Introduction

Finding the cure for the HIV infection remains the Holy Grail of modern medicine. Considering how technologically advanced we seem to be at present, it does not make much sense that a cure has not been found already. A valid argument I will say. It is common knowledge however that to find the cure to a disease you must first of all understand the disease. It is therefore of little wonder why researchers try to elucidate the underlying mechanisms of diseases before proceeding to finding their cure.

The quest to find a cure for HIV has been quite difficult. The discovery of antiretroviral therapy has gone a long way to curtail the spread of this virus as well as increase the life expectancy of individuals living with HIV. It is of common knowledge that HIV was discovered almost four decades ago, in the year 1983 specifically. It was seen as almost incurable but hopes were arisen in 1985 with the discovery and production of the first antiretroviral drugs.

The HIV virus could now be controlled although not cured yet and this is still the case. The question that abounds is, how close are we to finding a cure for the HIV infection ? Personally, I will like to say; How far are we from finding a cure ? I guess either way it means the same thing. So;

Let’s Have a Discussion

The HIV virus, you will agree with me, is one of the deadliest viruses known to man (cause maybe to an alien it may not be so deadly). Ah yes, you get the virus, it attacks you, you begin to notice strange and weird symptoms and you are on the brink of death. That is not even close to a summary of what happens. I will like to tell you, in the simplest terms ever, what the HIV virus really does to you. But before I do so, let me illustrate how your immune system can act as a military.

Your Immune System Acts like a Military.

The military is known to respond to threats according to how serious they are. There are threats that call for just the intervention of a squad of soldiers overseen by a sergeant. There are ones that call for a battalion overseen by a lieutenant colonel and there are threats that call for a field army overseen by a general. The immune system acts in an analogous manner. The immune system has three lines of defence (the first, second and third lines of defence). The first line of defence is made up of just the physical and chemical barriers. These barriers are not like walls or something. They are basically your sweat, skin, tears, mucus, intestinal bacteria, the acid in your stomach (and yes, our stomach is made up of a concentrated form of hydrochloric acid and how that does not kill us is a topic to another day ) e.t.c. The first line of defence could be seen as the squad of soldiers observed in the military.

The second line of defence is made up of cells that do not have specificity for certain invaders. I mean these guys are savages. They will literally attack anything and are not so tough but they do a good job anyway. They can differentiate the cells of the body they belong to from cells that decided to invade foreign territories (the invaders) so we do not have to worry about these guys going crazy and attacking us some day (although this happens at times and forms the basis of autoimmune diseases; a condition where immune components cannot differentiate self from non-self so attack cells they are not supposed to). This line of defence can be considered the battalion seen in the military.

The third of line of defence consists of the cells that have a brain of their own (well, not literally !!). These cells have specificity and attack specific invaders which are too strong to be eliminated by the first and second lines of defence. They are always just out there chilling until something extremely serious comes up then they have their game face on and it is a thanos vs the avengers kinda shit. They go from a resting state to an activated state according to the level of invasion occuring in the body. We can consider this line of defence the field army seen in the military.

The HIV Virus Beats these Three Lines of Defence. How ?

The squad is the easiest to beat for Mr HIV since our skin has to be breached mechanically for body fluids to get into us. An infected needle going into your body has breached your first line of defence already. So Mr HIV only has to deal with the second and third line of defence. Lol jk. Cells of the second line of defence (the battalion) do not even stand a chance against this guy. This guy is in fact in search for the field army as this is his primary target. Well, the field army feels tough and decides to come for Mr HIV. Mr HIV is not totally impressed as he thinks these guys of the field army are just stupid. Why does he considered them stupid ? They are all part of his ultimate plan and they do not even realise so.

So Mr HIV is fully armed. The soldiers of the field army come for him. He notices they have weaknesses. What are these weaknesses ? Their receptors. It is at this point that Mr HIV realises that he can actually possess these guys and have them making more copies of himself increasing his alliance and becoming much more plentiful than these guys. He goes on to interact with these receptors (CD₄ and CCR5 receptors). With time, he has gained entrance into these soldiers (the T cells) and now he has to alter the control units (the nucleus). Mr HIV however knows that he needs something similar to what is found in the control units of these guys (DNA) to be able to override their functions and he possesses something different (RNA).

