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A DNA virus is a virus whose genome is made of DNA and whose replication depends on a DNA-dependent DNA polymerase, which may be encoded by the virus or supplied by the host cell. In the reverse-transcribing DNA viruses, such as hepatitis B virus (HBV), replication also passes through an RNA intermediate. DNA viruses infect bacteria, archaea, and eukaryotes. They include the most abundant biological entities on Earth (tailed bacteriophages), the largest known viruses (giant viruses), and many important pathogens of humans, livestock, and crops.

Most RNA viruses and the reverse-transcribing viruses share a common ancestry of their RNA-directed polymerases and are grouped in a single realm, Riboviria. DNA viruses are polyphyletic. The International Committee on Taxonomy of Viruses (ICTV) places most of them in four realms, Duplodnaviria, Varidnaviria, Monodnaviria, and Adnaviria, and some families remain unassigned to any realm. In the Baltimore classification, DNA viruses occupy Group I (double-stranded DNA, dsDNA), Group II (single-stranded DNA, ssDNA), and Group VII (dsDNA reverse-transcribing viruses).

The chemistry of DNA shapes the biology of these viruses. DNA lacks the 2′-hydroxyl group of RNA and is far more resistant to spontaneous hydrolysis. Many DNA viruses also use replicative polymerases with 3′ to 5′ proofreading activity, and they replicate with lower error rates than RNA viruses, typically on the order of 10⁻⁶ to 10⁻⁸ substitutions per nucleotide per cell infection for dsDNA viruses. These properties are associated with genome sizes that span nearly three orders of magnitude, from about 1.7 kilobases (kb) in porcine circoviruses to about 2.5 megabases (Mb) in Pandoravirus giant viruses. RNA virus genomes are generally limited to roughly 30 to 40 kb, a ceiling usually attributed to the error threshold and to the lower fidelity of RNA replication.

Many DNA viruses of vertebrates have diverged in step with their host lineages over tens of millions of years, although host switches occur. They tend to establish lifelong latent or persistent infections, as in the Herpesviridae, Papillomaviridae, Polyomaviridae, Anelloviridae, and Hepadnaviridae. Four DNA viruses (human papillomavirus, hepatitis B virus, Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus) are classified as human carcinogens, and Merkel cell polyomavirus causes most Merkel cell carcinomas. DNA viruses also cause smallpox, the only human infectious disease eradicated by vaccination, as well as mpox, chickenpox, shingles, erythema infectiosum, and a range of adenoviral respiratory, ocular, and enteric diseases.

ICTV realms

No gene is shared by all DNA viruses. Comparative genomics and structural biology indicate that DNA viruses arose independently several times, in each case by combining modules derived from cellular DNA replication (helicases, primases, nucleases, and DNA polymerases of families A, B, and C) with different structural proteins used to build capsids. The ICTV recognizes the following realms, which are defined by conserved "hallmark" proteins.

Several DNA virus groups are not assigned to these realms, including the Anelloviridae and the Baculoviridae. The Hepadnaviridae belong to Riboviria (kingdom Pararnavirae), because their polymerase is a reverse transcriptase. Plant pararetroviruses of the family Caulimoviridae are also reverse-transcribing DNA viruses.

Within Duplodnaviria, the herpesviruses share the HK97-fold capsid protein, a portal, and a terminase with tailed phages. This is consistent with an origin from a tailed phage ancestor that lost its tail, although the details of that history are inferred and not directly observed. The family name Herpesviridae has been replaced in ICTV taxonomy by Orthoherpesviridae, but the older name remains in common use.

Within Varidnaviria, the phylum Nucleocytoviricota (formerly called nucleocytoplasmic large DNA viruses, NCLDVs) contains the poxviruses, asfarviruses, iridoviruses, phycodnaviruses, and the amoeba-infecting giant viruses (Mimiviridae, Marseilleviridae, Pandoraviridae, and Pithoviridae). Their genomes range from roughly 100 kb to 2.5 Mb. Giant viruses encode genes unusual for viruses, including components of translation such as aminoacyl-tRNA synthetases. Poxviruses have lost an icosahedral capsid in mature virions, but a related double jelly-roll protein (D13) acts as a scaffold during assembly of immature virions.

Within Monodnaviria, the Papillomaviridae and Polyomaviridae have small circular dsDNA genomes of about 5 to 8 kb. Their initiator proteins (E1 of papillomaviruses and large T antigen of polyomaviruses) retain a superfamily 3 helicase domain related to that of the ancestral Rep proteins, but they no longer rely on a rolling-circle mechanism.

