect must be overcome. Therefore, this shot gun approach of injecting a patient with a large variety of bNAbs in order to HIV treat HIV is an interesting idea.