Presented by Zia H Shah MD

Abstract

The history of mammalian evolution is inextricably bound to the history of viral infection. Traditional biological paradigms have long categorized viruses solely as pathogens—agents of morbidity, mortality, and cellular destruction. This “warfare model” posits an eternal conflict between the host immune system and the invading viral genome. However, the advent of deep genomic sequencing and the emerging field of paleovirology have necessitated a fundamental restructuring of this perspective. We now recognize that the mammalian genome is not a pristine, isolated entity but a chimeric structure, heavily infiltrated by viral sequences that have been co-opted over millions of years to serve essential physiological functions. This report provides an exhaustive analysis of the positive genetic contributions of viruses to the mammalian lineage.

It distinguishes between two primary modes of viral influence: the Exogenous Selector, exemplified by the Rhinovirus, which exerts profound selective pressure to drive the diversification of mammalian immune genes; and the Endogenous Integrator, exemplified by Retroviruses and other non-retroviral elements (Bornaviruses, Filoviruses, Circoviruses), which physically merge with the host germline to provide novel genetic material. The analysis details how these “domesticated” viral genes have become the architects of the mammalian placenta (Syncytins, PEG10), the mediators of synaptic plasticity and memory (Arc), the regulators of innate immunity (Fv1, MER41), and the guardians of pluripotency (HERV-H). By examining the molecular mechanisms of these co-options, this report argues for the Holobiont theory of evolution, suggesting that mammals are not singular individuals but symbiotic consortia, whose very existence relies on the structural and regulatory integration of ancient viral invaders.

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1. Introduction: The Dual Nature of Viral Influence

The biological identity of the mammal is often defined by its physiological traits: hair, mammary glands, a neocortex, and, in the case of eutherians, a complex placenta. Yet, a genomic audit reveals that a staggering proportion of the DNA encoding these traits—and the regulatory networks that control them—is of viral origin. Approximately 8-10% of the human genome consists of identifiable Endogenous Retroviruses (ERVs), with a much larger percentage comprised of retrotransposons and other mobile genetic elements that share a viral ancestry. This contrasts sharply with the roughly 1.5% of the genome that codes for “host” proteins.

To understand how viruses contribute positively to the making of a mammal, one must navigate the dichotomy between the virus as a distinct, transient organism and the virus as a permanent genetic component. The user’s query specifically highlights “rhinoviruses,” which represent the former category, alongside “other viruses” that typically represent the latter. This report structures the analysis around this duality:

1. The External Forge (Rhinoviruses): These viruses do not typically integrate into the germline. Their “positive” contribution is indirect but evolutionarily potent. By infecting the respiratory tract and challenging the host, they force the rapid evolution and diversification of host defense genes. They are the “fitness landscape” against which the mammalian immune system is carved.
2. The Internal Architect (Endogenous Viral Elements): These viruses (Retroviruses, Bornaviruses, etc.) enter the germline, lose their infectious potential, and are repurposed. They provide the raw materials—fusogens, capsids, promoters, and enhancers—that the host uses to build new tissues and regulatory networks.

This distinction is crucial. While the Rhinovirus drives the quality of the mammalian genome through purifying selection, the Endogenous Retrovirus drives the complexity of the mammalian genome through genetic addition.

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2. The Rhinovirus and the Crucible of Selection

The Rhinovirus, a member of the Picornaviridae family, is the predominant cause of the common cold in humans and a significant pathogen in other mammals. Unlike retroviruses, rhinoviruses have a positive-sense single-stranded RNA genome and replicate in the cytoplasm without a DNA intermediate stage. Therefore, they do not naturally integrate into the host genome. However, their contribution to the “making of the mammal” is best understood through the lens of the Red Queen Hypothesis: organisms must constantly adapt, evolve, and proliferate not merely to gain reproductive advantage, but simply to survive against ever-evolving opposing organisms.

