Short abstract

It is generally accepted that human immunodeficiency virus (HIV) is theetiological agent of acquired immune deficiency syndrome. According to thisclaim, HIV was transferred to humans from contact with monkeys around 35–50years ago. However, this claim has not been sufficiently confirmedepidemiologically. The spread and incubation period of the plague epidemic hasled to the theory that the Black Death was caused by hemorrhagic viruses. Havingexamined detailed historical data, we have concluded that the bacteriumYersenia pestis was an infectious agent in the epidemic,together with another agent which we suggest was HIV. Our considerations weremainly based on the existence of theCCR5 delta 32 mutation,which protects against HIV infection and has been present in the Caucasianpopulation for over 2000 years. The combination of two infectious agents led tothe devastation of the Black Death, the removal of HIV carriers, and an increasein the number of CCR5Δ32 mutations in the Caucasian population. In sub-SaharanAfrica, this epidemic and subsequent sanitation process did not occur, whichexplains the much higher level of HIV genetic information in this part of theworld.

Introduction

Despite great success in the diagnostics and therapy of acquired immune deficiencysyndrome (AIDS), many unanswered questions remain. Without answers to thesequestions, further advances in the treatment of patients cannot be expected. Insupport of this prediction is the fact that it appears impossible to prevent theworldwide spread of AIDS, especially in Africa. At present, 35 million people inAfrica are HIV-positive, which is the largest group worldwide.

The notion that HIV was transferred from monkeys to humans in Africa around 35 to 50,or even 100, years ago is generally accepted.^1–10 It is also widely acceptedthat Africa is the geographic source of HIV, with AIDS recognized as a logicalconsequence of HIV infection. This claim is supported by the fact that mostHIV-positive individuals are currently in Africa. Such a viewpoint can only bedisproved by developing new hypotheses that are sufficiently convincing, but nonehave so far been presented.

The quality of human health has changed over time, with the biggest changes occurringduring a series of epidemics in Europe, Africa, and Asia.¹¹ The first of these dates back to the Peloponnesian War in 525 BC. Later,Justinian’s plague in 541 AD killed 100 million people, representing 40% to 50% ofthe Roman (Byzantine) Empire. The agent(s) responsible for these epidemics isunknown. The largest known plague epidemic, the Black Death, was caused by thebacteriumYersinia pestis. This epidemic broke out in Italy in1346, from where it spread throughout Europe and then to Asia, decreasing thepopulation by 40% to 50%. At least 60 million people died in China, as well as 50 to70 million in Europe. In the Middle East, the epidemic wiped out 30% to 40% of the population.¹² It did not affect people from the Americas or sub-Saharan Africa. Thisintense, long-standing epidemic lasted until the 18th century, but could also beconsidered a ‘sanitation’ process.

The most common victims of the epidemic were people suffering from malnutrition, andthose with weakened immune systems. In comparison, the survivors had better healthand overall life expectancy increased after the epidemic, when it was not uncommonfor people to live to 70 or 80 years of age; this was very rare prior to theepidemic. Individuals carrying the mutated delta 32 allele of theCCR5 coreceptor gene that is predominantly expressed in Tcells, macrophages, dendritic cells, and eosinophils also survived. This mutation isknown to protect againstY. pestis infection as well as pox virusand HIV infection.^13–16 Homozygous carriers of themutation are also resistant to M-tropic strains of HIV-1.¹⁷ Because the entry of HIV-1 into cells requires CD4 receptor and either CXCR4or CCR5, individuals carrying CCR5Δ32 on both alleles ofCCR5 areresistant to HIV-1 infection. A mathematical model indicated that this mutation isat least 1500 to 2500 years old.^12,18,19 A study of ancient DNA at theUniversity of Queensland reported the detection of CCR5Δ32 mutant alleles in fourskeletons dated at 900 BC from a grave in Germany.¹⁸ The CCR5Δ32 mutation has a relatively high frequency in the Caucasianpopulation, but is absent from individuals in sub-Saharan Africa, East Asia, and theAmericas. Moreover, its absence was confirmed in most tribes in India.²⁰ This suggests that it is a single mutation that likely occurred following thedivergence of Caucasian Africans from their ancestors. This is also supported bygenetic analysis of binding, which indicated that the mutation has a homogeneousgenetic background, so emerged from a common ancestor.¹⁹