Baltimore groups

Origins and relationships

Because capsid proteins and replication proteins are both frequently exchanged between viruses, and between viruses and cells, the evolutionary history of DNA viruses is modular. The self-synthesizing DNA transposons known as polintons and the related polinton-like viruses show structural and genetic similarity to adenoviruses, tectiviruses, virophages, and giant viruses, and they have been proposed as evolutionary intermediates among these groups.

The origin of giant viruses is debated. One view holds that they descend from cellular ancestors by genome reduction. Another, which is supported by most phylogenetic analyses of their core genes, holds that they evolved from smaller viruses by acquiring genes from hosts and from other viruses, including by gene duplication.

DNA virus sequences are also found within host genomes as endogenous viral elements. Examples include hepadnavirus sequences in the genomes of birds, parvovirus sequences in many mammals, and chromosomally integrated human herpesvirus 6 (see below). These sequences provide a fossil record for dating viral lineages.

Capsid architecture

Most DNA viruses form icosahedral capsids, which are built from a small number of repeated proteins. The geometry of an icosahedral capsid is described by the triangulation number T, which depends on two integers, h and k, that describe the lattice position of adjacent pentamers:

A capsid with triangulation number T contains 60_T_ protein subunits arranged as 12 pentameric and 10(T − 1) hexameric capsomers. Parvoviruses have T = 1. Papillomaviruses and polyomaviruses have T = 7, with 72 pentameric capsomers of 360 subunits of the major capsid protein. Adenoviruses have T = 25 and a capsid of about 90 nm, and herpesvirus nucleocapsids have T = 16 and a diameter of about 125 nm. Herpesvirus nucleocapsids are surrounded by a protein layer called the tegument and by a lipid envelope, whereas adenoviruses, papillomaviruses, polyomaviruses, and parvoviruses are non-enveloped. Poxviruses form large brick-shaped or ovoid particles (about 300 × 250 × 200 nm) with a lipid membrane and a dumbbell-shaped core. Archaeal viruses of Adnaviria form helical filaments.

DNA packaging and capsid pressure

Double-stranded DNA is a stiff, highly charged polymer with a persistence length of about 50 nm (roughly 150 base pairs) and a charge of two electrons per base pair. Compacting a genome of tens or hundreds of kilobases into a capsid requires overcoming electrostatic repulsion and the energy cost of bending. In tailed phages and herpesviruses, a portal-terminase complex hydrolyzes ATP to pump DNA into a preformed procapsid. In bacteriophage φ29, one ATP is consumed for about every two base pairs packaged, and the internal pressure reaches several megapascals (on the order of tens of atmospheres). The stored energy contributes to ejection of the genome during infection. For herpes simplex virus, evidence indicates that the genome can be ejected at the nuclear pore through a similar pressure-driven mechanism.

In papillomaviruses and polyomaviruses, the circular genome is complexed with host histones to form a nucleosomal minichromosome inside the virion. The HBV cccDNA is likewise chromatinized in the nucleus of infected hepatocytes.

Entry

Entry strategies differ greatly. Herpes simplex virus attaches to heparan sulfate and engages receptors such as nectin-1 or HVEM through glycoprotein D, and fusion of the envelope with a cellular membrane is triggered by glycoproteins B and H/L. Human adenoviruses of many species use the coxsackievirus and adenovirus receptor (CAR), CD46, or desmoglein-2, followed by integrin-mediated uptake. Polyomaviruses bind gangliosides and are transported through the endoplasmic reticulum. Papillomaviruses bind heparan sulfate on the basement membrane after microtrauma, and a furin cleavage event exposes the receptor-binding region. Poxviruses attach to glycosaminoglycans and other surface molecules and enter cells by fusion or macropinocytosis-like uptake, and many cell types are permissive. Host range is determined largely after entry, by whether viral proteins can antagonize the host's intracellular defenses.

Small nuclear DNA viruses

Papillomaviruses and polyomaviruses (genomes of about 5 to 8 kb) encode too few genes to supply their own DNA polymerase or nucleotide metabolism enzymes and depend on host S-phase machinery, including DNA polymerase α-primase, polymerases δ and ε, PCNA, and replication factor C. They infect differentiated, quiescent cells in which this machinery is switched off, and they have therefore evolved early proteins that force the cell into S phase. These proteins target the two central regulators of the G₁/S checkpoint, the retinoblastoma protein (pRB) and p53:

• The papillomavirus E7 protein, the polyomavirus large T antigen, and the adenovirus E1A protein bind pRB through a conserved LXCXE motif. This releases E2F transcription factors and drives unscheduled S-phase entry.
• Unscheduled S-phase entry normally stabilizes p53 and triggers cell-cycle arrest or apoptosis. The papillomavirus E6 protein recruits the ubiquitin ligase E6AP to degrade p53, polyomavirus large T antigen binds and inactivates p53, and adenovirus E1B-55K together with E4orf6 degrades p53.