2.1 Genetic Diversification and Host Pressure

Rhinoviruses exhibit extraordinary genetic diversity. Phylogenetic analysis divides them into three species: Rhinovirus A, B, and C. Within these species, particularly Rhinovirus A and C, there is significant evidence of episodic positive selection and intra-species recombination.¹

• Recombination as a Driver: Analysis of complete genomes reveals that Rhinoviruses are not static; they are an ensemble of distinct lineages (seven genetically distinct subpopulations have been identified) that constantly swap genetic material.¹ This immense variability presents a shifting target for the mammalian immune system.
• The Positive Consequence for Mammals: This viral diversity exerts a “positive” pressure on the mammalian genome by selecting for high polymorphism in immune-related genes. The Major Histocompatibility Complex (MHC) in humans (HLA) is the most polymorphic region of the genome. This diversity is essential for population survival. Without the constant, low-level mortality and morbidity pressure from ubiquitous viruses like Rhinoviruses, the mammalian immune system might stagnate, leaving the population vulnerable to extinction events from novel pathogens.

2.2 The Biochemical Arms Race

The Rhinovirus life cycle is governed by interactions with host receptors (e.g., ICAM-1, LDLR, CDHR3). The virus drives the evolution of these surface proteins. For instance, variations in the CDHR3 gene are associated with susceptibility to severe Rhinovirus-C infections and asthma.³ While this manifests as disease in the individual, on an evolutionary scale, it drives the selection of receptor variants that balance physiological function with viral resistance.

Furthermore, the viral protease 2A (2Apro) of Rhinovirus targets host transcription factors to shut down cellular protein synthesis and dampen the interferon response.⁴ This forces the mammalian host to evolve redundant antiviral pathways and more robust interferon signaling networks. Thus, the complex, multi-layered innate immune system of modern mammals is, in part, a monument to millions of years of combat with picornaviruses like the Rhinovirus.

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3. The Placental Revolution: Viral Origins of Viviparity

If Rhinoviruses sharpened the shield of immunity, Retroviruses forged the cradle of life itself: the placenta. The transition from oviparity (egg-laying) to viviparity (live birth) is the defining characteristic of eutherian mammals. This transition required the evolution of a new organ capable of invading the maternal uterus, establishing a nutrient interface, and—crucially—suppressing the maternal immune rejection of the semi-allogeneic fetus. Evidence is now irrefutable that this evolutionary leap was powered by the domestication of retroviral envelope (env) genes.

3.1 Syncytins: The Molecular Glues of Life

The mammalian placenta is anchored by the syncytiotrophoblast, a tissue layer formed by the fusion of individual trophoblast cells into a single, multinucleated barrier. This fusion is mediated by proteins called Syncytins.

3.1.1 Mechanisms of Co-option

Retroviruses are enveloped viruses. To enter a host cell, they use an envelope protein (Env) to fuse the viral membrane with the cell membrane. Evolution has co-opted this exact mechanism. In the placenta, the “host” cells (cytotrophoblasts) express the viral Env protein (Syncytin), which binds to a receptor on adjacent cells, causing them to fuse. This creates the syncytium, which mediates nutrient and gas exchange.⁵

Crucially, viral Env proteins also possess an Immunosuppressive Domain (ISD). In a viral context, this domain prevents the host immune system from attacking the virus. In the placental context, this domain induces local tolerance, preventing the mother’s immune system from attacking the fetus, which carries paternal antigens.⁷

3.1.2 Convergent Evolution: A Repeated Strategy

The co-option of env genes for placentation is not a singular accident; it is a convergent evolutionary strategy repeated across distinct mammalian lineages. This implies a biological necessity: the easiest way to build a placenta is to borrow a viral gene.

• Primates (Syncytin-1 and -2): Humans utilize Syncytin-1, derived from the HERV-W family (integrated ~25 million years ago), and Syncytin-2, derived from HERV-FRD (>40 million years ago).⁶ Syncytin-2 is highly conserved and retains significant immunosuppressive activity, while Syncytin-1 is primarily fusogenic.⁷
• Rodents (Syncytin-A and -B): Mice utilize two distinct genes, Syncytin-A and Syncytin-B, derived from Murine Leukemia Virus (MLV)-related retroviruses acquired ~20 million years ago. These are not orthologous to human Syncytins; they are different viruses performing the same job.¹⁰
• Carnivores and Ruminants: Independent capture events have been identified in cats (Syncytin-Car1), dogs, and sheep.¹²
• Marsupials and Lizards: Even the viviparous Mabuya lizard expresses a retroviral envelope protein (Syncytin-Mab1) in its placenta-like structure, suggesting this viral mechanism predates mammals or evolved independently in reptiles.¹³

3.2 Suppressyn: The Viral Regulator

The use of a potent viral fusogen is dangerous; unchecked fusion could destroy tissue architecture. Therefore, the mammalian genome has co-opted other viral genes to regulate Syncytins.

