Day 224: Looking for keys to a preventative vaccine

A recent PNAS paper with a huge group of authors from UAB and about half a dozen other universities (Shaw and Hahn are in the grandfather spots), attempts to discern whether there are conserved features of the HIV envelope (Env) gene at the time of transmission. I believe that this type of study is probably our best shot at developing a preventative vaccine.

 

I’ll explain. There is always interplay between viral diversity (quasispecies) and the host immune response. With less immune pressure, virus can replicate readily and the most fit viral quasispecies will dominate—that is, there is no selective pressure to drive viral evolution and, therefore, less viral diversity in the host. With heavy immune pressure, there is selection for whichever viral quasispecies can evade this pressure—again leading to less viral diversity in the host. Somewhere in the middle you get a scenario where the immune system exerts enough pressure to drive viral diversity, yet not enough pressure to control replication. So, you get a high number of quasispecies. Why is this important? Well, quasispecies and viral diversity are some of the problems for developing a vaccine; it’s difficult to effectively target many slightly different viral sequences. However, when HIV is transmitted, it may go through a “bottleneck”; there may be constraints on which viruses are fit to establish infection, so only a few viral quasispecies may be involved in the establishment of infection. So, if we can figure out the envelope sequences for these viral variants that are transmitted, we could potentially develop a vaccine to target these sequences.

 

The problem is that it’s not terribly easy to find these sequences. By the time most people reach treatment, the virus has long since passed this bottleneck and they have a large number of viral variants. Finding those patients who have been recently infected is difficult. On top of that, there are technical issues in figuring out the envelope sequences of the viral variants which established infection. Lastly, it’s entirely possible that a person may be infected with several different viral variants during transmission.

 

This may be the reason why there are about 30 authors on this paper—this is hard stuff. Keene and colleagues had access to samples from 102 acutely infected patients. They had stored blood on which they could sequence the patient’s envelope gene. Each patient had their HIV Env genes sequences an average of 25 times. As there are multiple sequences (HIV often mutates quite rapidly, as you may have heard), the authors used mathematical modeling to try and determine which sequence likely established infection (the founder sequence). Now, I am certainly no mathematician (one of the reasons why my lab work was less than stellar), so I can’t comment on the model they used. As usual, the validity of this sort of study depends in large part on the validity of the model, so just remember that these findings may be colored by their choice of model.

 

The authors found that 78 of the subjects had Env gene sequences that suggest infection with a single virus (homogeneous infection). The other 24 subjects showed evidence of infection with multiple quasispecies: around 2-5 different variants (heterogeneous infection). This is important because, in conjunction with similar studies, it appears that infection frequently occurs from establishment of a single or a few viruses. If these viruses have common features, then we can design a vaccine to target these features.

 

The authors then tested 55 of these envelope proteins for some common features. They found that 54 of these Env proteins were CCR5 dependent—something we’ve known for a while, but it always good to see further validated. The other envelope protein was dual-tropic. All of the envelopes were susceptible to several broadly neutralizing monoclonal antibodies (mAbs), while most were resistant mAbs targeting the V3 loop of the viral envelope. It appears that the V3 loops of these proteins are hidden from the antibodies, and not absent. They also found that the viral Env gene does not appear to mutate very rapidly in the period up to peak viremia, which you might expect if the patient does not mount a robust immune response to the virus (see above). The authors comment that “studies aimed at further analyzing Env glycoproteins of transmitted or early founder viruses may help to identify unique features and potential vulnerabilities relevant to vaccine design. Beyond this, the present study illustrates a strategy for identifying and characterizing full-length genomes and proteomes of transmitted or early founder viruses including, but not limited to, HIV-1. Such analyses may facilitate a better understanding of virus natural history and virus-specific cellular and humoral immune responses in naive and vaccinated individuals.”

 

The authors also note that different modes of transmission may lead to different founder Env sequences. So, it may be that there may eventually (hopefully?) be a vaccine that has sequences designed to target sexually transmitted HIV and sequences designed to block HIV transmitted through needle-use. The authors are currently looking at whether there are differences in the Env genes based on mode of transmission.