In 2001, the epidemiologists Scott and Duncan from Liverpool University in the UK,and the medieval historian Kohn from the University of Glasgow proposed the theorythat the Black Death was caused by hemorrhagic viruses, such as Ebola, rather thanbacteria such asY. pestis.¹⁸ Scott and Duncan advocated that Ebola resistance genes are very widespreadthroughout Europe, and that the virus can enter cells of the immune system using theCCR5 coreceptor.¹⁸ They also argued that the plague spread much faster than usual epidemics, andthat the incubation time was unusually long.^18,21–23 Longer incubation times (up to30 days) allow the carrier to travel further and infect more people. If the primaryvector was a human, such distances could be around 3 miles a day. Indeed, the BlackDeath spread remarkably rapidly: from Sicily to the Arctic Circle in less than 3years during which it covered vast areas of Europe. This is in complete contrast toa bubonic plague epidemic which moved very slowly.²³

The black rat, the plague vector, has a home range of 100 m and rarely strays outsideof this.²⁴ The plague has also been documented in parts of Europe where rats did notlive, such as Iceland.²⁵ Epidemiological studies showed that the plague was transmitted from aninfected human to a human susceptible to infection diseases within a 4-m range.²² The plague epidemic in Europe served to strengthen the frequency of theCCR5Δ32 mutation in the area, with the Black Death increasing it to around 10% ofthe European population.²⁶ In Finland and northern Russia the increase was 16% to 20%. The fact that theallele is present in such a high percentage of one population but was absent fromanother population suggests that selective pressure was strongly in favor of thisallele. The most likely source of this genetic pressure is the Black Deathitself.

The relationship between CCR5Δ32 and the Black Death mutation between 1346 and 1353is described in detail by Stephens.¹⁹ In Northern Europe and Russia where the population frequency of CCR5Δ32 was>10%, mortality levels were below 25%. In areas of southern Europe and the MiddleEast where the population frequency of CCR5Δ32 was below 6%, mortality ratesexceeded 50%. Importantly, mutations have not been detected in sub-Saharan Africa,America, and Southeast Asia²⁰ where infections have not occurred. The question that remains is how has theCCR5Δ32 mutation that induces HIV resistance existed for so long in the humanpopulation? Is it possible that the human population was in contact with HIV beforethe 20th century?

There are several reasons to reflect on this, especially when considering theintensity of the Black Death epidemic. First, it is estimated that there were morethan 200 million victims in Europe and Asia, the most in history. Second, it islikely that the epidemic was a combination of diseases caused by agents such asYersenia pestis and (an)other, still unknown, agent(s). If wedo not accept the standard viewpoint about the origin of HIV, we might reach theconclusion suggested by Scott and Duncan. Indeed, if we consider other viruses aspossible agents, we should include HIV because the CCR5Δ32 mutation clearly providesprotection against infection.

Duncan and Scott do not assume that the CCR5Δ32 mutation preventsY.pestis from entering T cells.¹⁸ This option was tested by infecting wild-type and CCR5-deficient mice withY. pestis.²⁷ No differences in the survival of the two groups were found, as seen in astudy by Mecsas et al.¹⁴ However, a significant reduction ofY. pestis absorption byCCR5-deficient macrophages was observedin vitro. These resultsindicated that the role of CCR5 in infection may be more complex than previouslythought, and thatY. pestis may infect mammalian cells by othermeans. This was also supported by the fact that CCR5 co-factor-binding glycoproteinssuch as HIV gp120 and HIV gp41 and bacteria such asY. pestis haveno glycoproteins.^27,28

Epidemiologists very rarely consider the role of the CCR5Δ32 mutation in the true poxepidemic because it does not spread, remaining in one area.¹⁸ However, some experts advocate a theory that highlights the effect ofsmallpox in a given epidemic.²⁹ They surmise that smallpox virus has been infecting humans for thousands ofyears, with the oldest epidemic believed to have occurred long before 1000 AD. Ifthe receptor for the pox virus is CCR5, then smallpox is a candidate for theselection pressure responsible for the fixation of the CCR5Δ32 resistance allele inthe Caucasian population.^29,30 This option has not yet been tested and it is not possible tobe proven experimentally at the present time.

The hypothesis

The claim that HIV was transmitted from African monkeys to humans through randomcontacts 35 to 50 years ago is not sufficiently confirmed epidemiologically orstatistically.