Suppressyn (SUPYN) is a protein derived from the envelope of the HERV-H family (specifically the ERVH48-1 locus) found in hominids.¹⁴ Suppressyn binds to the ASCT2 receptor—the same receptor used by Syncytin-1. However, unlike Syncytin-1, Suppressyn does not induce fusion. By occupying the receptor, it acts as a competitive inhibitor, effectively putting a “brake” on Syncytin-1 activity.¹⁶

This reveals a stunning complexity: the human placenta is regulated by a network of domesticated viral genes fighting each other. One viral gene (Syncytin) pushes for fusion/invasion, while another viral gene (Suppressyn) restrains it. Dysregulation of this viral balance—such as the downregulation of Suppressyn—is implicated in preeclampsia, a condition characterized by abnormal placental invasion.¹⁷

3.3 The Ty3/Gypsy Legacy: PEG10 and RTL1

Beyond the envelope proteins, the core structural proteins (Gag) and enzymes (Pol) of retrotransposons have also been domesticated. The SIRH (Sushi-ichi-related retrotransposon homologs) family describes a group of genes derived from the Ty3/gypsy class of LTR retrotransposons.¹⁹

• PEG10 (Paternally Expressed Gene 10): Derived from a Gag-Pol protein, PEG10 is an imprinted gene (expressed only from the paternal allele) essential for the formation of the placental labyrinth and spongiotrophoblast layers. Knockout of PEG10 in mice is lethal mid-gestation, as the placenta fails to develop.²¹ PEG10 proteins form capsid-like structures and bind RNA, potentially transporting growth factors like Hbegf to facilitate differentiation.²³
• RTL1 (PEG11): This gene is critical for the maintenance of fetal capillaries in the placenta. Overexpression or loss of RTL1 leads to severe vascular defects and fetal death.²⁴ It is highly conserved in eutherian mammals, suggesting it was a key innovation in the establishment of the fetal-maternal circulatory interface.

Summary of Viral Contributions to Placentation

Viral Gene	Viral Origin	Host Function	Mechanism	Consequences of Loss
Syncytin-1	HERV-W (Env)	Cytotrophoblast fusion	Binds ASCT2 receptor to fuse membranes	Impaired syncytium formation
Syncytin-2	HERV-FRD (Env)	Immunosuppression	Binds MFSD2 receptor; ISD domain activity	Fetal rejection; failure of implantation
Suppressyn	HERV-H (Env)	Regulation of fusion	Blocks ASCT2 receptor (Competitive Inhibition)	Preeclampsia; excessive invasion
PEG10	Ty3/Gypsy (Gag-Pol)	Labyrinth formation	RNA binding/transport; Structural scaffolding	Early embryonic lethality
RTL1	Ty3/Gypsy (Gag-Pol)	Vascular maintenance	Endothelial cell integrity	Late fetal death; vascular anomalies

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4. Neurological Domestication: The Viral Mind

While the viral origins of the placenta are increasingly accepted, the viral origins of the mammalian brain represent a newer and more startling frontier. Research suggests that the very mechanisms of memory storage and synaptic plasticity—the foundations of cognition—are derived from ancient retroviral infections.

4.1 Arc: The Neuronal Retrovirus

The gene Arc (Activity-Regulated Cytoskeleton-associated protein) is a “master regulator” of synaptic plasticity. It is an immediate-early gene, meaning it is rapidly transcribed in neurons following stimulation (e.g., during learning).

