HIV vaccine failed because of interaction with microbiome

Scanning electron micrograph of HIV-1, colored green, on a lymphocyte.

From 2009 to 2013, scientists at Duke University and the National Institute of Allergy and Infectious Diseases had been working on what looked like a promising cure to HIV. The study was terminated in 2013 because it was clear that the vaccine was not effective in protecting against HIV infection. An article recently published by Science Magazine gave insight into why the HIV vaccine unfortunately failed. Hint: it has something to do with the microbiome.

The vaccine was administered in the study to adult males in the form of an initial vaccine as well as a second booster vaccine. The HIV vaccine looked promising because it stimulated the body’s immune system to produce antibodies that recognize HIV. The unexpected result, however, was that these antibodies also recognized bacteria like Escherichia coli, a very important bacteria that lives in the human gut. It should be easy to see why this is a bad thing for the microbiome. Destroying important gut bacteria is very detrimental to humans, which we see over and over again here on the blog. Additionally, because the antibodies were reactive to bacteria as well as the HIV virus, it took away from the effectiveness of fighting HIV.

This study is very important in the search towards finding a cure to HIV, because it presented an unexpected obstacle that a lot can be learned from. Moving forward, questions are already being raised by the scientists such as, would this vaccine work for children if immunization was given to pregnant mothers? Perhaps the still-developing immune system would better be able to work with the vaccine. Only more research can prove whether the HIV vaccine is indeed still promising.  In addition, this may provide insights into the efficacy of vaccines for other diseases.  Perhaps the microbiome plays a large role in their effectiveness.  Vaccine research going forward should begin to take the microbiome into account.

New test developed that rapidly profiles the human virome

Molecular representation of an antibody (green) binding with an HIV virus (red and yellow).

The viruses that live in our body may be just as important to our health and development as their bacterial counterparts.  Unfortunately, testing which ones currently exist, or have at point infected us is expensive, time consuming, and laborious using current techniques.  Making matters worse, these techniques, which usually rely on measuring the amount of antibodies against specific viruses that exist in our blood, are often times ineffective when the antibodies are in low levels.  Recently though, scientists from Harvard University developed a new technique that can accurately, rapidly, and inexpensively (~$25) screen for the existence of over 200 viral antibodies in less than a drop of blood.  They call their technique VirScan, and they published their method last week in Science.

The scientists combined two advanced biological screening tools to create their method: DNA microarray synthesis and phage display.  In short, the scientists created libraries of peptides that represented 206 known human viruses, like HIV and influenza, and expressed them on simple bacteriophages.  They then combined these bacteriophages with a drop of blood, which itself contains antibodies that combat viruses that someone currently has, or has been infected from in the past.  The antibodies that exist specifically bind to the phages that represent a virus.  They then eliminate all the phages not bound to antibodies, and measuring what remains gives the scientist an indication of which antibodies were in the blood.  This explanation of the researchers’ technique may not satisfy our more curious readers, so those that wish to learn more should definitely check out the paper. When the scientists screened over 500 people using this method, the results showed that most people tested positive on average for 10 viruses (i.e. they had antibodies against these viruses).  Interestingly, 2 individuals tested positive for 84/206 viruses.  The most commonly detected virus was Epstein-Barr virus, followed by types of rhinovirus (common cold), and adenovirus.  Also of interest was that the viral structures differed geographically between continents.

This assay has many immediate implications in many areas.  The most obvious is its use as a diagnostic tool for easily screening people for their viruses.  In addition though, by discovering which peptides antibodies efficiently bind to, and how those differ between humans, more effective vaccines can be developed that treat more people.  Also, it should be interesting to discover how infection with certain viruses influences long term health and chronic disease.  For example, were those two individuals that tested positive for antibodies against 84 viruses more, or less healthy than those who tested positive for very few, and whether infection with certain viruses is associated with any chronic conditions.

Our immune system selectively chooses which gut bacteria to keep, and which to eliminate

We have come a long way in our understanding how exactly pathogenic bacteria can invade and populate the gut.  Yet, there still remains uncertainty as to how exactly our immune system responds to and eliminates these infectious bacteria.  A recent study addressed this by investigating the immune response to pathogenic bacteria in mice guts. 

Some Escherichia coli can be pathogenic and infect the human gastrointestinal tract.  In these instances, these Gram-negative bacteria attach to and populate the gut and cause lesions to the epithelium through a well-characterized attaching-and-effacing behavior.   It is currently understood that IgG antibodies are produced in response to E. coli infection, but the exact cellular underpinnings as to how the bacteria are eliminated are unknown. 

To model this, researchers infected germ free mice with Citrobacter rodentium, a bacterial strain known to carry genes that exhibits effacement pathology in mice.  The specific genes of interest that induce enterocyte effacement (LEE) are referred to as a pathogenicity island, loci responsible for virulent behavior, and they are present in both E. Coli and C. rodentium.   The researchers measured adaptive immunity reaction in response to C. rodentium infection, and specifically looked to see if LEE - the virulent bacterial signature - was down-regulated. 