But well, he smiles in an evil way cause he brought his bag pack along. Inside his bag pack is an enzyme called reverse transcriptase. He is about to revert a point in the central dogma. He laughs again because these guys actually thought the reversal of this step was impossible. He goes on to make DNA from RNA. He attaches this component to the control units of these guys using another tool from his bag pack called integrase and well, they begin to build and enforce his army aided by another tool called the HIV protease. He has bypassed the three lines of defence and now, he is the boss.

So The Cells of the Immune System get Assistance from the Outside

Now, the immune system is beaten and defeated by Mr HIV and it has to wait on a miracle. Fate decides to smile on it and new sophisticated guys are introduced to help it win this war or maybe, just help it take control of everything. The new guys are known as The Antiretroviral Therapy and they have much more efficient ways of fighting Mr HIV. These new guys do not adopt a similar approach taken by the guys of the field army. These guys are basically impersonators. They act like materials required by Mr HIV and Mr HIV incorporates them into his ongoing project (synthesis of cDNA) and it leads to the production of a failed product (non-functional DNA).

They can also attach themselves to the one or more (still a possibility) tools used by Mr HIV leading to the deactivation of this tool. The tool in this case is HIV protease. This prevents Mr HIV from enforcing and gathering his army (virus assembly and maturation). The ultimate result is a cessation in the production of more copies of Mr HIV (viral replication discontinues). The balance is shifted in favour of the guys of the field army (CD₄ cells).

Not all CD₄ Cells Are Prone to Attack by Mr HIV

Some of the guys of the field army are quite advanced and different. Maybe they did more pushups or whatever. They have one of their receptors quite different from the ones found among their regular counterparts (the CCR5 gene has a 32 bp deletion thus there arises a mutant form of the CCR5 known as the CCR5 delta-32). Mr HIV has one approach which is interaction with these receptors so he cannot possess these ones. They ultimately defeat him and well, mission aborted.

So, With The Introduction of Those New Guys (ARTs), Can The War Against Mr HIV be Considered Won ?

Well, unfortunately, no. The war is far from over. Let us say Mr HIV has found a new home and he cannot be possibly chased away. The new guys can help in preventing the enforcement of Mr HIV’s army (Viral replication can be stopped by ARTs) but they can only do this for HIV viruses that can be detected. Some copies of Mr HIV decide to stay low in compartments where they cannot be detected. They do not try to enforce. They just lay low and wait for these new guys to leave and then they come back in full force to mess things up. This is known as latency and it has been the main reason HIV has not been successfully eliminated from the body just yet.

Hol’ up. The Berlin Patient and The Mississippi Baby ?

In 2006, a man named Timothy Ray Brown was diagnosed with acute myeloid leukemia , a type of cancer of the white blood cells and had to undergo chemotherapy. Well, he did so but that didn’t alleviate his condition however. So he had to undergo a bone marrow transplant where his entire bone marrow will have to be replaced. Well, luckily, he had a perfect matching donor and the transplant was successful, technically. It was noticed afterwards that he was no longer testing positive for HIV and this was particularly surprising. Could it be that his HIV was cured by a bone marrow transplant ?

It was observed that the T cells of the donor had mutated CCR5 receptors and this may have been the reason he was no longer infected as these T cells were now predominant in him. But this could not explain why the HIV viruses had to disappear so suddenly. Suggestions were made that the chemotherapy probably killed the HIV viruses or maybe it was the graft-vs-host immune response (the host cells fighting the foreign cells) that somehow killed the virus. It is all still up for debate. Many scientists immediately concluded that an HIV viral rebound was destined to occur but this has not been the case even up until now. Specific high profile analysis of different tissues from his body did not show the presence of HIV even up until now. This man a.k.a the berlin patient is considered the first man to be cured of HIV. This paper published by the clinician that carried out this procedure pours more light on this case.

The Mississippi baby is another interesting case. A baby who was infected by HIV directly from its mother was put on intensive antiretroviral therapy just six hours after delivery. Viral levels were seen to have dropped below detectable levels in the course of the therapy. Mr HIV could be controlled and possibly eradicated because newborns do have long living memory T cells where Mr HIV likes to hide when he sees the war is actually greater than him so he could be killed easily.

Well, there was a viral rebound in this case after 3 years and this was possibly due to the fact that her mother decided to discontinue her ART after tests came back negative in multiple occasions. Was she to blame ? I do not know. Was she to continue administering ART to her baby even when multiple tests came back negative ? I do not know. When was she supposed to stop giving these drugs at some time without being 100% sure her baby was truly cured of this disease? I do not know. These two cases established a new path for the search of an HIV cure as scientists began to believe that they could indeed find a means to cure people of HIV. Researches in this area have really intensified and it definitely holds many promises.