Parvoviruses use a different strategy. Autonomous parvoviruses such as parvovirus B19 cannot induce S phase and depend on the host cell entering it, which explains their tropism for dividing cells such as erythroid progenitors in the bone marrow, the fetal liver, and the intestinal crypt epithelium. Adeno-associated virus (AAV) depends additionally on a helper virus such as an adenovirus or herpesvirus.

Adenoviruses

Adenoviruses have linear dsDNA genomes of about 26 to 45 kb. They encode their own family B DNA polymerase, a single-stranded DNA-binding protein, and a precursor terminal protein that primes replication, so replication is protein-primed and proceeds by strand displacement from both ends of the genome. Early proteins E1A and E1B modify the host cell cycle and apoptosis, and E3 proteins modulate immune recognition. Adenoviruses replicate in the nucleus.

Herpesviruses

Herpesviruses (genomes of about 125 to 240 kb) deliver linear dsDNA to the nucleus, where it circularizes. Gene expression is a cascade in which host RNA polymerase II transcribes three kinetic classes of genes:

• Immediate-early (α) genes are transcribed without prior viral protein synthesis. In herpes simplex virus 1 (HSV-1), the tegument protein VP16 forms a complex with the host proteins Oct-1 and HCF-1 to activate these genes. Their products, such as ICP0 and ICP4, disrupt nuclear defense structures such as PML bodies and activate early genes.
• Early (β) genes encode the viral replication machinery. In HSV-1 this comprises seven proteins: the DNA polymerase UL30 and its processivity factor UL42, the origin-binding protein UL9, the helicase-primase complex UL5/UL8/UL52, and the single-stranded DNA-binding protein ICP8 (UL29). Early genes also include nucleotide metabolism enzymes such as thymidine kinase and ribonucleotide reductase, which allow replication in non-dividing cells such as neurons.
• Late (γ) genes encode structural proteins and are expressed most strongly after viral DNA synthesis begins. Replication produces long head-to-tail concatemers that are cleaved by the terminase during packaging.

Poxviruses

Poxviruses replicate entirely in the cytoplasm, because host RNA polymerase II and the mRNA-capping machinery are nuclear. A naked poxvirus genome is therefore not infectious. Each virion carries a multisubunit DNA-dependent RNA polymerase, an early transcription factor, a capping enzyme, and a poly(A) polymerase, and early genes are transcribed within the core immediately after entry. DNA replication takes place in cytoplasmic "factories" and uses the viral E9 polymerase, which is associated with a processivity factor (the A20/D4 complex, in which D4 is a uracil-DNA glycosylase). Progeny virions are assembled as intracellular mature virions, and a fraction is wrapped with additional membranes to form extracellular enveloped virions that spread between cells.

Hepadnaviruses

After entry through the bile acid receptor NTCP, the HBV rcDNA is transported to the nucleus and repaired by host enzymes to form cccDNA. This stable minichromosome is the template for all viral transcripts, including the 3.5 kb pgRNA. The pgRNA is encapsidated with the viral P protein, which then reverse-transcribes it to produce new rcDNA inside the capsid. Capsids either are enveloped and secreted or return rcDNA to the nucleus, which maintains the cccDNA pool. The HBV genome is only about 3.2 kb and its four overlapping open reading frames constrain the evolution of every nucleotide. The cccDNA is not affected by nucleoside analogues, which accounts for the persistence of infection during treatment. Linear forms of viral DNA can also integrate into the host genome, a process that does not contribute to replication but does contribute to oncogenesis.

Single-stranded DNA viruses

In circoviruses, geminiviruses, and anelloviruses, a Rep initiator protein with HUH endonuclease activity nicks the circular genome at a stem-loop origin and starts rolling-circle replication using host polymerases. In parvoviruses, terminal hairpins serve as primers, and the NS1 protein (or Rep protein in AAV) initiates replication by a rolling-hairpin mechanism. In all cases a double-stranded replicative form is produced first and is transcribed by host RNA polymerase II.

