hope for an AIDS vaccine and bNAbs
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?
due Oct 31
There have been multiple trials and efforts in AIDS vaccines but have failed to make a dent it defeating the virus. Traditional vaccines try to make an individual produce antibodies which target the docking/fusing protein gp120 of HIV.
ReplyDeleteThe problem with that is Gp120 is a highly variable region. It genetically varies from one HIV subtype to another. In this way, HIV masks itself from antibodies made using traditional vaccine methods. Other traditional vaccines use adenovirus vectors, like the cold virus, to carry HIV genes and deliver the HIV genes into healthy cells. The problem with that is most of the human population already have antibodies to adenovirus from previous infections with naturally occurring virus. Their bodies would immediately send T cells to kill the adenovirus leading to a highly toxic situation. Also, if a person were to become infected with HIV after vaccination, the HIV virus would have the perfect environment to thrive and spread.
Why are bNAbs effective?
ReplyDelete-bNAbs are effective in that they can target highly variable regions of specific protiens of HIV that are used by HIV to infect cells. The viral spike glycoproteins, which are gp120 and gp41, are highly variable and have evolved to completely escape an immune attack. But studies have been shown that PG9 and PG16 (both antibodies) target regions of gp120 that do not change, which probably accounts for their breadth of neutralization. Breadth is the measurement or wide range of neutralization the Antibody has. Studies have also suggested that these antibodies give rise to an idea that the human immune system has evolved a response that is more potent and works against more variants of the virus. These antibodies prevent the virus from attaching to a host cell by attaching to these highly conserved regions.
Why are they more effective in early infection? Why are they produced later in HIV infection?
-These antibodies are more effective in early infection because they provide a way to inhibit the function of the virus docking and infusing host cells. This is why researchers are buzzing right now because this is a natural way of fighting the virus and if they can manipulate these antibodies to make a vaccine, it raises questions to a possible cure. Most patients that have these antibodies are because their body has found a way, later on in infection of evolving different immune responses, or different levels of potency of antibodies to a highly mutating virus. These antibodies are isolated from patients that have failed to control their HIV infection for many years. Researchers take HIV-infected individuals with broadly neutralizing sera and from their they can take individual monoclonal antibodies and isolate them. Researchers have also taken synthetic peptides containing conserved protein sequences as immunogens to produce neutralizing monoclonal antibodies.
Do you think an effective AIDS vaccine will be developed?
-I think it is a long ways away since this virus is still "new" but reading about the antibody approach seems attractive to making new strides to a vaccine. After seeing how antibodies can help in certain strains of breast cancer, antibodies seem to be the new approach to aid in the fight of destructive viruses. HIV is a very complex and highly mutating virus and I do not see a vaccine in the near future, but the antibody approach seems to definitely raise some new ideas for a possible cure.
The epitopes of the HIV viral envelope are more variable than other viruses. Also the functionally important gp120 proteins are masked y glycosylation, trimerisation and receptor-induced conformational changes. This makes it difficult to block with neutralizing antibodies. Another reason that HIV is hard to make a vaccine for is that HIV is constantly changing. The virus has the ability to rapidly respond to pressures posed by the immune system. It mutates in order to evade the adaptive and humoral immune system. It has also been suggested by other researches that the AIDS vaccine could have made the individual’s immune system more susceptible to the actual HIV virus. A trial led by Eric Kremer, showed that people who received the STEP vaccine (an AIDS vaccine) were more likely to be infected with HIV-1 than those who hadn’t been exposed to the virus.
ReplyDeletebNAb’s are more effective because they do not merely flag antigens. Instead, they bind and neutralize the effects of the antigen. This in turn would reduce the effect that this virus would have on the immune system. They would be more effective if released earlier in the HIV infection because they are capable of blocking viral receptors. This would allow for better containment of the infection and, as a result, fewer cells, if any would be hindered by the virus. The host does not release NAbs until the HIV virus has had time to replicate and be tagged by the immune system. It is at this point that the NAbs are produced. However, they are effective to only a small subset of infected cells because HIV has mutated so much that only certain cells can bind the NAbs. However, if researchers figure out a way to have the immune system begin to produce their NAbs before the infection grows so rampant that it’s uncontrollable, then there is hope for a possible vaccine for HIV.
