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SARS‐CoV‐2, Covid‐19 Origins, Speculations etc

14 Feb 2021

 This an extract from the original article, which can be found here 

Abbreviations




1. INTRODUCTION

We are currently facing a pandemic of an acute respiratory syndrome that first emerged in Wuhan, China. Shortly after the identification of cases, a novel human coronavirus (CoV), officially named as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), was identified as the responsible agent of this escalating outbreak. 1 The associated disease, officially termed coronavirus disease 2019 (Covid‐19), has been confirmed in more than 75 million cases worldwide with more than 1.6 million fatalities. As the name implied, the virus has similarity with SARS‐CoV that caused the SARS outbreak in 2002–2003. At the whole genomic level, SARS‐CoV‐2 has ±80% identity with SARS‐CoV. 2

Since the pandemic arose, online and social media (including Facebook, Twitter, YouTube and others) have been continuously updating and discussing these situations. 4 The government and research communities use social media to update the outbreak situation in real‐time regularly. 8 However, with the increasing popularity of social media, one person's opinions and beliefs can also instantaneously spread across the world. 9 , 10 Thus, it is not surprising that the media plays a major role in disseminating false information related to viruses, vaccines, as well as diseases. 11 12 13 There is a tendency for conspiracy theories to arise during times of crisis, including during the outbreak of emerging viruses or during a public health crisis in general. 13 , 14 Accordingly, these media can have a powerful effect by influencing ways of thinking and behaviour in the general public, thereby creating more chaos and negatively affecting containment measures and behavioural changes needed to halt the pandemic. 15 16 17 This tendancy may be exacerbated by mistrust of governments or health regulatory organisations as well as medical and scientific communities so that the public are less likely to obey and practise proper preventive and containment measures. 18 , 19 Indeed, belief in a conspiracy is one of the most important driving factors of mistrust of medical sciences and the medical profession. 20

Currently, there are some fictitious and pseudoscientific claims as well as conspiracy theories associated with the Covid‐19 pandemic. 19 , 21 Some people have alleged that SARS‐CoV‐2 is of laboratory origin and the result of deliberate genetic manipulation. According to these conspiracy theories, a novel virus is a human‐made biological weapon, not the result of natural evolution and selection. 22 23 24 SARS‐CoV‐2 is said to be engineered by the Chinese government with economic or political background and agenda. 17 , 19 There are also rumours that SARS‐CoV‐2 ‘leaked’ from a famous laboratory in Wuhan working on bat CoVs, the ancestral virus of SARS‐CoV‐2. 23 Believers in conspiracy theories also alleged that this current pandemic was ‘created’ by physicians or pharmaceutical industries to distribute new vaccines against SARS‐CoV‐2 for financial profit. Allegations of collusion between pharmaceutical companies and physicians are present to obtain benefits from vaccines. Even worse, some people (including those holding high political office) believe that SARS‐CoV‐2 and its associated disease Covid‐19 do not exist at all.

It is not surprising that one potential contributing factor to the current outbreak is misunderstanding among the general population of the facts and dissemination of conspiracy theories. 21 Therefore, counteracting this false information is highly important to decrease the possibilities of the virus spreading and thus, threaten global health. 4 , 17 These efforts are also pivotal to reduce panic and paranoia during the epidemic crisis. 25 In this review, I discuss common conspiracy theories associated with SARS‐CoV‐2 and Covid‐19 and how we can address and counterbalance these issues based on information and studies gained from science.

2. IS SARS‐CoV‐2 GENERATED IN THE LABORATORY?

2.1. Is it possible to ‘make’ or ‘manipulate’ a virus in the laboratory?

It is possible to construct (‘to make’) or manipulate a virus in the laboratory. Scientists perform these kinds of experiments to study the function of specific viral genes, virulence, cell tropism (cross‐species transmission), and infectivity. Additionally, it is also valuable to predict the pandemic potential of certain viruses (e.g., influenza virus and CoVs) and finally, to develop antiviral drugs and vaccines. 26