Drake's rule

Across many DNA-based microbes, including DNA viruses, the mutation rate per nucleotide per replication (μ) varies approximately inversely with genome size (L), so that the genomic mutation rate per replication remains roughly constant:

This empirical relationship is called Drake's rule. It describes DNA genomes replicated by proofreading polymerases and does not apply to RNA viruses, which have genomic mutation rates around 0.1 to 1 per replication. It holds less well for ssDNA viruses and for reverse-transcribing viruses.

Evolutionary rates

Long-term substitution rates (measured in substitutions per site per year) differ among DNA viruses, and estimates depend on the calibration method. Rates measured over short intervals tend to be higher than rates calibrated against host divergence over millions of years, a phenomenon known as time dependency of rates.

The poxvirus genomic accordion

Large DNA viruses can adapt to host restriction factors by changing gene copy number as well as by point mutation. In experimental evolution of vaccinia virus under selection by the host kinase PKR (which phosphorylates eIF2α and halts translation), recombination produced tandem amplification of the viral antagonist gene K3L to many copies. Increased gene dosage allowed the virus to overcome PKR while rare point mutations that improved K3L function accumulated. Once such a mutation arose, the extra copies were lost again by recombination. This "genomic accordion" allows adaptation on a timescale that point mutation alone would not permit.

Recombination and genome rearrangement

Recombination is frequent in many DNA viruses. It occurs between co-infecting herpesviruses, adenoviruses, poxviruses, and papillomaviruses, and it mixes gene variants in circulating populations. Recombinant strains of adenoviruses have repeatedly been associated with new respiratory and ocular pathogens. In phages, extensive horizontal gene transfer gives rise to mosaic genomes.

Stability of DNA

DNA is chemically stable for two main reasons. It lacks the 2′-hydroxyl group that makes RNA susceptible to intramolecular cleavage of its phosphodiester backbone, and base pairing in a duplex shields the bases from hydrolytic damage. The use of thymine (5-methyluracil) instead of uracil also allows repair enzymes such as uracil-DNA glycosylase to recognize and remove uracil that results from spontaneous deamination of cytosine. Single-stranded DNA is more vulnerable to such deamination, which contributes to editing by APOBEC enzymes in ssDNA and in replication intermediates.

Persistence outside the host

Persistence of infectious particles in the environment depends on the structure of the virion as well as on its genome. Examples include:

• Variola virus and mpox virus remain infectious for long periods in dried material such as skin crusts.
• Non-enveloped adenoviruses and polyomaviruses persist in wastewater and survive some treatment processes, and they are used as indicators of human fecal contamination.
• African swine fever virus remains infectious for months in blood, feces, and meat products, and for longer periods in frozen or cured pork, which allows it to travel with food products.
• Ancient DNA has been recovered from archaeological and permafrost samples. Genomes of hepatitis B virus (from several thousand to about 10,000 years old), variola virus (from Viking Age and 17th-century remains), and parvovirus B19 have been sequenced, and these datasets provide calibration points for molecular clocks. They have also shown that some viral lineages are much older than dates inferred from modern sequences alone.

Co-divergence and zoonosis

Phylogenies of primate herpesviruses, papillomaviruses, and polyomaviruses largely parallel the phylogeny of their hosts, which indicates long-term co-divergence, although cross-species transmission and recombination have also contributed. Persistent DNA viruses typically dedicate a substantial fraction of their coding capacity to proteins that modulate host immunity, and they cause mild or no disease in their natural hosts. When they cross to a new host species, the same mechanisms may fail, with serious consequences. For example, Macacine alphaherpesvirus 1 (B virus) causes mild oral lesions in its natural host, Asian macaques, but causes fatal encephalomyelitis in untreated human cases, with a reported fatality rate of about 70 to 80 percent.

Mpox virus is maintained in African rodents, and the exact reservoir has not been definitively identified. Rope squirrels (Funisciurus), Gambian pouched rats, and dormice have been implicated. Cowpox virus circulates in European rodents such as voles and wood mice.

Immune evasion

DNA viruses encode many proteins that interfere with innate and adaptive immunity. Representative strategies include:

• Antigen presentation: HSV ICP47 blocks the TAP peptide transporter, and several human cytomegalovirus (HCMV) proteins (US2, US3, US6, US11) remove or retain MHC class I molecules. KSHV K3 and K5 ubiquitinate MHC class I for degradation.
• Natural killer cells: HCMV encodes an MHC class I homolog (UL18) and other ligands that engage or inhibit NK cell receptors.
• Apoptosis and signaling: Adenovirus E1B-19K and herpesvirus and poxvirus Bcl-2 homologs inhibit apoptosis. Poxvirus serpins such as SPI-2 (CrmA) block caspases and inflammatory pathways.
• Cytosolic DNA sensing: Many viruses antagonize the cGAS-STING pathway, and poxviruses encode "poxin" nucleases that degrade the second messenger cGAMP.
• Cytokine and complement mimicry: EBV encodes a homolog of interleukin 10, KSHV encodes a viral interleukin 6 and a chemokine receptor-like protein, and vaccinia virus encodes a complement control protein.