4.1.1 Viral Phylogeny

Sequence analysis reveals that Arc is derived from a Ty3/gypsy retrotransposon lineage, making it a close relative of the retroviral Gag gene.²⁶ This “neuronal Gag” is conserved across tetrapods (mammals, birds, reptiles, amphibians), indicating an ancient domestication event ~350-400 million years ago.²⁸

4.1.2 Mechanism: Intercellular Communication via Capsids

The function of Arc was mysterious until it was discovered that the Arc protein self-assembles into virus-like capsids.²⁷ These capsids are not mere structural curiosities; they are functional transport vehicles.

1. Assembly: Upon synaptic activation, Arc protein assembles into capsids and encapsulates its own mRNA.
2. Release: These capsids are packaged into Extracellular Vesicles (EVs) and released from the neuron.
3. Transfer: The EVs traverse the synaptic cleft and are endocytosed by neighboring neurons.
4. Translation: Once inside the recipient, the mRNA is released and translated.

This process allows neurons to physically transfer genetic information in an activity-dependent manner. This transfer mediates Long-Term Depression (LTD) by regulating the density of AMPA receptors at the synapse.³⁰ Essentially, the mammalian brain uses a domesticated viral infection cycle to encode memories. Dysregulation of Arc is linked to neurological disorders including Alzheimer’s, autism, and Fragile X syndrome.³²

4.1.3 Epilepsy and the Viral Shadow

The viral nature of Arc also has pathological echoes. During epileptic seizures, neurons generate massive amounts of Arc capsids. While usually regulatory, this “overproduction” of viral-like particles acts as a shadow of the original infection, suggesting a link between the viral mechanism of the protein and the susceptibility to hyperexcitability states.³³

4.2 PRODH and Human-Specific Cognition

Viral elements also contribute to brain evolution by acting as regulatory switches (enhancers) rather than coding for proteins. The gene PRODH (proline dehydrogenase) is critical for neuromediator synthesis and is a strong candidate gene for schizophrenia susceptibility.

In humans, PRODH expression in the hippocampus is driven by a human-specific endogenous retrovirus (hsERV) related to the HERV-K family. This viral element acts as a tissue-specific enhancer, containing binding sites for the transcription factor SOX2.³⁵

• Evolutionary Impact: Since this enhancer is not present in chimpanzees, it implies that the integration of this specific retrovirus contributed to the evolution of human-specific neural traits. The virus rewired the regulation of a key metabolic enzyme in the brain, potentially boosting cognitive capacity but also introducing vulnerability to psychiatric disorders.³⁷

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5. Wiring the Innate Immune System

One of the most ironic twists of evolution is that mammals use viral genes to fight viruses. This phenomenon, known as “fighting fire with fire,” involves the co-option of viral genes to serve as restriction factors or immune regulators.

5.1 Fv1: The Prototype Restriction Factor

The Fv1 (Friend virus susceptibility 1) gene in mice was the first identified retroviral restriction factor. It confers resistance to Murine Leukemia Virus (MLV) infection. Cloning revealed that Fv1 is an ancient retroviral Gag gene derived from the MuERV-L family.³⁹

• Mechanism: The Fv1 protein retains the capsid-binding domain of the original viral Gag. It binds to the capsid of incoming MLV particles, freezing them in the cytoplasm and preventing their nuclear entry and integration.⁴¹
• Selection: Fv1 has been under intense positive selection in the rodent lineage (specifically Muridae) for over 7 million years, evolving new binding specificities to keep up with mutating exogenous viruses.⁴² This demonstrates a direct conversion of a viral structural protein into an intracellular immune sentry.

5.2 Refrex-1 and Hemo: Soluble Viral Decoys

In addition to intracellular defense, mammals have evolved soluble viral decoys.

• Refrex-1 (Felines): Domestic cats possess a gene called Refrex-1, which is a truncated envelope protein from the ERV-DC family. This protein is secreted into the blood. It binds to the CTR1 receptor (the entry receptor for FeLV-D). By saturating these receptors, Refrex-1 physically blocks the exogenous virus from binding, creating a “sterile” environment for the host cells.⁴³
• HEMO (Humans): The HEMO gene is an ancient, full-length retroviral envelope (HERV-MER34) that is highly expressed in the human fetus and placenta. The protein is shed into the maternal circulation. While its precise mechanism is still being elucidated, it is hypothesized to act as a decoy or immunomodulator, potentially protecting the developing fetus from viral infection or maternal immune attack.⁴⁶

5.3 MER41: The Interferon Switch

Perhaps the most systemic contribution comes from the MER41 family of ERVs. Research has shown that these primate-specific viral elements function as interferon-inducible enhancers.

