HIV and AIDs is by far the worst epidemic we’ve seen in the 21st century. Approximately 1 in 4 people are infected and many cultures are affected without the healthcare to prevent or care for the people who have the disease. The prevalence for the disease in our language is lackluster when compared to cancers, heart disease, or even Alzheimer’s, however that further portrays this disease as the silent and deadly killer that we associate with it. Often going unsaid, those effected will suffer through stages of depression and hopelessness. The people around them will also be brought down, and there is not much support available for HIV/AID’s patients. After the epidemic increases to a legitimate danger to life & health of the immediate region effected, then those support programs will pop up. For example, AVERT & UNAIDS are doing great work in containing and supporting those who are affected and their families in highly infected regions of the world, such as South Africa.
When we speak as scientists regarding HIV and AIDs, we first need to ask ourselves how and why it has been a recent problem, if it has been a recent problem at all. Given the virus at a fundamental level, biologists are pointing their fingers are a definite link between HIV, SIV, Polio, and the Bubonic Plague. The history is primarily linked to a protein identified as C-C Chemokine Receptor type 5 (CCR5). CCR5 lives on the surface of white blood cells and stimulates infection, when the white blood cells try to repair the infection, host cells are entered and infected. Those host cells attach to T-cells to proliferate them (or rapidly rises the count), and then the attached cells go through a process called apoptosis (or a rapid death), when the virus reaches the tipping point between proliferation and apoptosis, we identify HIV as AIDs. Generally, this is done by a test called “a1b2/a2b1 interface” which is designed to test hemoglobin and oxygen carriers. Prior to the monitoring of HIV and AIDs, we did not have the technology to monitor and record this phenomenon. Though, we can cut corners looking at animals and how they interact with each virus.
Looking all the way back to the bubonic plague, biologists see a “… selection of certain genetic variants during epidemics [e.g., selection of C-C chemokine receptor type 5 (CCR5) variants presumably by plague] reduces susceptibility to HIV infection in modern Europeans compared with Africans (6).” (Laayouni et al.) Meaning that the same natural selection that the CCR5 protein went through during the plague to eradicate the disease is being seen as a vulnerability in the apoptosis of HIV and AIDs cases throughout the world. Specifically, Laayouni et al. are speaking about the CCR5-Δ32 mutation found in the CCR5 gene which protects, most commonly, Europeans from the strains of HIV that attach to the CCR5 proteins. The plague had spread through seagulls, rats, fleas, and other insects who carry the CCR5 protein but are unable to hold the Δ32 mutation in the CCR5 gene. Although rats, fleas, and gull are unable to be affected by the ‘black death’ due to a difference in physiology, the disease was initially spread through these animals and then carried airborne. This inability prevented the natural selection of the protein from evolving more rapidly. The CCR5-Δ32 mutation is the primary way which inhibits SIV & HIV-1 from being spread, however, this mutation was not prevalent in Africa among Simian or Human populations, and because of that, the Polio vaccine which targeted the CCR5-Δ32 mutation in the CCR5 gene was inefficient. Instead, the Δ32 genome became a catalyst for the immune system to rapidly spread the polio virus and allow its natural selection, which became SIV & HIV-1 in the 1950’s. This study will focus on how we may have been able to avoid the evolution of CCR5 and its mutation counterpart, Δ32. (Laayouni et al.)
Tracking the Plague: The Beginning of a Human-bred Pathogen
The migratory patterns of gulls, and the trade routes from Central Asia allowed the spread of the plague via shipboard stowaway rats. The plague originated in Central Asia, what is currently China, then moved to the Italy in 1334, from Italy the plague spread, and the epidemic started. Active port cities had the highest infection and mortality rates, and the disease spread across Europe, to North Africa and from Central Asia to Eastern Asia. Though India was a major trade route, we do not have data to verify the effect on South Asia. Additionally, the spread stops in Northern Africa around the Libya region. This is primarily due to the lack of trade through the Sahara Desert at the time. It is most likely the seclusion of the African population from the Black Plague prevented the evolution of the CCR5 protein and as a result, the Polio vaccination was unstable in that part of the world.
Looking further, humans could have prevented the spread of the disease by preventing shipboard stowaways or by shipboard sanitation. Both of which are a goal in modern shipping. However, without the resources or medical knowledge, the blame of HIV-1 can not be pinned on the Bubonic Plague, nor it’s victims. However, scientists can speculate that if the Polio vaccination in the 1950’s had not been used on a test group in Africa, then SIV or HIV-1 would not have evolved from the CCR5 protein. Additionally, had protocols been in order for the administration and monitoring of the Polio Vaccination, then the spread would have most likely not occurred.
Instead, we see a deliberate modern malpractice of medicine in a fundamentally fragile set of conditions which promoted the natural selection of certain proteins and cells to create the earliest forms of HIV; SIV and HIV-1. (Xu Y et al).