 

For those of you that follow this stuff, there are some other interesting observations in this paper, including 13 subjects who had G-to-A hypermutation in the HIV genome, indicative of APOBEC deamination, and the longitudinal evolution of Env followed in 10 subjects.

 

Of note, this study followed acute infection with clade B virus, which is likely necessary for studies conducted among US and European patients. Clades C and E virus dominate in Africa and Southeast Asia, so these sorts of studies need to be conducted among those populations to help elucidate the differences in transmitted virus among the different clades. I believe that some of this work is also being conducted, so it will be interesting to see if there are any conserved features of the virus during transmission and if these features are observed across clades. I hope so, because that would be the ideal scenario for vaccines designed based on these findings.

 

M. Linde

Day 124: Is this really a controversy?

There was a brief report in Nature Biotechnology that recently caught my eye.  The title wasn’t a big draw (“HIV Vaccine Controversy”), but I have to admit I was intrigued that it was in Nature Biotechnology. I thought it had the potential to discuss some real basic immunology. Of course, it turned out to be a news story and didn’t have any real science in it.

I’m glad I came across the article, though, because it’s an interesting story. Essentially, the International AIDS Vaccine Initiative (IAVI) conducted a vaccine trial among 30 participants in India despite the fact that the vaccine had been shown poor results in an earlier European trial. The IAVI claims that it did not act unethically, which I agree with. They argue that response to the vaccine could differ by host genotype, which presumably would be different between your average European and your average Indian. However, I found myself wondering why the IAVI didn’t try and enroll different ethnicities in the European trial—certainly they could have found 30 Indians living in Europe. I don’t know the details, but maybe the IAVI had a good reason for structuring this trial the way they did. 

Still, the whole thing sounded bad, so I am sure the IAVI will be a little more careful in the future. 

M. Linde

Day 47: Thoughs on “Will there ever be an HIV vaccine?”

Robert Steinbrook presents an interesting commentary on the prospect of an HIV vaccine in this week’s New England Journal of Medicine. The article focuses on the Merck vaccine failure and what it means for the future of HIV vaccines. The most sobering part of the article comes not from Dr. Steinbrook, though, but Anthony Fauci, who says “To be brutally honest with ourselves, we have to leave open the possibility . . . that we might not ever get a vaccine for HIV. People are afraid to say that because they think it would then indicate that maybe we are giving up. We are not giving up. We are going to push this agenda as aggressively and energetically as we always have. But there is a possibility—a clear finite possibility—that that’s the case.”

In my interactions with HIV basic scientists and immunologists, I get the impression that most researchers are not too favorable on the prospect of a workable vaccine anytime in the near future. While I hate to be pessimistic and I think all options must be considered, I tend to agree. There are only two approaches to a preventative vaccine that I think are really worth merit and, unfortunately, most of the vaccine candidates are not looking at these options (more below). Currently, most vaccine candidates are relatively traditional, focusing on generating an immune response against viral proteins. HIV reverse transcriptase is so error prone, though, that I think the virus will be able to squeak out of any response targeted against the viral proteins. Everyone knows this and yet all of the vaccines I see still target the viral proteins. Other methods have looked at creating antibodies that target the CD4-gp120 complex—when conserved aspects of the viral spike are no longer shielded by sugars and are exposed. While I think that these antibodies might block infection, I wonder about the concentrations needed to provide protection. These epitopes are exposed for extremely brief periods of time, meaning that you need an antibody with a very fast on-rate at very high concentrations. It doesn’t seem reasonable to me. Then again, as I like to frequently point out, I am often wrong.

One of the roads that I do find promising that some are looking at is the composition of the virus at infection. When HIV infection is established, there are certain aspects of the virus that are conserved. Once infection is established, the virus quickly mutates and evolves to be better suited to the environment. Thus, the viral particles that establish infection are different from the majority of viral particles during infection. It may be that there are certain characteristics of HIV that are important for establishing infection that can be targeted by a vaccine. If we can tease out the aspects of the virus that are important for the initial establishment of infection, we could design vaccines against these features. It’s a tricky prospect, though, because you have to get viral samples very soon after initial infection. I know that at least a couple of groups are working on this, including Julie Overbaugh at the University of Washington.