Latency

During latency, the viral genome persists in the nucleus of a long-lived cell while lytic gene expression is largely silenced, so few viral peptides are displayed to cytotoxic T cells. Latency allows a virus to persist in populations too small to sustain acute immunizing infections such as measles, which requires a community of several hundred thousand people.

Temperate bacteriophages such as phage λ provide a parallel, in which the viral genome is maintained as a prophage integrated in or replicating with the host chromosome and is induced to enter the lytic cycle by cellular stress such as DNA damage.

Roughly 8 to 10 percent of new cancer cases worldwide are attributed to infection with viruses, and most of these are caused by DNA viruses. The International Agency for Research on Cancer (IARC) classifies human papillomavirus (HPV), HBV, EBV, and KSHV as carcinogenic to humans (Group 1). The other Group 1 viruses are hepatitis C virus, HTLV-1, and HIV, which are RNA or retroviruses. Merkel cell polyomavirus (MCPyV) was classified as probably carcinogenic (Group 2A) in its 2012 evaluation, and it is regarded as the cause of most Merkel cell carcinomas. The current classification should be checked, because the evidence has strengthened.

Malignant transformation is not a part of the viral life cycle. A transformed cell that harbors an integrated or defective viral genome often cannot produce progeny virions. Cancer results when viral proteins that evolved to drive cell-cycle entry or prevent apoptosis act in a cell where the lytic program is blocked, for example after integration of a viral genome that disrupts regulatory genes, or when chronic infection and inflammation promote cumulative host damage.

EBV infection is also strongly associated with multiple sclerosis. Large cohort studies show that the risk of developing the disease rises sharply after EBV infection and that it is rare in people never infected. This is widely regarded as evidence for a causal role, but the mechanism is not established and other factors contribute.

Acute immunizing infections

Viruses that cause acute infection followed by lasting immunity, such as variola virus, can be described by susceptible-exposed-infectious-recovered (SEIR) models. The basic reproduction number R₀ is the mean number of secondary infections caused by one infectious person in a fully susceptible population, and the herd immunity threshold is:

Estimates of R₀ for smallpox lie roughly in the range of 3.5 to 6, which corresponds to a threshold of about 70 to 85 percent. Smallpox had no animal reservoir, no latency, no chronic carriers, and few subclinical infections, and these properties made eradication feasible. Parvovirus B19 spreads by respiratory droplets, causes epidemics every few years, and has been reported to resurge in several countries in 2023 and 2024 after a period of suppressed circulation.

Latent and reactivating infections

For viruses such as VZV, HSV, EBV, and HCMV, infected people do not move to a sterile recovered compartment, because latent virus can reactivate and be transmitted again. A simple conceptual model separates the contribution of primary infection from that of reactivation:

where R_p is the number of secondary infections from primary infection, f_L is the fraction of infected people who establish latency, ω is the reactivation rate, μ is the host mortality rate (so that 1/_μ_ is the mean lifespan and _ω_/_μ_ is the mean number of reactivation episodes over a lifetime), and R_r is the number of secondary infections per reactivation episode. The model ignores age structure and waning immunity and is intended only to illustrate the principle.

VZV illustrates this. Chickenpox is highly transmissible by respiratory aerosols, with reported R₀ values commonly in the range of about 5 to 10. After recovery, the virus remains latent in sensory ganglia and may reactivate decades later as shingles, when virions shed from lesions can infect susceptible children. This allows VZV to persist in small populations with few births.

Mpox

Mpox (species Orthopoxvirus monkeypox) has two clades: clade I (formerly Congo Basin) and clade II (formerly West African), each with subclades. Smallpox vaccination provided substantial cross-protection against mpox (estimates of about 85 percent). While most people in affected regions were vaccinated, human-to-human chains of transmission usually ended quickly, consistent with an effective reproduction number R_e = R₀S below 1, where S is the susceptible fraction. In a subcritical branching process, the expected total size of a transmission chain started by one case is:

so that values of R_e between 0.3 and 0.8 correspond to chains of about 1.4 to 5 cases. Smallpox vaccination ceased globally by about 1980, and a large and growing proportion of people worldwide have no orthopoxvirus immunity.