Of note, virus manipulation must consider the biosecurity issue of dual‐use research of concern (DURC). DURC applies for any type of manipulation resulting in viruses with increased virulence, transmissibility, or host susceptibility. Additionally, it is also applied to experiments resulting in resistance to antiviral drugs, viral variants capable of avoiding established host immunity, and to regenerate extinct (eradicated) viral pathogens. ‘Dual‐use’ means that in addition to societal benefit and humanity, this kind of ‘gain‐of‐function’ (GOF) experiment could be misused to generate a bioweapon. In addition, there is a risk of accidental escape that subsequently leads to human diseases or outbreaks. Therefore, research institutes and laboratories that perform this ‘dual‐use’ biotechnology must guarantee and comply with bisafety and biosecurity practices, and do not intend to threaten individual's safety and general community. 27 , 28

The reverse genetic system is commonly used in ‘modern’ virological research to manipulate viruses. The reverse genetic approach starts with a gene to create a mutant version of viruses because that gene (or its product) is abnormal (genotype‐to‐phenotype approach). Vice versa, the forward genetic approach is employed in classical virological research by first identifying mutant viruses to identify the abnormality in their genes or proteins (phenotype‐to‐genotype approach). 29 Reverse genetic approaches have been commonly used to construct or ‘to customize’ positive‐strand RNA virus (polio), 30 negative‐strand RNA virus (rabies virus), 31 and segmented negative‐strand RNA virus (bunyavirus, influenza A and B viruses). 32 33 34 35

In the influenza virus, GOF experiments have been controversial issues. 28 In 2011, two research groups in the Netherlands and the USA performed genetic alteration of the H5N1 virus that resulted in a highly transmissible virus by serial passage in ferrets. 36 , 37 In these ‘passage experiments’ from one animal to another, viruses can be selected or ‘forced’ to mutate without direct manipulation of their genomes. These reports indicate that the influenza H5N1 virus could potentially acquire a capacity for human‐to‐human transmission. Construction of the influenza virus can also be performed by cotransfecting plasmids encoding each gene segment. 38 , 39 Additionally, plasmid‐based reverse genetics was employed to reconstruct the pandemic H1N1 virus of Spanish flu (1918 pandemic). 40 , 41

Several reverse genetic systems to construct infectious cDNA clones exist for CoV, including by in vitro ligation. The cDNA fragments spanning the full‐length genome of CoV are cloned into separate plasmids incorporated with unique restriction sites at each terminus. Those contiguous fragments are then assembled into infectious clone cDNA in vitro. 42 , 43 Reverse genetics were employed to rescue the transmissible gastroenteritis virus, 44 , 45 porcine epidemic diarrhoea virus strain PC22A, 46 human CoV 229E, 47 SARS‐CoV, 48 , 49 and Middle East respiratory syndrome coronavirus (MERS‐CoV). 50 Currently, this system was employed to reconstruct infectious cDNA clone of SARS‐CoV‐2 by yeast‐based synthetic and bacterial artificial chromosome platforms. 51 , 52

The reverse genetic system can also be performed by constructing chimeric viruses. Chimeric viruses are constructed by joining genomic fragments from at least two different types of viruses. 42 One of the examples is the dengue virus (DENV) vaccine of the Sanofi Pasteur CYD‐TDV containing four chimeric live flaviviruses. The chimeric construct backbone is the genome of the yellow fever virus (YFV) 17D strain. Two gene segments of each four DENV serotypes (precursor membrane and envelope [E] genes) replaced the position of the corresponding genes in the YFV genome. A similar construct is also used in the DENVax vaccine (Takeda). However, DENVax used DENV serotype 2 (DENV2) genome as the viral backbone. 53

Chimeric constructs are also employed in the study of CoV pathogenesis. The spike (S) gene of bat‐derived CoV is inserted to replace the corresponding gene of replication competent SARS‐CoV as the backbone. This construct is employed to study the potential of animal CoV‐derived‐S gene to mediate human infection and diseases. 42 For example, mouse‐adapted (MA) SARS‐CoV (MA15 strain) was used as the backbone to construct chimeric viruses by replacing its S gene with those derived from bat CoV SHC014 and WIV1 strains. 54 55 56 SARS‐CoV MA15 strain was generated by serial passaging of the original human SARS‐CoV Urbani strain in the respiratory tract of young BALB/c mice. 54 Both constructs showed efficient replication in human cells, indicating the potential for bat‐derived CoV to cause re‐emergence of SARS‐CoV in the human population. 55 , 56