The other road that I think is at least worth considering is looking at host factors on the virus. I have mentioned this a couple of times in the blog, but HIV is highly enriched in host proteins in the envelope including MHC molecules. Unlike viral proteins, host proteins won’t mutate and evade a vaccine. Plus, MHC molecules are some of the most immunogenic molecules out there. An allovaccine would be easy to create and might have activity against HIV and other retroviruses. There are, of course, serious considerations with this type of vaccine, though, not the least of which is its effect on fertility. It’s still worth looking at, although I fear that almost no one is considering this option.

 

M. Linde

Day 5: What happened with the Merck vaccine?

While the prospect of a therapeutic vaccine might be looking up, there still isn’t much good news on the prospect for a preventative vaccine. Merck announced last week that their new vaccine candidate may have actually increased subjects’ risk for HIV infection. How they didn’t see this until the large scale clinical trial is amazing, but I am guessing that they were as surprised by this as everyone else was.

 

But should they have been so surprised? We know that HIV infects activated CD4 cells. Some in the field have wondered whether providing a source of activated T cells by traditional vaccination would actually increase the risk of infection. So maybe that’s the answer to the question. Add to this that it has been shown that HIV preferentially infects HIV-specific CD4 cells and you can see a pattern where an immediate immune reaction might give HIV a greater chance of establishing infection. It’s hard to prove that this is what happened, but I certainly think it is a possibility.

 

The other possibility of that the vector had some synergistic effect with HIV. The vaccine was a modified adenovirus, designed to express parts of HIV. There are several examples of two viruses working synergistically. There’s even some evidence that mutants from the same virus can work together to increase pathogenesis (Vignuzzi Nature 2006—really interesting article). Maybe a viral vector isn’t the proper vehicle for the vaccine. I suppose we can’t say until Merck sorts out what happened. Either way, in spite of the vaccine failure, we are going to learn something about immunology and HIV. So I guess the trial wasn’t a total loss.

 

M. Linde

Day 3: The first good therapeutic vaccine idea in a long time

There was an interesting paper that came out of Doug Nixon’s lab at UCSF. The paper, reported in PLoS Pathogens (open access), looks at the relationship between HIV and human endogenous retroviruses (HERVs). HERVs are retroviruses that are already in your genome. Presumably, they entered into the human genome in ancient times and now are stably integrated. They are held in check by host proteins that presumably evolved in response to these retroviruses.

 

As HIV is a retrovirus, some of these proteins can also hold HIV in check. It would be nice if they did (I would happily be out of a job), but HIV has found a way to negate the action of these proteins. Further, some HIV proteins that help HIV replicate also help HERVs replicate. So HIV also activates the dormant HERVs in the cells it infects. Lots of work in this field has been done by Brad Jones (who is second author on the paper), a grad student at University of Toronto who seems poised to be a real player in HIV research. Let’s hope he stays in the field.

 

Now, when the immune system is presented with cells producing proteins that are abnormal, it generates a response. This usually results in suppression of whatever it is that causes the abnormal proteins. HIV, however, mutates rapidly and can escape from the immune system. HERVs are encoded in the genome, though, so they don’t mutate like HIV. Therefore, the immune system can generate a response against HERVs and kill the cells that express them. As these would also be HIV infected cells, this would likely be a good thing.

 

First, Garrison and colleagues show that HIV-positive subjects have significantly greater HERV expression than HIV-negative subjects. They also found that the HIV-positive subjects generated an immune response to HERV-specific sequences, while the HIV-negative subjects did not. These responses looked normal for what one would expect in a controlled response against an infection. One of the patients who showed good response against HERV sequences was also able to control HIV infection without the use of antiviral therapy and, overall, patients who showed good response to HERV sequences also had lower amounts of virus in the blood. It’s easy to visualize how HERV responses might also help control HIV spread in the body.

 

So, the authors suggest that maybe by vaccinating infected patients against HERV sequences could help HIV-positive patients control their infection without anti-HIV therapy. It would be cheap and easy—more than I can say for most therapeutic vaccine ideas out there. Seems like a good idea, don’t it? I hope it pans out.

 

M. Linde