In this video, Dr. Seheult of MedCram discusses why it appears that some people never seem to get COVID. He does this video in conjunction with an article written by Emily Laurence in Parade magazine. It turns out that (surprise surprise) genetics may play a role.
What are HLA genes?
What first needs to be understood are HLA genes which are explained in detail here. Dr. Seheult emphasizes that the following summary of the HLA genes is a major oversimplification of the processes. There are two major types of proteins that are coded for by the HLA genes (these are not the only proteins). In this video, Dr. Seheult focuses mainly on MHC-1 proteins (which stands for major histocompatibility complex) and MHC-II proteins. The MHC-1 protein is coded for by the HLA-A, -B, and -C genes and is present on every nucleated cell in the body except for the RBCs which do not have a nucleus. Each person gets two different copies, one from your father and one from your mother. Each person’s set of proteins are very specific to the individual and are different from other individuals. This is why organ donations need to be HLA matched, otherwise the body will reject the new organ if there is not enough HLA matching. The MHC-1 proteins are what tells the immune system that a cell is infected and needs to be destroyed.
How do the HLA genes work?
There are three regions on the HLA gene which are designated as class I, class II, and class III. In this video, Dr. Seheult focuses on class I and class II. Class I has three different gene products known best as HLA-A, -B, and -C. The function of these is to present antigen peptides (tiny protein pieces) on the surface of the cell to responding CD8 T cells. The class II molecules HLA-DR,-DP, and -DQ primarily present peptides to CD4 helper T cells.
What are CD8 T cells?
CD8 T cells are the cells that go around the body and kill infected cells. They are also known as cytotoxic or killer T cells. If the CD8 T cells are strong and can effectively remove infected cells, then the likelihood of a severe infection is less. Conversely, if they are weak, then a viral infection may spread more easily in the body.
How do CD8 T cells work?
The CD8 T cell receptor is what binds the MHC-I protein that is presenting the piece of the foreign peptide or antigen. What scientists are learning is that the MHC protein can also contribute to the amount of binding that killer T cell will have to it. If a MHC protein has a strong affinity to the binding with the killer T cell, this can result in a more robust immune response. When the CD8 T cell binds to the infected cell, there is a signal sent to the infected cell’s nucleus telling it that the cell is infected. The infected cell then initiates a cascade process that will lead to its destruction.
What is HLA-B15:01 and why is it of interest?
In this study that is in the process of being peer reviewed, they have found that the HLA-B15:01 gene allele may be associated with asymptomatic SARS-CoV-2 infections. In essence, an individual with this gene allele can be infected with SARS-CoV-2, but never go on to develop a symptomatic stage. This HLA gene makes a MHC-1 protein. In this study, they looked at a bone marrow bank where they had almost 30,000 people in the database with known information on their HLA A, B,C status. Participants were asked to fill out a survey about whether they had SARS-CoV-2, how it was diagnosed, and what their symptoms were. 21,893 people completed the baseline survey. In this cohort, the researchers found that in the individuals that were infected but asymptomatic, there was a larger proportion of people with the HLA-B15:01 gene. The researchers then did two phases in the study with an initial discovery phase and then a replication phase. The paper stated that the HLA-B15:01 gene was significantly increased in asymptomatic individuals in the discovery cohort compared to symptomatic individuals with an odds ratio of 2.45. This was able to be reproduced in the replication cohort with an odds ratio of 2.32. They found that have 2 copies of the gene (homozygosity) was associated with an increase of more than eight times of remaining asymptomatic after a SARS-CoV-2 infection. They concluded that the HLA-B15:01 gene was strongly associated with asymptomatic infection with SARS-CoV-2 and was likely to be involved in the mechanism underlying early viral clearance.
Proposed mechanism of HLA-B15:01
This gene allele HLA-B 15:01 appears to be associated with asymptomatic infection. It is a relatively common gene allele in the population. If you had one copy of the gene, it was associated with twice the likelihood of having an asymptomatic infection vs up to eight times if you as an individual had two copies of the gene. It is felt that the reason this happens is because this gene allele has a high binding affinity for a specific gene sequence (epitope) of the SARS-CoV-2 virus. This peptide known as WTAGAAAYY (these are the amino acids) is highly immunogenic and is predicted to elicit a strong CD8 T cell response. Another alternate explanation from the authors of the study is that the HLA-B 15:01 carriers had previously been infected by other coronaviruses and have pre-existing cross reactive CD8 T cells with a high affinity for a specific epitope conferred by the HLA molecule.
B cells vs T cells
There are misconceptions about the role of B cells (which make antibodies) vs T cells in the immune response. B cells seem to get more importance placed on them. In reality, B cells do not change very easily and do not have a wide range of response as they produce a particular antibody. T cells on the other hand change with the virus in the environment. T cells adapt much more quickly than B cells and as mentioned above, a prior coronavirus infection could be enough to cause a high affinity for a specific epitope. In fact, a lack of antibodies in an infection could be due to the possibility that the T cells had such a robust response, that they eliminated the infection before the B cells even had a chance to make antibodies.
We have known that specific HLA genes can enhance the bodies immunity innately against viruses such as Hepatitis B and C and now we can add SARS-CoV-2 to that realm. More research is of course still needed.
LINKS / REFERENCES:
COVID-19 Cases and Deaths by Vaccination Status Dashboard (Texas DSHS) | https://www.dshs.texas.gov/immunize/c…
The T cell immune response against SARS-CoV-2 (Nature Immunology) | https://www.nature.com/articles/s4159…
If You Haven’t Gotten COVID Yet, This Might Be Why (Parade) | https://parade.com/health/why-some-pe…
Major histocompatibility complex: Antigen processing and presentation (NIH) | https://www.ncbi.nlm.nih.gov/books/NB…
Mutation profile of SARS-CoV-2 spike protein and identification of potential multiple epitopes within spike protein for vaccine development against SARS-CoV-2 (NIH) | https://pubmed.ncbi.nlm.nih.gov/34754…
HLA-B*15:01 is associated with asymptomatic SARS-CoV-2 infection (NIH) | https://www.ncbi.nlm.nih.gov/pmc/arti…
All coronavirus updates are at MedCram.com (including more discussion on delta variant COVID, COVID Delta, COVID children, natural immunity COVID 19, and more).
MedCram Update 46: https://youtu.be/EFRwnhfWXxo
MedCram Update 47: https://youtu.be/H1LHgyfPPQ8
MedCram Update 132: https://youtu.be/9OZZ6_M4OB0
Stay Tuned for More Updates
Our COVID-19 videos are always available for free (and ad-free) at MedCram.com. In addition, check out our full library of courses and lectures on subjects ranging from Hypertension Explained Clearly to Sleep Apnea Explained Clearly Course and many more!
Meanwhile, you can find all of our COVID-19 videos compiled here.
Visit MedCram.com for updates on Monkeypox virus infectious disease and more.