2.2. The characteristics of S protein, the hotspot of CoV evolution

Similar to SARS‐CoV, SARS‐CoV‐2 infection is first mediated by engagement of E‐anchored S protein to angiotensin‐converting enzyme 2 (ACE2)‐expressing cells. Thus, the S protein is a key determinant for viral tropism, infectivity, and transmissibility of these CoVs. 57 Following the first introduction into the human population, SARS‐CoV‐2 rapidly evolves by accumulating mutations at the S protein. 58 Thus, scientists mainly focus on S protein to track the origin and evolutionary history of emerging CoVs.

The S protein is structurally divided into three domains: (1) an extracellular domain (EC), and short (2) transmembrane and (3) cytoplasmic tail domains. 59 The EC domain contains two functional subunits, S1 and S2 subunits. Within S1 subunits, receptor‐binding domain (RBD) is present, which specifically recognises ACE2 via its receptor binding motif (RBM). An early study reported variability in the amino acid residues of the RBD between SARS‐CoV and SARS‐CoV‐2. 60 Based on the SARS‐CoV studies, there are five critical residues in the RBD responsible for optimal binding to human ACE2, that is, Y442, L472, N479, D480, and T487, which correspond to L455, F486, Q493, S494, and N501 in SARS‐CoV‐2 genome. 22 , 61 S2 contains fusion peptide and thus, is a membrane‐fusion subunit responsible for the fusion process with the cellular membrane of the target cells. 59 Importantly, the interaction between RBD and ACE2 regulates both cross‐species and subsequent human‐to‐human transmission of SARS‐CoV‐2.

During viral entry, the S protein of SARS‐CoV‐2 is cleaved into two subunits, S1 and S2 by host cell‐derived protease(s). This event is similar to the cleavage of hemagglutinin (HA) protein of the avian influenza virus (AIV). Of note, the sequence of the cleavage site in HA is a key determinant for viral tropism and pathogenicity in AIV. 62 The cleavage site of low pathogenic AIV (LPAIV), containing a single arginine or lysine, is recognised by the host proteases whose expression is restricted to the gastrointestinal and respiratory tract. In contrast, for highly pathogenic AIV (HPAIV), the cleavage site is recognised by the host (furin) protease ubiquitously expressed in various tissues, leading to systemic viral replication and severe disease. 62

Therefore, similar to AIV, the host protease is a key factor determining cell tropism and transmissibility of SARS‐CoV‐2. 63 A previous study in MERS‐CoV showed efficient proteolytic cleavage of the S protein by adding exogenous trypsin enabled bat‐derived MERS‐like CoVs (PDF2180‐CoV and HKU5‐CoV) to efficiently infect human cells. 64 SARS‐CoV‐2 requires the transmembrane protease serine 2 (TMPRSS2) for efficient cleavage of the S protein. 65 Another in vitro study in VeroE6 cell line showed that constitutive expression of TMPRSS2 enhanced its susceptibility to SARS‐CoV‐2 infection. 66 It was found that TMPRSS2 inhibitor (camostat mesylate) could block the entry of SARS‐CoV‐2, raising a possible treatment option. 65 , 67 The genome of SARS‐CoV‐2 contains four amino acid insertions (PRRA) at the junction of S1 and S2 which represent a unique characteristic of SARS‐CoV‐2 since it is absent in other lineage B beta‐CoVs. 22