ReplyDelete1)So far, the immune system has been completely bullied by HIV. Because of its mutation prone RNase, it changes constantly. As soon as the body creates antibodies that can latch onto one surface protein, that protein disappears or is mutated. What makes bNAbs effective is that it is able to bind to sugars (glycans) on the surface of HIV's envelope. Normally these glycans protect HIV from attacks from the immune system by growing close to the envelope protein gp120 and inhibiting binding. However, the bNAb PGT 128 is able to bind to the glycans, and then attack gp120. The result of the attack is that HIV is unable to enter cells and replicated. The glycan envelope that PGT 128 binds to is highly conserved across the HIV spectrum. This means that PGT 128 is capable of fighting over 70 percent of infections caused by HIV.
ReplyDelete2) bNAbs are only efficient early on in infection because of how quickly HIV infects. It enters T cells and then lies dormant for years. Because it proliferates so quickly, it can reside in all T cells before a bNAb is even produced. bNAbs prevent the virus from entering new cells, but if the cells are all already infected, than it can do nothing.
3) I couldn't find any conclusive research to answer this question, but this is my theory. It takes a lot of exposure to HIV to create antibodies specifically designed for such a well hidden protein. Our body can't produce a solution to something that it can't sense, so if the part on the protein that doesn't change is hidden well enough, then the immune system won't be able to create the antibodies for it. It might also take a longer time for our body to realize that the loop on gp120 that is targeted doesn't mutate. Once it has detected the loop, it is usually too late, and HIV has already infected too many cells.
4) I do hope that eventually there will be a vaccine for HIV, but it won't be soon. So far researchers have only found about one bNAB that has actually been effective. In order to develop a vaccine, they need to find several. This is especially difficult because bNAbs are so rare in the population of HIV+ people. Only 20% of people who are healthy for the first 4 years of infection actually have a bNAb. Finding these people is another problem in itself. I have hope that with enough time they will be able to develop a vaccine this way, but I would also develop other routes to a virus. For instance, there has got to be a way to remove the glycan envelope. If that could happen, then hopefully everyone would be able to produce bNAbs on there own. With the amount of people that have been working on HIV research for so long, I hope that it is inevitable that we find either a vaccine or a cure.
The main reason why previous AIDS vaccines have not worked is that the AIDS virus is highly mutable. The AIDS virus can rapidly adapt, so when a vaccine is administered against a certain form of the AIDS virus, the virus has already mutated into something that the vaccine can no longer target.
ReplyDeleteWhile HIV can escape from a single type of antibody administered, combinations of bNABs can control HIV infection and suppress the virus levels to below detection. The longer half-life of bNABS can also control the spread of the virus throughout the rest of the body. These bNABs are able to actually bind to the antigen and not just signal that there is an antigen but actually neutralize the activity of the antigen as well.
HIV infects patients very quickly due to its ability to bypass the immune system as well as reproduce rapidly. bNABs work better at the beginning of infection because they are able to attack HIV before it has a chance to reproduce and infect the body to the point of no return. bNABs are a preventative tool; they cannot fix cells that have already been infected. Thus, bNABs are most effective early in infection so they can stop HIV from infecting too many cells.
HIV prevents the immune system from doing its job. When HIV infects cells, it prevents them from contributing to the immune response. Without this immune response, there is no attack on the invasion of HIV. Perhaps the reason bNABs are produced so late in the infection is that it takes the immune system too long to respond to the infection. HIV attacks the immune system quickly, disabling the immune system from producing the necessary immune components until much later in the infection. Another possibility is that our immune system needs time to sense that it is infected and further time to figure out what specifically it is infected by. Due to the high rate of mutation in the AIDS virus, perhaps by the time the body figures out what to make an antibody to, it is far too late for anything to be done
While a vaccine for AIDS is an uphill battle, I remain optimistic that a vaccine will be found. As more research is done, more is discovered about the AIDS virus and the immune system it attacks, and more theories are proposed. While this vaccine may not be discovered soon, I believe that eventually a vaccine will be found and lives can be saved.
