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Several studies conducted in the 90’s suggested that prevalence of HIV infection was smaller in patients with sickle cell anemia than in healthy individuals. Although the mechanism behind that is still not fully understood, today we know a lot more than we did back at the end of the century. In order to understand the connection between sickle cell anemia and HIV infection, let us first take a look at both of them separately.
Types of anemia
Anemia in general is a condition where organs are not getting enough oxygen, due to unfunctional hemoglobin, or lack of nutrients needed for it’s synthesis.
Aplastic anemia is a condition in which body is not producing enough red blood cells. This type of anemia is relatively rare, but very dangerous and it can develop at any age. Since the core of the problem is in the bone marrow (the main producer of blood cells), pretty much everything that targets bone marrow or impacts it’s function can cause aplastic anemia. Most common causes are radiation and chemotherapy, autoimmune disorders, some drugs (including a few antibiotics), exposure to toxic chemicals, viral infections (hepatitis, Epstein-Barr, cytomegalovirus, HIV) and pregnancy. If none of the above is the case, one might have an idiopathic aplastic anemia – anemia with no known cause.
Iron deficiency anemia is the most common one, but usually curable with iron supplements. In this type of anemia, a lack of iron causes lower hemoglobin levels. Iron is a crucial part of hemoglobin, sort of like a bridge between two parts of a hemoglobin, and it plays an important role in binding oxygen. Most common causes are loss of blood, lack of iron in the diet, inability to absorb iron and pregnancy.
Thalassemia is a type of anemia that is inherited. Mutations in the genes for hemoglobin cause cells to produce faulty hemoglobin which can’t bind oxygen. Since hemoglobin consists of two types of chains – alpha and beta – depending on which genes are mutated one can develop alpha thalassemia or beta thalassemia.
Vitamin deficiency anemia is, as well as iron deficiency anemia, relatively easy to control with vitamin B-9 (folate) and B-12 supplements. Both B-12 and folate are important for hemoglobin synthesis and red blood cells function, therefore the lack of any or both of them can cause decreased hemoglobin and oxygen levels. This type of anemia is mostly caused by low intake of B-12 and folate, gastrointestinal bleeding and gastrointestinal diseases.
Sickle cell anemia
So, after this long introduction, we can finally talk about sickle cell anemia. Sickle cell anemia is also an inherited disease, in fact, it is the most common genetic disorder in the world. What’s interesting, it most often affects people of Sub-Saharan Africa, South Asia, the Middle East and the Mediterranean. Mutated gene encodes for beta chain of hemoglobin and in order for a child to develop a sickle cell anemia, it needs to inherit mutated genes from both parents. In case the child inherits one healthy gene and one mutated gene, half of it’s red blood cells is healthy and half of them is “sick”. There are also cases of mixed inherited anemias, where a child inherits mutated gene for alpha chain from one parent and mutated gene for beta chain from the other parent. This mix of thalassemia and sickle cell anemia is especially complex and hard to treat.
The exact mutation that happens is the replacement of glutamic acid with valine on a hemoglobin beta chain, causing the hemoglobin to bend in the wrong way. Since the hemoglobin can’t bend in a stable formation, it starts to connect with other molecules of hemoglobin in a process called polymerization. All of these changes are in the end seen as an alteration in the shape of red blood cells (erythrocytes), which form a distinct shape of a sickle – hence the name of the disorder.
Sickle shaped erythrocytes are very sticky and tend to pile up. Those little piles can either grow on one place without ever moving, or they sometimes might slowly grow while travelling through blood vessels until they get stuck in the small vessels causing occlusion. Either way, the piles of sickle cells block the blood flow causing tissue damage, stroke, pain episodes and acute chest syndrome. Such erythrocyte aggregates trigger the release of inflammatory mediators and free radicals that further contribute to tissue damage. Another problem with sickle cell disease is that, the ones that don’t end up on piles, are destroyed rapidly, thus contributing to development of anemia and hypoxia (lack of oxygen) in the tissues. Furthermore, rapid elimination of sickle cells also damages the spleen (the organ which degrades all blood cells), liver and kidneys (which are important for elimination of what’s left of blood cells after they go through spleen).
The symptoms include severe fatigue, painful swelling of hands and feet, yellowish skin color due to increase in bilirubin concentration after degrading a large number of erythrocytes in the spleen. Relatively early in their lives, patients with this type of anemia experience acute pain across the entire body and acute chest syndrome, both due to the occlusion of blood vessels and deprivation of oxygen. Through the years many also develop heart, kidney and eyes problems due to obstruction of small vessels in the tissues. Patients are also very prone to infections, which are also one of the most common causes of death.
The only cure for sickle cell disease at this point in time is bone marrow transplantation. However, emerging field of gene therapy offers promise of a less invasive and potentially more potent treatment.
The idea is to correct the defective gene in bone marrow outside the body and inserting the healthy gene back in the patient. In order to edit the genes this way, we have to have a vector. Most common vectors are viruses, mostly because their genomes are relatively small compared to ours and are therefore easier to manipulate. Also, some viruses have a very clever way of inserting their genome into the genome of a hosting organism. One very important part of their genomes are transcription enhancers, which essentially make the hosting cell produce a lot of the proteins the rest of their genome encodes.
Back to the beginning
Now wait a minute, I promised you the story of how people with sickle cell anemia are protected from HIV infection. Well, as it turns out, that story just doesn’t add up. Despite a great effort scientific community has put in trying to unravel the mechanism behind observed connection between the sickle cell anemia and HIV infection, the numbers are just not in our favor. Although in practice this seems to be the truth and there is less HIV infection in people with sickle cell anemia, the in vitro studies just didn’t give us the proof that we were seeking.
However, it wasn’t all for nothing, as HIV is now being investigated as a potential vector for sickle cell gene therapy. A number of clinical studies are being conducted as you are reading this article and some of them will hopefully become available to sickle cell anemia patients across the globe, saving many lives.
I know, I know, this article may not be what you expected, might even tell me I click-baited you. Well, this is actually a great example of how things don’t always turn out the way you wish or imagine. I once read somewhere that people with sickle cell anemia can’t get infected by HIV virus and when thinking about the topic of my next article, I decided to explore the hypothesis and read more about it. However, not only did I discover that the hypothesis has been proven wrong several times, half way through the writt but I also got stuck on reading about different anemias and voila – you got the article upon anemias and especially sickle cell anemia. As I’m sure, for many for many if you this is an every day issue, especially for those of you working in the lab. Hopefully, clinical studies of sickle cell gene editing using HIV won’t have many detours or end up completely different then what we hope for.