2.3. Current evidence supports the natural emergence of SARS‐CoV‐2

At the whole genome level, SARS‐CoV‐2 is most closely related to bat SARSr‐CoV RaTG13 (sampled from Rhinolophus affinis from Yunnan Province, China) that shares 96.1% nucleotide similarity. 2 A lower nucleotide sequence similarity (∼87%–88%) was observed with bat SARSr‐CoV ZC45 and ZXC21, collected in Zhoushan, eastern China in 2018. 2 , 60 This sequence similarity suggests that RaTG13‐like viruses could be the ancestor of SARS‐CoV‐2. Noteworthy, there are more than 1000 nucleotide differences between SARS‐CoV‐2 and RaTG13, dispersed throughout the genome. Thus, it is impossible that RaTG13 was manipulated via targeted mutagenesis to generate SARS‐CoV‐2. For the S region, RaTG13 shares 97.45% sequence identity with that of SARS‐CoV‐2 at the amino acid level. However, the identity in the RBD region is lower (89.3%). 68 Bat SARSr‐CoV RaTG13 differs from SARS‐CoV‐2 in four out of five critical amino acid residues in the RBD interacting with ACE2. 69 Moreover, RaTG13‐based pseudovirus is much less efficient in employing human ACE2 to infect cells than that of SARS‐CoV‐2 pseudovirus. 70 Collectively, RaTG13 could be the origin of SARS‐CoV‐2, although it is less likely that RaTG13 is the immediate ancestor of SARS‐CoV‐2.

Subsequently, pangolin‐derived CoVs were identified that share about 85%–91% sequence identity with that of SARS‐CoV‐2 at the whole genome level. 69 , 71 This identity is lower compared to RaTG13 with SARS‐CoV‐2 (96.1%). However, pangolin‐derived CoV has identical residues in five critical amino acids of the RBD region directly interacting with ACE2. 69 , 71 , 72 These identical residues support that those five amino acids can be naturally found in animal CoVs. However, RaTG13 and pangolin CoVs have no furin cleavage site as identified in SARS‐CoV‐2. These notable features indicate that it is impossible to manipulate pangolin CoVs to generate SARS‐CoV‐2. Additionally, pangolin CoVs were identified after the initial outbreak in Wuhan.

Bat sampling in Nengla County, Yunnan Province identified a novel bat CoV from Rhinolophus malayanus. This bat‐derived CoV, designated as RmYN02, is very closely related to SARS‐CoV‐2 in most of the genomic region. At the whole genome level, RmYN02 displayed 93.3% nucleotide sequence identity with that of SARS‐CoV‐2, compared to 96.1% identity between RaTG13 and SARS‐CoV‐2. In most of the genomic region, particularly in the longest 1ab gene, RmYN02 had 97.2% nucleotide sequence identity with SARS‐CoV‐2. In the S gene, RmYN02 demonstrated much less nucleotide and amino acid sequence identities to SARS‐CoV‐2 (71.9% and 72.9%, respectively) compared to the identities between RaTG13 and SARS‐CoV‐2 (92.9% and 97.4%, respectively). 68 However, it is worth noting that RmYN02 contained the insertion of three residues of the polybasic cleavage site (P‐AA) at the junction between the S1 and S2 regions. Although this insert is not identical to SARS‐CoV‐2 (i.e., PRRA), its presence in bat‐derived CoV strongly supports the idea that this insert can be naturally obtained via recombination. A previous study in AIV demonstrated an acquisition of HA cleavage site typical of highly virulent strain after serial passages in chickens. 73 This study indicates that low pathogenic influenza A virus may convert to highly pathogenic strain while naturally circulating in the chicken population. 74

It is worth noting that the S protein of SARS‐CoV‐2 binds to human ACE2 with a stronger affinity than that of SARS‐CoV. 70 , 75 , 76 However, structural studies indicated that some critical residues in the RBM of SARS‐CoV‐2 are not optimal for binding to human ACE2, as compared to SARS‐CoV. 61 This finding reduces the possibility that SARS‐CoV‐2 is a laboratory‐generated virus; in other words, SARS‐CoV‐2 emerged through natural evolution selecting the virus with a high receptor‐binding affinity to human ACE2. 22 , 72

In conclusion, there are several arguments supporting the natural emergence of SARS‐CoV‐2. First, the identification of RaTG13 which is closely related to SARS‐CoV‐2 at the whole genome level. Secondly, the presence of RBD sequence in pangolin CoVs and polybasic cleavage site in RmYN02 that are both similar to SARS‐CoV‐2. Third, the absence of a published sequence of progenitor viruses with very high similarity with that of SARS‐CoV‐2 before the pandemic. Last, SARS‐CoV‐2 likely interacts with ACE2 from various animals, suggesting that the ancestor of SARS‐CoV‐2 naturally passed through these animals before introduction to humans. 61 All these pieces of evidence strongly support the natural emergence of SARS‐CoV‐2.