• The Network: MER41 sequences integrated into the genome of a primate ancestor 45-60 million years ago. These sequences contain binding motifs for STAT1 and IRF1, the key transcription factors of the interferon response.
• Impact: When a cell detects an infection and releases interferon, it is the viral MER41 elements that bind STAT1 and drive the expression of critical immune genes, including AIM2 (a sensor for foreign DNA).⁴⁸
• Conclusion: A significant portion of the human innate immune response is hard-wired through regulatory switches provided by ancient viruses. We use viral DNA to turn on the genes that fight viruses.⁵⁰

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6. The Non-Retroviral Frontier: Bornaviruses and Beyond

For decades, it was believed that only retroviruses (which encode integrase) could colonize the germline. We now know this is false. “Fossils” of non-retroviral RNA and DNA viruses—Endogenous Viral Elements (EVEs)—are present in mammalian genomes, integrated via hijacking host retrotransposon machinery (specifically LINE-1).⁵¹

6.1 Endogenous Bornavirus-Like Nucleoproteins (EBLNs)

Bornaviruses are negative-sense RNA viruses that replicate in the nucleus.

• Integration: Ancient bornaviruses were reverse-transcribed and integrated into the genomes of humans, primates, and rodents over 40 million years ago.⁵³
• Function: In the thirteen-lined ground squirrel (Ictidomys tridecemlineatus), an endogenous bornavirus element (itEBLN) encodes a protein that interferes with the replication of modern bornaviruses. It acts as a dominant-negative inhibitor, effectively immunizing the squirrel against the virus.⁵⁴
• piRNA Defense: Some EBLNs are located in piRNA clusters. These loci produce small RNAs (piRNAs) that guide the silencing machinery to degrade the RNA of related exogenous viruses, acting as a form of heritable genomic “memory” of past infections.⁵⁵

6.2 Filoviruses and Circoviruses

• Filoviruses (Ebola/Marburg): Endogenous filovirus elements have been found in bats, marsupials, and rodents. In bats, these elements may modulate the extreme tolerance these animals show toward lethal viruses, possibly by acting as decoys for viral proteins like VP35.⁵⁷
• Circoviruses: These single-stranded DNA viruses have also left traces (CVe) in the mammalian genome. While functional studies are nascent, their conservation and expression in carnivores suggesting a role in cellular regulation or antiviral defense.⁵²

6.3 Parvoviruses

Endogenous Parvoviruses (EnPVs) in rats and wallabies retain intact Open Reading Frames (ORFs) for capsid and non-structural proteins. The maintenance of these ORFs over millions of years, despite the lack of infectious potential, serves as strong evidence of positive selection, likely for a physiological function in the host.⁶⁰

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7. Genomic Architecture and Stem Cell Identity

Viral elements do not just code for proteins; they act as the structural scaffolding of the genome itself.

7.1 HERV-H and the Definition of Pluripotency

HERV-H is a primate-specific ERV family. It is one of the most highly expressed transcripts in human Embryonic Stem Cells (hESCs).

• The Pluripotency Loop: HERV-H elements function as boundaries for Topologically Associating Domains (TADs). They recruit transcription factors and chromatin remodelers to create physical loops in the DNA. These loops bring enhancers into contact with the promoters of key pluripotency genes.⁶²
• LncRNAs: The RNA transcribed from HERV-H acts as a Long Non-Coding RNA (lncRNA) that scaffolds the pluripotency machinery. Knocking down HERV-H causes stem cells to differentiate (lose their stemness).⁶³
• Implication: The “ground state” of human development—the stem cell—is maintained by a retroviral network.

7.2 Viral Promoters Driving Tissue Specificity

Evolution uses viral LTRs (Long Terminal Repeats) as “plug-and-play” promoters to drive gene expression in specific tissues.