Why is Mr HIV Choosing to go Incognito Such A Huge Stumbling Block for Modern Medicine and What is The Way Forward ?

Mr HIV chooses to go incognito when things go south. You can also blame the guys of the field army who decide to go to sleep when the war is still on. In scientific terms, HIV infects resting T cells and also activating T cells which then become resting T Cells contributing to latency. The latent reservoir where Mr HIV resides is so hard to detect maybe because it occurs in 1 in a million cells. It could also be because Mr HIV is not replicating so uninfected T cells cannot pick up a signal and attack. Or maybe it is doing so at a very low and undetectable rate.

The idea of converting these resting T cells to activated T cells so they can be detected and attacked has been put forward but there are a lot of limitations surrounding that. First of all, the reservoirs for HIV are found in more places than just resting T cells and these other places are yet to be discovered. Some macrophages can also act as reservoirs for HIV. Secondly, HIV resides in places like the brain and the cerebrospinal fluid where most drugs cannot gain access to so agents that will induce viral replication cannot work fully since they cannot gain access to those areas.
So basically agents that can reverse HIV latency offer a prospect to finding a functional cure for HIV. The limitations highlighted above remain difficult to overcome.

You are probably wondering why repeating the procedure for the berlin patient on HIV patients is not a feasible prospect yet but that procedure was repeated by the same clinician in two more patients and there were viral rebounds. So we may consider the berlin patient’s case, a rare case of luck. So more research needs to be done even though researches like this, for example are actively being carried out.

There is also a prospect of gene therapy which entails altering our CCR5 genes so they begin to produce mutant forms of CCR5 proteins which will go a long way to impede the invasion of T cells by Mr HIV as he cannot interact with these ones so he remains locked out of the party .

Final Thoughts

The ability of the HIV virus to hide in latent reservoirs makes it seem impossible to cure. First of all, it has been established by the success of antiretroviral drugs that the HIV virus is vulnerable. The first problem is location all latent reservoirs for HIV. The second problem is getting it out of its latent reservoirs without affecting uninfected cells in the process. This presents as a functional cure where HIV can be attacked through intense antiretroviral therapy while its latency is being reversed concomitantly. The HIV virus is kept at a level too low for detection and harmful effects and cannot rebound even in the absence of ART.

A sterilizing cure seems far from achievable as the idea of completely eradicating HIV from the body does not seem plausible just yet. I prefer a sterilizing cure and I know everyone does but you know beggars cannot be choosey. We might have to just hope for a functional cure for now. All in all, an HIV vaccine would be the best thing even better than a cure as prevention is better than cure but maybe I am asking for too much. One thing is for sure, we are not too far neither are we too close to finding a cure. Time will surely tell.

References

1. https://www.webmd.com/hiv-aids/features/hiv-cure-in-reach
2. https://theconversation.com/amp/remind-me-again-how-close-are-we-to-a-cure-for-hiv-62483
3. https://m.health24.com/Medical/HIV-AIDS/Management-of-HIV-AIDS/how-far-are-we-from-a-cure-for-hiv-20171130
4. https://www.ncbi.nlm.nih.gov/m/pubmed/17845138/
5. https://idp.nature.com/authorize?response_type=cookie&client_id=grover&redirect_uri=https%3A%2F%2Fwww.nature.com%2Farticles%2Fnm1639
6. https://www.ncbi.nlm.nih.gov/m/pubmed/19213682/
7. https://www.bbmt.org/article/S1083-8791(12)00433-8/pdf
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11. http://www.bloodjournal.org/content/bloodjournal/117/10/2791.full.pdf?sso-checked=true
12. https://www.sciencedirect.com/science/article/pii/S1083879115018741/pdfft?md5=f65766e98fa5315665498359cd316928&pid=1-s2.0-S1083879115018741-main.pdf
13. https://scholar.google.com/scholar_url?url=http://www.jimmunol.org/content/196/11/4437.abstract&hl=en&sa=T&oi=ucasa&ct=ufr&ei=pIojW5TAOYWemgHxm6i4DQ&scisig=AAGBfm22nU-428PANYNdG9ZN__FxUZAmBw
14. https://www.jci.org/articles/view/80142
15. https://www.annualreviews.org/doi/pdf/10.1146/annurev.med.59.062806.123001#article-denial
16. http://science.sciencemag.org/content/332/6031/784.long
17. http://annals.org/aim/fullarticle/746972

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