3. IS SARS‐CoV‐2 THE RESULT OF A LABORATORY ACCIDENT?

3.1. Former laboratory accidents involving live viruses, including SARS‐CoV

Running a laboratory that works with dangerous and pathogenic microorganisms requires a strict biosafety management program in line with a culture of safety to protect laboratory workers and the general community. However, there are multiple reasons why laboratory workers may not comply with these biosafety practices when handling biological agents. Thus, it is important to emphasise that it is always impossible to decrease to zero the risk of a laboratory accident.

One of the most prestigious laboratories in the world, the United States Centers for Disease Control and Prevention (the US CDC) has previously reported major biosafety accidents. These accidents include the unintentional release of viable Bacillus anthracis spores due to the implementation of modified and unauthorised inactivation protocols of bacterial spores. About 75 staff were potentially exposed to live B. anthracis and were monitored intensively. 77 Another biosafety event was cross‐contamination of a LPAIV H9N2 with a HPAIV H5N1 and subsequent shipment of this contaminated culture. 78 Cross‐contamination also led to the first laboratory‐acquired human cowpox virus infection in the US in a laboratory worker conducting research on nonorthopoxvirus. 79 Importantly, the pandemic H1N1 virus in 1977 was likely associated with accidental laboratory release of the virus isolated in 1950. 80 , 81

Accordingly, any laboratories working with CoVs must have standardised laboratory practices to minimise laboratory‐associated infection. 82 However, several reports have documented transmission of SARS‐CoV in laboratory settings. The first case was involved a 27‐year‐old student working in a laboratory in Singapore. Epidemiologic investigations revealed that it was likely that this patient acquired the infection due to contamination of the West Nile virus sample with SARS‐CoV. Fortunately, no further human‐to‐human transmission was identified. 83 The second case was a 44‐year‐old researcher testing herbal remedies against SARS‐CoV. Investigations revealed that this event was likely due to contact with waste liquid spilled in the biosafety level 4 laboratory (BSL4). 84 The third case was the worst since it spread beyond the affected laboratory personnel. In this case, one graduate and one post‐doc student were likely exposed to SARS‐CoV at the Institute of Viral Disease Control of the Chinese CDC. Unfortunately, one death of contact cases was reported, eight people were confirmed or suspected, and hundreds were placed in quarantine. 85 These three cases raised concerns about biosafety issues while handling SARS‐CoV in the laboratory following the initial outbreak.

3.2. SARS‐CoV‐2 and laboratory release theory

Following the first SARS outbreak in 2002, a lot of efforts were made to conduct years of surveillance in the bat population. Scientists from the Wuhan Institute of Virology (WIV) sampled a particular cave near Kunming city, Yunnan Province, China, inhabited by multiple species of horseshoe bats. For 5 years (April 2011–October 2015), they collected 602 anal swabs and faecal samples and tested for the presence of CoVs. They found 11 novel SARSr‐CoVs closely related to SARS‐CoV and other bat SARSr‐CoVs. 86 Another exhaustive 5 years bat surveillance (2010–2015) was conducted in numerous Chinese provinces by the same institute. Importantly, phylogenetic analysis revealed that SARS‐CoV‐2 may derive from bat CoVs in Rhinolopus spp. 87 Intense bat surveillances were also conducted by various institutes in China. 88 89 90 91

Wuhan, the epicentre of the outbreak, is home to two research laboratories, that is, the WIV and the Wuhan Centre for Disease Control and Prevention (the Wuhan CDC). Few laboratories in the world are designated BSL4, a maximum security laboratory, and the WIV is one of them and is the first and the only BSL4 laboratory in China. The Wuhan CDC is a BSL2 laboratory facility that also kept bat CoVs. This situation is different from the former SARS outbreak (2002–2003) that first emerged in Guangdong province, China. There are no laboratories working with live viruses near Guangdong province.