Clade IIb lineage B.1 caused a global outbreak from May 2022, mainly in sexual networks of men who have sex with men, and about 100,000 cases were reported in more than 100 countries in the first two years. Heavy-tailed distributions of partner numbers allow R₀ to exceed 1 within the core of such networks even when it is below 1 in the general population. In 2023, a new lineage, clade Ib, was identified in South Kivu in the Democratic Republic of the Congo and spread to neighboring countries and, through travel, beyond. It carries a deletion affecting the ortholog of the complement-control gene C3L and is transmitted in sexual and household settings. The World Health Organization declared the second mpox public health emergency of international concern in August 2024. The emergency was declared over in September 2025, although transmission continues.

Sequencing of human mpox viruses shows a high rate of substitution, about 6 to 12 substitutions per genome per year (roughly 3 to 6 × 10⁻⁵ per site per year), which is about an order of magnitude higher than rates for other orthopoxviruses. The great majority of these changes are in the TC→TT and GA→AA dinucleotide contexts that are the signature of APOBEC3 enzymes (consistent with APOBEC3F) acting on single-stranded replication intermediates, which indicates sustained human-to-human transmission with host editing.

Bacteriophages and the viral shunt

Tailed bacteriophages (class Caudoviricetes) are the most abundant biological entities, with an estimated 10³¹ particles globally. In the oceans, viral lysis is estimated to kill a substantial fraction of bacterial production each day (commonly estimated at 20 to 40 percent). It releases dissolved organic matter and nutrients that are recycled by other microbes, a process called the viral shunt. Traditional morphological names (myovirus, siphovirus, podovirus) are now treated as morphotypes rather than taxa.

Giant viruses and algal viruses

Algal viruses of the Phycodnaviridae and relatives help terminate blooms of marine phytoplankton. Giant viruses infect amoebae and other protists, and some of them are parasitized by virophages.

Animal disease in aquaculture and wildlife

• Ostreid herpesvirus 1 (OsHV-1): Infection of Pacific oysters (Crassostrea gigas) by the variant OsHV-1 µVar causes severe mortality in juveniles when water temperatures rise above roughly 16 °C, with losses that can approach 100 percent in affected batches in a few days. Temperature affects both viral replication and host immunity.
• Ranaviruses: Members of the Iridoviridae cause systemic disease in amphibians, fish, and reptiles. The effect of temperature on outcomes differs among host-virus systems, with warming increasing disease in some and decreasing it in others.
• African swine fever virus (ASFV): ASFV (family Asfarviridae, about 170 to 190 kb) is the only known DNA virus transmitted by arthropods. In Africa it circulates in a sylvatic cycle among warthogs and soft ticks of the genus Ornithodoros (O. porcinus and relatives), where it replicates persistently in the ticks. In domestic pigs and wild boar, virulent strains cause hemorrhagic fever with a case fatality approaching 100 percent. A genotype II strain was introduced to Georgia in 2007 and has since spread through Europe and Asia and, in 2021, to Hispaniola. Spread is driven mainly by movement of infected pigs and contaminated pork products, and wild boar maintain transmission in Europe. Climate effects on wild boar populations and tick distributions have been proposed as contributing factors, but the evidence is indirect.

Environmental change and human DNA viruses

Several links between environmental change and DNA virus disease have been proposed, and the strength of evidence varies.

• Ultraviolet radiation: UV-B radiation suppresses cutaneous immunity and can trigger HSV reactivation, and UV damage is implicated in the mutations that inactivate Merkel cell polyomavirus large T antigen in tumors. Beta-papillomaviruses are associated with cutaneous squamous cell carcinoma, mainly in immunosuppressed people. How climate change will alter population UV exposure is uncertain.
• Malaria and Burkitt lymphoma: Endemic Burkitt lymphoma is geographically linked to holoendemic P. falciparum malaria, which expands EBV-infected B cell populations and increases expression of AID. Changes in the geographic range of malaria could in principle change the risk of Burkitt lymphoma, but direct evidence is lacking.
• Permafrost: Viable giant viruses that infect amoebae have been revived from Siberian permafrost samples as old as about 48,500 years. They do not infect humans. Fragments of variola virus DNA have been detected in a roughly 300-year-old Siberian mummy, but no viable virus has been recovered, and the risk of re-emergence of smallpox from permafrost is considered very low. The Arctic is warming about three to four times faster than the global average.
• Heavy rainfall and water contamination: Intense precipitation can overload sewer systems and contaminate water with non-enveloped viruses such as enteric adenoviruses (species F, types 40 and 41, which are a leading cause of viral gastroenteritis in young children).

