Viral Life Cycle Overview - US (2024)

As viruses are obligate intracellular pathogens they must depend on host cells for reproduction and metabolic processes. The life cycle of viruses can differ greatly between species and category of virus, but they follow the same basic stages for viral replication. The viral life cycle can be divided into several major stages: attachment, entry, uncoating, replication, maturation, and release.

On this page:

  • Viral attachment to host cell
  • Viral entry
  • Viral replication
  • Viral maturation and release
  • References

Viral attachment to host cell

For a virus to infect a host organism, the viral genome must be transferred from a virus particle into the cytoplasm of a host cell. This process begins when proteins on the outer layer of a virus bind to attachment factors on the host cell surface. These attachment factors concentrate virus particles on the cell surface, bringing them into proximity to virus receptors that are responsible for entry into the host cell [1]. For example, CD4 is the primary receptor for human immunodeficiency virus (HIV), but further interactions with chemokine receptors CCR5 or CXCR4 are required for virus penetration [2]. Virus receptors can be proteins, glycolipids, or carbohydrates [3]. Often, a single virus can recognize multiple cell surface receptors, enabling the virus particle to bind with high affinity even if individual receptors have low affinity [4]. The presence or absence of a given receptor determines the virus host tropism (whether a given virus can infect a certain type of cell). Viruses continuously evolve to recognize the cell surface receptors best suited for virus entry and infection of host cells.

Table 1. Common human viruses and their receptors.

Adenovirus 2AdenoviridaeCAR and αv integrins
Old World arenavirusesArenaviridaeα-Dystroglycan
New World arenavirusesArenaviridaeTransferrin receptor
SARS coronavirusCoronaviridaeACE 2 or L-SIGN
Japanese encephalitis virusFlaviviridaeHsp70
HCVFlaviviridaeCD81 and SR-B1 (claudin-1 and occludin)
Ebola virusFiloviridaeTIM-1 and NPC1
Epstein–Barr virusHerpesviridaeCD21 and MHC-II
Herpes simplex virus 1/2HerpesviridaeNectin-1/2 or HVEM
Influenza AOrthomyxoviridaeSialic acid
HenipavirusParamyxoviridaeNephrin B2
Measles virusParamyxoviridaeSLAM or Nectin-4
Enterovirus 71PicornaviridaePSGL-1 or SR-B2
Hepatitis A virusPicornaviridaeTIM-1
Rhinovirus (major group)PicornaviridaeICAM-1
Rhinovirus (minor group)PicornaviridaeLDLR
Coxsackievirus BPicornaviridaDAF and CAR (occludin)
John Cunningham polyomavirusPolyomaviridaeLSTc
SV40 polyomavirusPolyomaviridaeGM1
Human T cell leukemia virus 1RetroviridaeGLUT-1 or Neuropilin-1
RotavirusReoviridaeSialic acid and integrins
HIVRetroviridaeCD4 and CCR5 or CXCR4
Sindbis virusTogaviridaeLaminin receptor
Abbreviations: ACE2, angiotensin-converting enzyme 2; CAR, coxsackievirus and adenovirus receptor; CCR5, cysteine-cysteine chemokine receptor type 5; CD, cluster of differentiation; CXCR4, cysteine-X-cysteine motif chemokine receptor 4; DAF, decay accelerating factor; DC-SIGN, dendritic cell–specific intercellular adhesion molecule-3-grabbing non-integrin; GLUT-1, glucose transporter type 1; GM1, monosialotetrahexosylganglioside; HBGA, histo-blood group antigen; Hsp, heat shock protein; HVEM, herpesvirus entry mediator; ICAM-1, intracellular adhesion molecule 1; JAM, junctional adhesion molecule; L-SIGN; liver/lymph node-specific ICAM-3 grabbing non-integrin; LDLR; low-density lipoprotein receptor, LSTc; lactoseries tetrasaccharide c; MHC-II, major histocompatibility class II; PSGL-1, P selectin glycoprotein ligand 1; SLAM, signaling lymphocytic activation molecule; SR-B2, scavenger receptor class B; TIM-1, T cell immunoglobulin and mucin domain

Viral entry

Once bound to cell surface receptors, viruses enter eukaryotic cells through two main pathways. Some viruses gain entry to cells by directly fusing with or penetrating the cell membrane, but most viruses traffic into a cell via endocytosis (coronaviruses are able to enter both ways) (Figure 1) [5,6]. Most often this endocytosis occurs via clathrin-coated pits, whose cargo is shuttled to increasingly acidic organelles, from early endosomes to late endosomes to lysosomes [7]. For example, coronaviruses can undergo fusion at different stages of endocytosis: MERS coronavirus fuses with early endosomes, whereas SARS coronavirus fuses with late endosomes [4]. Viruses that require an even more acidic pH will not undergo fusion until they reach the lysosome [2]. These endocytic and lysosomal vesicles have low pH and abundant proteases that can trigger conformational changes in a virus, leading to uncoating, fusion, or penetration into the cytoplasm. Even those viruses without a low-pH requirement exploit endocytosis as a convenient route to rapidly cross the plasma membrane and transit through the cytoplasm to their sites of replication [2]. Labeling virus particles with pH-sensitive dyes such as the pHrodo IFL Green STP ester dye can enable visualization of virus entry [8].