As seen in Figure 2, most of countries effected by Polio are either non-Caucasian majority countries or those unaffected by the initial spread of the Bubonic Plague. This further illustrates the point of the Δ32 mutation’s importance in preventing the spread of these viruses in the first place. However, instead, scientists moved to the epicenter of the Polio disease in Africa to try to develop a vaccination, which at the time made the most sense. However, it was also the worst available option due to the instability of the CCR5 protein in the vaccination and the possibly of the virus evolving past the Polio stage. (Rosenberg AS).
Tracking HIV-1 & Subtypes
As seen in this image, most continents with European influence such as Europe, the Americas, and Latin America have a majority of HIV-1 Subtype B, which is more infectious in individuals with the CCR5-Δ32’s lineage. Akin to the Polio diagram, Asia and Africa do not have the same resistances that were built in the Dark Ages with the Plague. The HIV-1 subtype in those regions are less evolved but not less of a problem. Those subtypes evolve and adapt just as much as subtype B does, creating a deadly network of viruses.
The differentiation, besides medically, is the predicted origin of the subtype. We can predict that B evolved with Caucasians and spread to colonies of Europe in the Americas, as well as North Africa and the Middle East. AG, A, J, and D are primarily seen in Africans, while subtype C is seen in South Africa, India, Nepal, and China. AE is most common in heterosexual males and effects the entirety of Southeast Asia. (The Lancet Infectious Diseases, 565 - 575).
Timothy Ray Brown, a Berlin recipient of a bone marrow transplant in 2009 had been cured of HIV-1 after receiving the transplant and two cells that contained the Δ32 mutation. However, two patients in Boston received bone marrow transplants without the Δ32 mutation, the virus had rebounded. (Hütter, Gero, M.D et al; Petz LD et al).
Those in opposition of this theory will focus on biological differences or symptoms of the disease, such as physical features that differ from disease to disease. However, the genealogy of these diseases all link to the CCR5 protein and genes in relation to the protein. The evolution from the plague to HIV-1 is apparent in the biochemistry of those affected or unaffected by the diseases. Without a groundbreaking interaction of the protein which denies this theory, there is not much to oppose the argument that the diseases evolve and survive in tandem with our own evolution and primary selection. At an elementary level, the diseases seem far between without any ties, however, with the evidence provided, the elementary view is muddied between distinct and hard concrete evidence.
Additionally, we see the CCR5 link in smallpox, but the trace evidence and demographic area of infection do not support this theory. Smallpox is an airborne virus and has several differing observable symptoms which do not show a link to the previously mentioned diseases. (Lalani, 286).
In conclusion, the link that brings together the largest epidemics in human history is through a protein called CCR5, which has a mutation, Δ32, that rejects the disease’s primary method of infection. Focusing our research on this mutation could provide an immunity to the evolution of these diseases and halt the tandem parasitic relationship between ourselves and the diseases. The cure is not a possibility for today, but rather for generations to come after geneticists, biologists, and other scientists spread the Δ32 mutation to new offspring and allow the mutation to co-evolve with this lineage of disease.
Focusing on today prevents us from protecting tomorrow and futures to come. If we could invest today to help tomorrow instead of focusing on instant gratification methodologies, we may have a chance to finally get rid of the HIV epidemic once and for all.
References & Further Reading
A. S. Lalani (1999). Use of Chemokine Receptors by Poxviruses Science, 286 (5446), 1968-1971 DOI: 10.1126/science.286.5446.1968
Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study; The Lancet Infectious Diseases , 1999 Volume 16 , Issue 5 , 565 - 575
Hütter, Gero, M.D., Nowak, Daniel M.D. et al. Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation N Engl J Med 2009; 360:692-698February 12, 2009 DOI: 10.1056/NEJMoa0802905
Hafid Laayouni, Marije Oosting, et al. Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors
PNAS 2014 111 (7) 2668-2673; published ahead of print February 3, 2014, doi:10.1073/pnas.1317723111
Petz LD, Burnett JC, Li H, et al. Progress toward curing HIV infection with hematopoietic cell transplantation. Stem Cells and Cloning : Advances and Applications. 2015;8:109-116. doi:10.2147/SCCAA.S56050.
Rosenberg AS, Roivainen M et al. CCR5 deficiency and severe polio infection in the 1984 outbreak in Finland. J Med Virol. 2013 Dec;85(12):2139-40. doi: 10.1002/jmv.23739. Epub 2013 Sep 13.
Xu Y, Phetsouphanh C, Suzuki K, et al. HIV-1 and SIV Predominantly Use CCR5 Expressed on a Precursor Population to Establish Infection in T Follicular Helper Cells. Frontiers in Immunology. 2017;8:376. doi:10.3389/fimmu.2017.00376.
Zaunders J, Xu Y, Kent SJ, Koelsch KK, Kelleher AD. Divergent Expression of CXCR5 and CCR5 on CD4+ T Cells and the Paradoxical Accumulation of T Follicular Helper Cells during HIV Infection. Frontiers in Immunology. 2017;8:495. doi:10.3389/fimmu.2017.00495.