Quantitative PCR, Serology, and Histopathology

Diagnosis of DNA virus infections relies on several approaches. Quantitative PCR detects and quantifies viral DNA and is used to monitor HCMV, EBV, adenovirus, BK polyomavirus, and HBV viral loads in transplant recipients and in patients on antiviral therapy. Serology (antibodies against viral antigens, such as the HBV surface and core antigens) defines the stage of infection and immunity. HPV DNA testing is now the primary method of cervical screening in many countries, and it can be combined with cytology. Histology remains useful and shows characteristic changes, such as enlarged cells with nuclear inclusions in HCMV infection (owl's-eye cells), multinucleated cells with nuclear inclusions in herpes simplex infection, koilocytes in HPV infection, and cytoplasmic inclusions in poxvirus infection. Metagenomic sequencing is increasingly used to identify unexpected or novel viruses.

Smallpox eradication and orthopoxvirus preparedness

Smallpox killed an estimated 300 million people in the twentieth century. The last natural case occurred in Somalia in October 1977, and the World Health Assembly declared eradication on 8 May 1980. Contributing factors included the lack of an animal reservoir, the absence of latency or chronic carriage, the visible rash that made cases easy to identify, a single stable serotype, and a heat-stable freeze-dried vaccine delivered with the bifurcated needle. Surveillance and containment, in which cases were isolated and their contacts vaccinated (ring vaccination, developed by teams that included Donald Henderson and William Foege), replaced mass vaccination in the final phase. Stocks of variola virus are held at two WHO-approved repositories, in the United States and in Russia.

Current orthopoxvirus vaccines include:

• MVA-BN (Jynneos, Imvanex, Imvamune): a modified vaccinia Ankara strain, attenuated by repeated passage in chick embryo fibroblasts with loss of about 15 percent of the parental genome. It cannot replicate in human cells and can be used in immunocompromised people. Observational studies estimate two-dose effectiveness against clade IIb mpox of roughly 66 to 89 percent.
• ACAM2000: a replication-competent vaccinia vaccine with a higher risk of adverse events.
• LC16m8: a minimally replicating attenuated vaccinia strain with a truncated B5R gene, licensed in Japan and approved for use in children.

Vaccines against HPV, HBV, and VZV

An oral live adenovirus type 4 and 7 vaccine is used in military recruits and sharply reduces febrile respiratory illness caused by these types. Vaccines against HCMV and EBV have been difficult to develop. An mRNA vaccine encoding HCMV glycoproteins entered phase 3 trials, and EBV vaccines based on gp350 and other antigens are in early clinical evaluation. Congenital HCMV infection affects roughly 0.5 to 1 percent of births and is the leading infectious cause of non-genetic sensorineural hearing loss, so a maternal vaccine is a priority. The status of these programs should be checked against current sources.

Antiviral drugs

Because large DNA viruses encode their own polymerases and some nucleotide-metabolizing enzymes, selective antiviral drugs have been developed.

• Acyclovir and related nucleoside analogues. Acyclovir (developed by Gertrude B. Elion and colleagues, who shared the 1988 Nobel Prize) is an acyclic guanosine analogue active against HSV and VZV, and it is given orally as the prodrug valacyclovir. It is selectively activated in infected cells because it is phosphorylated efficiently only by the viral thymidine kinase, and host kinases then convert it to the triphosphate. Acyclovir triphosphate is preferentially incorporated by the viral DNA polymerase and, because it lacks a 3′-hydroxyl group, terminates the growing chain. Ganciclovir, which is used against HCMV, is phosphorylated by the viral UL97 kinase and is not an obligate chain terminator. Resistance usually arises from loss or alteration of the viral thymidine kinase (HSV and VZV) or the UL97 kinase (HCMV).
• Drugs that bypass viral kinases. Foscarnet mimics pyrophosphate and binds the viral polymerase directly. Cidofovir is a nucleoside phosphonate that needs only host kinases for activation, and its lipid conjugate brincidofovir is approved for smallpox in the United States.
• Other targets in cytomegalovirus. Letermovir inhibits the viral terminase complex and is used for prophylaxis in transplant recipients, with less bone marrow toxicity than ganciclovir. Maribavir inhibits the UL97 kinase and is approved for refractory post-transplant infection.
• Tecovirimat. Tecovirimat inhibits the orthopoxvirus F13L protein (p37) and thereby blocks formation of extracellular enveloped virions. It protected animals in challenge studies, but randomized trials in clade I mpox (PALM007) and clade II mpox (STOMP) found no improvement in the rate of lesion resolution compared with placebo. Resistance mutations in F13L have been described.
• Hepatitis B. Entecavir, tenofovir disoproxil, and tenofovir alafenamide inhibit the HBV polymerase with a high barrier to resistance. They suppress viral DNA and reverse fibrosis in many patients but do not eliminate cccDNA or integrated DNA, so treatment is often continued indefinitely. Experimental approaches to a "functional cure" include small interfering RNAs and antisense oligonucleotides that reduce HBsAg (for example bepirovirsen, which has reached phase 3 trials), capsid assembly modulators, immune modulators, and gene editing nucleases targeting cccDNA. Bulevirtide, which blocks the NTCP entry receptor, is approved in Europe for chronic hepatitis D, a disease caused by a satellite agent that depends on the HBV envelope.
• Latent herpesviruses. Gene-editing approaches against latent HSV episomes have shown substantial reductions of latent genomes in animal models, but they remain preclinical.