• Salivary Amylase (AMY1C): The ability of humans to digest starch in the mouth is due to the high expression of amylase in saliva. This expression is driven by a retroviral insertion upstream of the amylase gene that acts as a parotid-specific promoter. This viral insertion likely facilitated the dietary shift to starch-rich foods in human evolution.⁶⁵
• CYP19 (Aromatase): In primates, the expression of aromatase (essential for estrogen production) in the placenta is driven by an upstream ERV promoter. This dictates the hormonal environment of the developing fetus.⁶⁷

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8. Theoretical Frameworks: The Holobiont and Virocentric Evolution

The aggregate weight of this evidence forces a shift in the philosophy of biology, moving away from an organism-centric view toward a Holobiont and Virocentric perspective.

8.1 The Holobiont Theory

The Holobiont concept postulates that an individual organism (e.g., a mammal) cannot be biologically defined in isolation. It is a composite entity consisting of the host and its persistent community of symbionts (microbiome and virome). The Hologenome—the sum of host and symbiotic genes—is the true unit of evolutionary selection.⁶⁸

• Integration: Under this theory, ERVs are not “junk DNA” or “selfish elements” but essential symbionts that have become vertically transmitted. The mammalian immune system does not just “tolerate” them; it requires them.⁶⁹

8.2 Virocentric Evolution and Viral Eukaryogenesis

The Virocentric view suggests that viruses are the primary drivers of evolutionary novelty.

• Origins of the Nucleus: The Viral Eukaryogenesis hypothesis proposes that the eukaryotic nucleus itself evolved from a large DNA virus that infected an archaeal host. The nucleus separates transcription (viral-like) from translation (cellular), mirroring the viral life cycle. The presence of viral-like machinery (like Arc capsids and mRNA transport) in the nervous system lends thematic support to the idea that the complex compartmentalization of eukaryotic cells is a viral legacy.⁷¹
• The “Kill the Winner” Dynamic: In the broader ecosystem, viruses (like bacteriophages and rhinoviruses) kill the most dominant organisms, maintaining diversity. In the genome, they kill the most static genes, forcing diversification (as seen with Rhinovirus pressure on MHC).⁷³

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9. Conclusion

The “making of a mammal” is not a solo act of the vertebrate lineage. It is a collaborative, albeit sometimes coercive, process involving billions of years of viral interaction.

1. Selection: Exogenous viruses like Rhinoviruses act as the anvil, forging the mammalian immune system through relentless selective pressure, driving the diversity of MHC and receptor genes.
2. Construction: Endogenous viruses like HERV-W and Ty3/Gypsy act as the mortar. They provided the Syncytins that built the placenta, the Arc capsids that enabled complex memory, and the PEG10 proteins that vascularized the fetus.
3. Regulation: Viral elements like HERV-H and MER41 act as the architects’ blueprints, organizing the 3D structure of the genome (TADs) and wiring the regulatory circuits of immunity (Interferon response) and development (Pluripotency).

The mammal is, therefore, a Holobiont in the truest sense. We are not merely hosts to viruses; we are constructed by them. Our boundaries—the placenta, the blood-brain barrier, the cell membrane—are defended by viral proteins. Our memories are encoded by viral capsids. Our genome is a graveyard of viruses, but it is a graveyard where the dead do not rest—they work.

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Thematic Epilogue: The Chimera in the Mirror

To look into the mirror is to see a chimera. We have long defined ourselves in opposition to the viral world—the “self” versus the “pathogen.” The Rhinovirus that inflames our throat is the “other,” the invader to be repelled. Yet, this binary is an illusion maintained only by the brevity of human perception.

Deep within the helix of our DNA, the “other” has become the “self.” The gene that allows a mother to hold her child in the womb without rejection is a viral gene. The gene that allows that child to form a memory of the mother’s face is a viral gene. The gene that alerts the child’s immune system to the first cold of winter is a viral gene.

The virus is not merely a destroyer of life; it is a mechanism of genetic transfer so potent that it forces life to transcend its own boundaries. In the grand evolutionary narrative, the mammal is perhaps the virus’s most successful host—or perhaps, the virus is the mammal’s most successful invention. The distinction has long since dissolved. We are the virus, domesticated.