Therefore, there are discussions and unjustified theory—promoted by the US President Donald Trump—whether one of the two laboratories in Wuhan could have been the source of SARS‐CoV‐2. 92 This theory emerged due to extensive research and collections of numerous bat SARSr‐CoVs and the close proximity of the WIV and the Wuhan CDC to the Huanan Seafood and Wildlife Market. There is an accusation that these viruses accidentally infected laboratory workers, either from the virus sample or the animal laboratory. Another accusation is that animals in the Wuhan laboratory escaped, or were smuggled, and sold in the Huanan market. 93 They also argued that Wuhan is far away (1500‐km away) from Yunnan, the home for the horseshoe bats known to harbour SARSr‐CoV. Should the virus have a natural origin, it would be more likely to first emerge in Yunnan, not Wuhan. 93 , 94

One of the hypothetical origins of SARS‐CoV‐2 is that of natural selection occurring in humans following zoonotic transfer. 22 The first case with SARS‐CoV‐2 may have had no contact history with the wildlife market, raising a possibility of undetectable chains of human‐to‐human transmission (infected laboratory worker to people outside the facility) prior to the outbreak. 95 Hence, there is a suspicion that the ancestral virus of SARS‐CoV‐2 was derived from the Wuhan Laboratory infecting the laboratory workers and subsequently, led to the outbreaks.

Despite these massive online speculations, scientific evidence does not support this accusation of laboratory release theory. Yet, it is difficult and time‐consuming to rule out the laboratories as the original source completely. It is highly unlikely that SARS‐CoV‐2 was accidentally released from a laboratory since no direct ancestral virus is identified in the current database. The complete genome of SARS‐CoV‐2 is deposited in the public database shortly after the outbreaks based on advanced next generation sequencing technologies. 96 There is also no record of laboratory accidents at the WIV, and the former SARS‐CoV accident did not occur at the WIV. Additionally, a recent study further supported the natural origin of SARS‐CoV‐2 from viruses found in Rhinolophus sp. 87 However, an independent forensic investigation is probably the only course of action to prove or disprove this speculation. Finally, we can always learn from the previous SARS‐CoV accidents that the best biosafety practices must be implemented to prevent any accidents in the future. 82

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5. SARS‐CoV‐2 AND HIV

HIV and its associated disease, AIDS, have been the subject of conspiracy theories for a long period of time. Conspiracy believers have alleged that some types of vaccines, including polio vaccines, have been deliberately contaminated with HIV. Additionally, a significant proportion of the African American community believes that HIV/AIDS is a human‐made or federal government‐made to ‘eliminate’ Black people and other minority groups. 119 , 120 Indeed, widespread beliefs that HIV is a genocidal conspiracy have a notable impact on HIV prevention and treatment behaviours, including reduced condom use, HIV testing, compliance with antiretroviral therapy, and participation in HIV‐related research. 20 , 121

A suggestion that SARS‐CoV‐2 might be the result of artificial manipulation involving the HIV‐1 genome emerged due to the presence of a manuscript deposited in bioRxiv, a manuscript sharing website prior to any peer‐review process. The authors claimed that SARS‐CoV‐2 had four HIV‐derived insertions in the S protein. The authors further speculated that these HIV‐derived insertions may enhance binding affinity to the host cell receptors (ACE2) and also expand the host cell tropism of SARS‐CoV‐2. The authors then suggest that SARS‐CoV‐2 might be intentionally generated by genetic manipulation employing gene fragments derived from the HIV‐1 genome. 122

To my knowledge, there are two rebuttal papers published to dispute these original claims. 123 , 124 Comprehensive and careful analysis showed that these insertions are present in multiple eukaryotic and prokaryotic viruses, and thus, not HIV specific. Noteworthy, those four insertions are very rarely found in the HIV‐1 sequence database, indicating that these insertions are not derived from the HIV‐1 genome. 123 In addition, comparative analysis with other CoV strains demonstrated that these insertions are identified in three strains of bat‐derived CoVs (ZC45, ZXC21, and RaTG13 strains). 123 , 124 These results clearly showed that these inserts had naturally existed before the emergence of SARS‐CoV‐2. Careful structural analysis also showed that these insertions are not located in the RBD of the S protein, in contrast to original assumptions of the bioRxiv paper. 124 Because of considerable controversies and concerns within the scientific community, the authors have finally withdrawn their original report. However, claims that the virus is laboratory‐created are more difficult to withdraw.