The previous vaccines that have been proposed for HIV/AIDs have not been very effective at all, and the main reason being that the vaccine is only effective on the lab-produced HIV strains, and not the wild strains. There is no possible way to manually manufacture a lab strain like all of the wild strains in order to test and create a vaccine. The HIV virus is a very complex virus that seems to continuously change and form new strains that become resistant to the proposed vaccine. In order for a vaccine to be introduced and successful, which I believe will happen in the future, it needs to target a more broad receptor and binding sites that are found on all of the different strains. If the vaccine is only created to bind to a specific few, then it will not work on any of the strains that do not have those binding sites. As technology and medical discoveries continue, I believe that an effective vaccine for HIV/AIDS will be discovered and implemented and help save lives. There may be different stages at which a vaccine is effective, but any amount helps. There could be a vaccine that catches the virus early and stops the infection completely, or one that minimizes the affects and inhibits the transferring of the virus. Either way, a type of vaccine will be created in the future and could save many lives.
ReplyDeletebNAbs are broad neutralizing antibodies that inhibits or neutralizes the biological effects of the cell that it binds too. The fact that they are BROAD antibodies mean that they can bind to a wide range of cells and inhibit a large range of biological functions. In the lab they have shown the ability to inhibit a variety of viral strains. These antibodies can be extremely effective in creating a vaccine for HIV/AIDS because they can block the virus from attacking the immune system. If the virus is blocked, it gives time for the immune system to destroy the virus before it can do too much damage to the body.
ReplyDeleteThese antibodies are most effective early in the infection because the virus has not yet shut down the immune system. If the body recognizes and signals an immune response to produce the bNAbs, then these antibodies have a chance of preventing the infection from spreading. They are however, not as effective later on in the infection because the viruses have already performed their biological function of shutting down the immune system.
If these antibodies are not produced early in the infection, it still is possible for them to be created and secreted later in the infection. This could be due to the immune system being infected quickly and not being able to produce the antibodies until later. New research is showing that a type of Envelope trimmer which is a 3-legged protein on the surface of the virus that is a possible binding site for antibodies. Recent studies have shown that later in the infection, just after it has docked with a receptor on the target cell. At this point, microscopy has shown that it opens up slightly which yields access to the inner surface of the virus. At this stage, maybe the body recognizes this and secretes the bNAbs to attack that specific region of the virus which will enable a more potent and quick destruction of the virus.
There are many projects and studies occurring worldwide in order to find a vaccine for the HIV/AIDS virus. Each new discovery allows for more possible combinations and methods in order to create the much needed vaccine.
Broadly neutralizing antibodies inhibit any negative effect the antigen has on the host. One of the ways HIV hides from the immune system is by its highly variable surface proteins Gp120 and Gp41. However, there is a section of the Gp120 called the Gp120 loop that is conserved. Broadly neutralizing antibodies target this conserved region in order to fight HIV. They are more effective in early infection because they bind to the surface receptor if HIV inhibiting its ability to bind to other cells. Early in infection, when many of the HIV cells have not bound to any cells yet the bNABs can bind to the GP120 loop and inhibit HIV function. Later in the infection the HIV has already bound to CD4 T cells so there is no place for the bNABs to bind. It is possible that they occur later in the infection because the body must adapt to fight HIV. Unfortunately, by this time it is usually too late for the immune system to catch up with the rate of HIV production. However, if researchers could somehow isolate or modify this response it is possible that they would have an effective way to fight HIV if the infection was caught early.
ReplyDeleteVaccines developed in the battle against HIV infections have been discouraging and highly complex. AIDS presents as an extremely complicated and difficult to attack pathogen, due mainly to its ability to cloak itself in the midst of a huge cell population within the body. The HIV virus is adept at inserting its genetic material into human cells, and allowing them to lay dormant there. Onset symptoms of AIDS are often very delayed due to the latent life cycle exhibited early on by the AIDS virus. AIDS also immediately sets out to handicap the immune system of the host organism, so that later attack against a viral flare-up induced by a lytic life cycle will be ineffective. As if this wasn't enough, the HIV virus is expert at mutating itself through poor replication standards. The HIV virus will present highly diverse viral populations for the immune system to react to. This is highly disabling to an already weakened immune system, and will basically ensure that the HIV virus wins out. Essentially, a vaccine that would be able to target HIV is impossible so far since the HIV viral envelop can be extremely diversified. Antibodies are usually ineffective against the many subsets of HIV that can develop in an organism's tissues.
