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