It was found that the LEE virulent strain was down-regulated concomitant to an increase in release of IgG antibodies.  These IgG antibodies were found to be specific to the LEE virulent expression, as supported by significant IgG binding affinity to the virulent strain.  The IgG antibodies eliminated the specific C. rodentium phenotype that expressed the LEE loci, and upon binding to the bacteria, they were removed by neutrophils.

Interestingly, the C. rodentium avirulent phenotype that lacked the LEE was not eliminated by IgG antibodies.  However, these bacteria were subsequently outcompeted by other microbiota populations.  Together, this information suggests that IgG could selectively eliminate the C. rodentium virulent phenotype, and innate immunity could eventually remove the non-virulent populations. 

This study provides excellent insight into how our immune system can distinguish between good and bad bacteria in addition to describing the underlying cellular mechanism.  Defining the molecular underpinnings of antibody action will allow us to make significant advancements in therapeutic approach.  Understanding the molecular pathways is a critical first step toward pharmacotherapeutic intervention, and this study could potentially lead to the development of some exciting advancements in the future.  

Gut bacteria protect against malaria transmission

Malaria is a deadly disease transmitted through mosquitoes and most widespread in tropical and subtropical regions around the world, especially in Africa. According to the Center for Disease Control and Prevention (CDC), 627,000 people died in 2012 and there were a total of 207 million cases worldwide. Through studying the microbiome, scientists last week published a major discovery in Cell that may lead to better vaccinations for malaria that could help prevent the disease from being transmitted.

Scientists in Portugal, collaborating with colleagues in the United States, Australia, and Mali, found that the parasite the causes malaria, Plasmodium, expresses the same sugar molecule that is seen in a type of Escherichia coli (E. coli).  This sugar molecule from the E. coli called alpha-gal (a-gal) results in the body’s immune system producing antibodies against this molecule and therefore also protecting against the malaria parasite. It is known that adults who are exposed to malaria are at lower risk of contracting the disease than children under the age of 5 and the researchers hypothesized that this was due to the children lacking this specific E. coli in their body and therefore unable to fight back against Plasmodium exposure.   

The scientists studied the gut bacteria of a group of individuals in Mali who had very high rates of malaria transmission. They found that those who had higher levels of anti-a-gal antibodies had lower risk of transmitting malaria and those with low levels of these antibodies had greater risk of transmitting the disease.  This showed that children are at greater risk for the disease because they do not produce enough anti-a-gal antibodies to prevent the parasite from infecting the body.

The scientists also found that the transmission of the parasite is blocked almost immediately following its introduction into the body through the skin. The antibodies against a-gal attach to the Plasmodium as soon as it is exposed to the body, and a part of the immune system called the component cascade is activated, killing the parasite before it can leave the skin and reach the blood stream.   

They found that by vaccinating mice against a kind of a-gal, the mice produced enough anti-a-gal antibodies that were highly efficient in protecting the mice from malaria transmission.  The scientists believe that it may now be possible to translate this work to humans and develop vaccines that would increase anti-a-gal antibodies and prevent malaria transmission. If successful, vaccinations could be given to children who are at high risk for the disease and could prevent hundreds of thousands of deaths every year.  These findings also illustrate the protective aspects of the microbiome in regulating immunity, and the potential treasure-trove of molecules produced by the microbiome that could be used in therapeutics.

Lupus, Sjögren’s syndrome, and the microbiome

Drawing of the typical 'butterfly rash' found in Lupus.

Sjögren’s syndrome is an autoimmune disorder characterized by the destruction of exocrine glands, like those that produce tears and saliva. Lupus is an autoimmune disease characterized by inflammation of various body tissues. People suffering from both these disorders produce antibodies and mount an immune response against a peptide, Ro60, that occurs naturally in the body. While this autoimmune response may not be the cause of these diseases, it likely contributes to their severity. An article published by Clinical Immunology shows that specific proteins derived from bacteria in the microbiome can activate the production of these self-destructive antibodies, suggesting that the microbiome could play a role in initiating autoimmunity.

Researchers at the University of Virginia used T cell hybridoma activation and epitope mapping to discover which peptides activate the specific Ro60 immune response.  When they compared these molecules with molecules known to be produced by the human microbiome, they found several instances of proteins produced by the microbiome that could potentially activate antibodies against Ro60.

The most potent peptide from the screening was derived from a specific bacterium, Capnocytophaga ochracea, that is commonly found in people’s mouths and is sometimes pathogenic. According to their data, these bacteria should produce a protein that most strongly activates the antibodies against Ro60. After experimentation, they found that the microbe alone was not able to activate the antibodies. However, a synthetically produced version of the protein from C. ochracea, was successful in activating the antibodies.   

This work is important because it suggests that host bacteria may have a strong connection in generating autoimmune responses.  At least in the cases of Lupus and Sjögren’s syndrome, certain bacteria may induce humans to create antibodies against natural body products, and this immune response contributes to the diseases.