ReplyDeleteBroadly neutralizing antibodies, however, have been found that are able to bind to many other epitopes and regions on the viral pathogens that are not understood even today by scientists in the field, and are thus able to respond to a much wider cohort of HIV than normal highly-specific targeting antibodies are. If these bNABs were to be stimulated in a person early on in viral replication, HIV would not have the chance to infect many human cells, and its proliferation would be kept to a minimum even in its latent life cycle. Once a host organism is able to develop and saturate its serum with a percentage of these broadly neutralizing antibodies, any HIV that enters into the lytic life cycle and begins to proliferate so as to infect more host cells will be stopped and prevented from spreading. This will keep the HIV virus sequestered to the point of infection, keeping much of the host's immune system intact and strong to ward off secondary infections and fight the HIV virus simultaneously.
In normal circumstances, unfortunately, these bNABs are not synthesized until much later in the viral infection since the immune system spends most of its time fighting off damaged tissues and trying to stop the spread of the pathogen. The immune system is unable to fully process all the relevant epitopes that can target and inhibit HIV's virulence. Many epitopes on an HIV envelope are designed to attract antibodies while preventing any effective inhibition, like a decoy epitope. Once the immune system has synthesized a broad-spectrum antibody for defense, it is too late in the infection, and the HIV has infected too many host cells with latent viral genes.
While the current prognosis for AIDS is grim, the finding of bNABs helps to restore hope for our eventual finding of a cure. While HIV is adept at mutating and remaining difficult to categorize well, these bNABs hold the secret to rooting out the primary epitopes needed for identification and destruction of an incoming HIV infection. Once scientists are able to isolate and synthesize these bNABs, work can be made toward stimulating their production in newly infected individuals so that HIV is neutralized before widespread genetic proliferation takes place.
Vaccines developed in the past have largely been ineffective in preventing AIDS because HIV changes its genetic makeup(mutates) so fast that it continuously evades targeting by the immune response. Furthermore, past vaccines try to produce antibodies which target the docking/fusing protein gp 120. This is a problem because gp120 is highly variable region, and varies genetically from one HIV subtype to another. Another reason why vaccines developed in the past have largely been ineffective is that they use adenovirus vectors to carry HIV genes and deliver the HIV genes into healthy cells. The problem with this is that humans have antibodies to adenovirus from previous infections, and if a person were o become infected with HIV after vaccination, the HIV virus has a perfect environment to thrive and spread. However, scientists may have found an effective AIDS vaccine that can potentially better target HIV by using broad neutralizing antibodies.
ReplyDeleteBroad neutralizing antibodies to HIV are produced by a minority of HIV-infected individuals and are distinct from other antibodies to HIV. These antibodies defend a cell from an antigen or infectious body by inhibiting or neutralizing any effect it has biologically. Furthermore, according to Dennis Burton, a professor of immunology at The Scripps Research Institute, he states that bNAbs are effective because bNAbs against HIV have functioned by binding to places on HIV that have proven difficult to exploit by means of vaccine design. For example, the two newly discovered bNAbs called PG9 and PG16 target regions of gp120 that do not change. Gp120 is one of the viral spike glycoproteins that are highly variable and used by HIV to infect cells. Other reasons why bNAbs are effective is because of their potency. Their high potency could give protection to the immune system when it has relatively low levels of antibodies. Another effectiveness of bNAbs is that their structural and biochemical analysis, and their method of binding to HIV, can show scientists how to achieve and construct a preventive vaccine.
ReplyDeleteBroad neutralizing antibodies can be more effective in early infection because they can attack HIV before HIV attacks the immune system. The bNAbs can basically deprive HIV of its full effect on the immune system.
I believe that coming up with a vaccine using bNAbs will be effective because unlike most antiviral vaccines, bNAbs does not depend on stimulating the antibody response to work effectively. Furthermore, according to Dennis Burton, “because of HIV’s remarkable variability, an effective HIV vaccine will probably have to elicit broadly neutralizing antibodies. [As a result], these bNAbs will prove to be valuable assets to the field of AIDS vaccine research”.