6. SARS‐CoV‐2 AND EXOSOMES

Exosomes are small endosomal‐derived microvesicles secreted by cells to transport biomolecules such as proteins, mRNA, microRNAs, and lipids to the recipient (target) cells. Exosomes are involved in intercellular communications between cells by altering the recipient cell's gene expression and overall function. 125 Exosomes are released both during normal physiological conditions and during pathologies, including viral infections and malignant transformations. 126 , 127 Thus, exosomes have potential to be employed as diagnostic and prognostic molecular biomarkers as well as novel therapeutic modalities. 125

Exosomes have gained popularity during the Covid‐19 pandemic since they are mentioned as one argument by Andrew Kaufman that SARS‐CoV‐2 does not exist. To support his argument, Andrew Kaufman stated that what was detected by PCR is actually not a specific virus, but exosomes. 128 It is clearly seen that this claim is extremely illogical and against common sense since SARS‐CoV‐2 was not solely detected and characterised by PCR but also other modalities, including viral cell culture, whole‐genome sequencing, and electron microscopy technologies.

Indeed, the virus (initially named as 2019‐nCoV) was first isolated from bronchoalveolar‐lavage samples collected on 30 December 2019 by passaging in human airway epithelial cells, Vero E6, and Huh‐7 cell lines. 1 The viral structure of SARS‐CoV‐2 and the cytopathic effect of the infected cells can be clearly visualised by a transmission electron microscopy. Importantly, two nearly full‐length and one full‐length sequences were then submitted and published in GISAID. 1 Subsequently, the genetic sequences of thousands of SARS‐CoV‐2 strains isolated from all over the world have also been published in GISAID, which have an approximate length of 30,000 bases. 129

Interestingly, in his video, Kaufman twisted Dr. James E. K. Hildreth's statement who spoke about HIV in his article, which he quoted as ‘ … the virus is fully an exosome in every sense of the word’ to support his claim that a contagious infectious virus does not exist at all. 128 However, what Dr. Hildreth meant in his paper was that HIV is a virus that hijacks the exosomes in the host cells for both biogenesis of viral particles and viral spread. 130 It is one common mechanism of immune evasion by pathogenic viruses, including hepatitis A virus (HAV) and HCV, since it may facilitate escape from neutralising virus‐specific antibodies. 126 , 127 Clearly, Kaufman intentionally skewed Dr. Hildreth's statement to support his claim that SARS‐CoV‐2 is not a virus, but it is an exosome. 128

Moreover, since SARS‐CoV‐2 is an RNA virus, while exosome can also contain RNA, it is possible to be mistakenly detected, according to Kaufman's statement. 128 Obviously, this is Kaufman's misunderstanding because even though both of them are indeed RNA, the human exosome merely contains human‐derived small RNA (mRNA and microRNA) and cannot release another RNA's species (e.g., virus‐derived small RNA). The human exosome is also unable to release virus‐derived small RNA if the virus itself does not exist in human cells. Exosomes can only release virus‐derived small RNA if the cell has been infected with a virus. 131 Exosomes can also transport fully infectious viral particles, including their genetic material, as has been shown in HCV. 126 Today's technology has been sophisticatedly developed since deep sequencing technology can distinguish between the chain of virus‐ and human‐derived RNA, so it is impossible to mistakenly confuse these clearly different RNA sequences.


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Information about the Paper/Article

Author: Mohamad S. Hakim
Mohamad S. Hakim, di.ca.mgu@mikah.s.m.
corresponding authorCorresponding author.
*Correspondence
Mohamad S. Hakim, Department of Microbiology, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada, 55281 Yogyakarta, Indonesia.
Email: di.ca.mgu@mikah.s.m,
This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

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