AAV, Adenoviral, Herpesviral, and Poxviral Vectors

The stability, episomal persistence, and large coding capacity of some DNA viruses have been exploited to make vectors for gene therapy, vaccination, and cancer treatment.

• Adeno-associated virus (AAV) vectors are made by replacing the viral rep and cap genes (retaining the 145-nucleotide inverted terminal repeats) with a therapeutic gene inside a capsid of chosen tropism. They deliver durable, mainly episomal transgenes to non-dividing cells. Approved products include onasemnogene abeparvovec (AAV9, for spinal muscular atrophy), voretigene neparvovec (AAV2, for _RPE65_-related retinal dystrophy), valoctocogene roxaparvovec (hemophilia A), and etranacogene dezaparvovec (hemophilia B). A gene therapy for Duchenne muscular dystrophy has been approved with restrictions because of safety concerns, and its use remains under review.
• Replication-deficient adenoviral vectors, made by deleting the E1 (and often E3) genes of human or simian adenoviruses (for example Ad26, Ad5, and ChAdOx1), have been used as vaccine platforms against Ebola virus and SARS-CoV-2. Replication-competent and engineered adenoviruses have also been used in oncolytic therapy.
• Oncolytic herpesviruses. Talimogene laherparepvec is an HSV-1 in which ICP34.5 (which counteracts PKR) and ICP47 are deleted and the gene for GM-CSF is inserted. It replicates selectively in tumor cells with defective interferon and PKR responses and is approved for melanoma.
• Poxvirus vectors, including vaccinia and modified vaccinia Ankara, accommodate large inserts and are used for vaccine development.

Why do poxviruses replicate in the cytoplasm whereas most other DNA viruses replicate in the nucleus?

Poxviruses (Poxviridae) replicate exclusively in cytoplasmic viral factories because their virions package a complete, multisubunit DNA-dependent RNA polymerase, an early transcription factor, and mRNA-capping and polyadenylating enzymes inside the viral core. Immediately upon cytoplasmic entry, these packaged enzymes transcribe early viral genes that encode the viral E9 DNA polymerase and replication factors, completely bypassing the requirement for host nuclear RNA polymerase II and S-phase replication machinery.

Why do single-stranded DNA viruses mutate almost as rapidly as RNA viruses?

Single-stranded DNA (ssDNA) viruses (such as parvoviruses, circoviruses, and geminiviruses) exhibit short-term substitution rates of 10⁻⁴ to 10⁻³ substitutions per site per year—approaching RNA virus rates—despite being replicated by high-fidelity host DNA polymerases. This elevated evolutionary rate stems from the chemical vulnerability of exposed single-stranded DNA to spontaneous hydrolytic cytosine deamination, enzymatic hypermutation by host APOBEC3 cytidine deaminases, and the absence of complementary-strand mismatch repair prior to replication.

Why cannot nucleoside analogue drugs eradicate chronic hepatitis B virus (HBV) infection?

Nucleoside and nucleotide analogues (such as entecavir and tenofovir) competitively inhibit the viral reverse transcriptase (P protein), halting the synthesis of relaxed circular DNA (rcDNA) from pregenomic RNA in the cytoplasm. However, they do not directly target or degrade the pre-existing nuclear pool of covalently closed circular DNA (cccDNA), which persists as a stable, histone-packaged minichromosome in infected hepatocytes and continues to serve as a transcriptional template via host RNA polymerase II.