If we consider the evolution of human health, the biggest changes occurred duringepidemics, which have left a strong footprint on the current status of health. TheBlack Death epidemic of the 14th century has most affected human health. It was alsoa form of sanitation that restored the microbial balance of the human body, and thehealth of the majority of the human population. The Black Death’s course wasepidemiologically unusual, so it is assumed that other agents besidesY.pestis were involved in its high mortality. Epidemiologists Scott andDuncan suggest that this was an Ebola-like virus. On the basis of our studies andresults, we propose that this was HIV. We suggest that HIV has a human origin andthat it has been an inseparable part of humankind since the beginning of ourexistence.^31–35 Moreover, its distribution inthe population is uneven and differs among families.

We suggest that the microbial balance has been disrupted, in ways includingintestinal dysbiosis, in the mid-20th century through the acceptance of antibiotics,drugs (including recreational), medicine, and lifestyle changes (such as anal sex).Additionally, bacteria and yeast containing extra genetic information in the form ofphages, plasmids, and viruses attack T cells, leading to the collapse of the immunesystem.

Has HIV been present in the human population since the beginning of its existence?There are important indications to this claim, particularly the presence of theCCR5Δ32 mutation. The role of CCR5Δ32 during the Black Death has not been discussedbefore because the existing dogma suggests that HIV only infected the humanpopulation in the 20th century. However, if this notion is rejected, the infectiousagent may be considered to be HIV itself. We may propose several alternatives to theinteraction ofY. pestis and the second agent, which could bethought of as HIV:

1. The first victims of the Black Death epidemic were people with a damagedimmune system caused by violation of the microbial symbiosis in theirbody.Y. pestis particularly infected carriers of HIVgenetic information. The immune system of these individuals was weakenedby the systematic penetration of pathogenic genetic information, and theinfection and lysis of T cells. The outcome of this sanitation processwas the destruction of carriers of HIV genetic information and thecomplete recovery of the Caucasian population. However, carriers of theCCR5Δ32 mutation survived this pressure, which increased the frequencyof CCR5Δ32 to 10%, and to 15% to 20% in northern parts of Europe.

2. Y. pestis served as a helper to activate ‘dormant’ HIVin its carriers, followed by HIV amplification. After the penetration ofHIV genetic information into the blood, T cells were infected and lysed,whereby the immune system collapsed and immunodeficiency followed.Because a considerable proportion of the population were carriers of HIVgenetic information, the pandemic had devastating consequences.

3. The epidemic of the 14th century was a combination ofY.pestis and HIV infection agents. The epidemic wasdevastating because it led to the death of carriers of HIV geneticinformation. This notion corresponds to the mode of transmission—fromhuman to human—and the rate and intensity of the epidemic, which differcompletely from classicalY. pestis infection. HIVco-occurrence in the epidemic increased the frequency of CCR5Δ32mutations in Caucasian populations. The importance of mutation CCR5Δ32has been certified and may be used therapeutically in the development ofmodels to induce resistance to HIV.^17,37–38

Historically, in sub-Saharan Africa individual communities have been geographicallyisolated, and lacking commercial and population exchange. As a result, there was notransfer of infectious agents, and this steady state lasted for many centuries.Because of the complete absence of an epidemic and subsequent sanitation process inthis part of Africa, HIV genetic information was not eliminated from humans. Thisexplains the much higher level of HIV there compared with other parts of the world.However, the situation changed in the middle of the 20th century, with massrural–urban migration. Water shortages, poor sanitation, a lack of sanitaryproducts, the use of antibiotics and drugs, and extreme sexual promiscuity havecaused a sharp increase in a wide range of bacterial and viral diseases, includingAIDS.

Highly active antiretroviral therapy is expensive, so is not available for allHIV-positive individuals. Therefore, we propose that the prevalence of HIV in thepopulation of sub-Saharan Africa could be reduced by administering probiotics toremove pathogenic microbes from the intestinal microflora.³⁹

Acknowledgment

The author is grateful to Dr. Ciernikova, Dr. L. Wachsmannova, and V. Stevurkova forparticipation in this work.

Declaration of conflicting interest

The author declares that there is no conflict of interest.

Funding

This work was supported by grants APPV-06-46-11, VEGA 2/0096/11, and VEGA 2/0170/13.This publication is also the result of the project implementation SF ITMS projectcode: 26240220058 supported by the Research & Development Operational Programmefunded by the ERDF.

References