Click image to enlarge

Figure 1. Pathways of virus entry into cells. (A) Enveloped viruses can bind to cell surface receptors and directly fuse with the plasma membrane. Virus particles can also be internalized via endocytosis, with escape to the cytosol occurring either from the (B) early endosome or (C) late endosome and lysosome. The acidic environment and proteolytic enzymes in these compartments are required for fusion and cytosol entry by different viruses.

Viral replication

Once a virus has entered a cell, it begins the process of uncoating and replication. As intracellular obligate pathogens, viruses must take control of cellular proteins and organelles to assist in replication. The cellular components required for viral gene expression and replication are organized into replication centers [2]. Some viruses replicate in the cytosol, whereas others such as herpesviruses, adenoviruses, and influenza viruses must navigate to the nucleus for replication (Figure 3) [1].

There are several methods used by viruses to release the viral genome from the virion, the complete, infective form of a virus outside a host cell (Figure 2). Certain viruses, including rhinoviruses, expand to form pores in the endosome through which the viral genome can escape. Influenza and other viruses induce fusion of the virion envelope with the endosomal membrane, releasing the viral genome. Many viruses, including reoviruses, maintain a partially intact capsid in the cytosol that acts as a “home base” for replication.

The process of viral genome replication varies between DNA and RNA viruses, and between viruses with positive or negative nucleic acid polarity [9]. Some viral genomes contain instructions for producing their own replicative proteins, such as the RNA-dependent RNA polymerase (RdRP) in yellow fever virus (positive-sense RNA virus) and SARS-CoV-2 coronavirus (negative-sense RNA virus) [10]. Like mRNA, +ssRNA (single-stranded RNA) viruses can immediately be translated byhost cell ribosomes and do not need to bring an RNA-dependent RNA polymerase (RdRp) into the cell. RNA viruses with dsRNA (double stranded RNA), −ssRNA (negative-sense single-stranded RNA), or ambisense genomes must carry their own RdRp protein into the cell in order for transcription to occur. Depending on the type of viral genome, different polymerases are produced, including RdRP, RNA-dependent DNA polymerase, DNA-dependent RNA polymerase, and DNA-dependent RNA polymerases [11]. These polymerases are often the target of antiviral drugs and can effectively incorporate ribonucleoside or deoxyribonucleoside analogs, which enable the detection of viral RNA or DNA synthesis using click chemistry. The ribonucleoside analog 5-ethynyl uridine can be used to study viral RNA synthesis using the Invitrogen Click-iT RNA Alexa Fluor assays; the deoxyribonucleoside analog 5-ethynyl-2’-deoxyuridine can be used to study viral DNA synthesis using the Invitrogen Click-iT and Click-iT Plus EdU Cell Proliferation Kits. Specific viral mRNA templates in a host cell can also be researched using the Invitrogen PrimeFlow RNA Assay Kit and assayed with the Invitrogen Attune NxT Flow Cytometer, or using the Invitrogen ViewRNA Cell Plus Assay Kit and imaged either on the Invitrogen EVOS M7000 Imaging System with EVOS Onstage Incubator or on the Thermo Scientific CellInsight High-Content Screening Platforms with HCA Onstage Incubator.

Click image to enlarge

Figure 2. Methods for viral genome release into host cells. (A) Certain viruses, including rhinoviruses, expand to form pores in the endosome through which the viral genome can escape. (B) Influenza and other viruses induce fusion of the virion envelope with the endosomal membrane, releasing the viral genome. (C) Many viruses, including reoviruses, maintain a partially intact capsid in the cytosol that acts as a “home base” for replication.

Click image to enlarge

Figure 3. Several viruses must transport their genomes into the nucleus for viral transcription or replication to occur. Influenza genome segments are transported through the nuclear pore into the nucleus. Herpesvirus capsids are transported along microtubules to the nuclear pore, where uncoating occurs. Adenovirus capsids disassemble at the nuclear pore, and the viral DNA is transported into the nucleus. Other viruses, including hepatitis B virus, are small enough that the entire capsid may pass through the nuclear pore.

Viral maturation and release

After the nucleic acid genome and other essential proteins are packaged within the capsid, which is assembled from one or several translated viral proteins, the final steps of virus replication occur: maturation and release. Maturation refers to the final changes within an immature virion that result in an infectious virus particle. Structural capsid changes are often involved, and these can be mediated by host enzymes or virus-encoded enzymes. After this maturation step, the virus is released from a host cell by either budding or lysis. Cytopathic viruses such as influenza type A and SARS-CoV-2 undergo fusion of virion-containing vesicles with the host cell’s plasma membrane, followed by exocytosis or budding of the new viral particle out of the cell (Figure 4). This process involves the endocytic recycling and secretory pathways and commonly the Rab11 pathway [12]. Cytolytic viruses such as Variola major (smallpox) cause the cell membrane to rupture, followed by death of the host cell and release of new viral particles.

Click image to enlarge

Figure 4. Nucleocapsid formation and formation of mature virions. After the production viral structural proteins, nucleocapsids are assembled in the cytoplasm and followed by budding into the lumen of the endoplasmic reticulum (ER)–Golgi intermediate compartment. Virions are then released from the infected cell through exocytosis.


  1. Casasnovas JM (2013) Virus-receptor interactions and receptor-mediated virus entry into host cells. Subcell Biochem 68:441–466.
  2. Grove J, Marsh M (2011) The cell biology of receptor-mediated virus entry. J Cell Biol 195:1071–1082.
  3. Wang Jh (2002) Protein recognition by cell surface receptors: Physiological receptors versus virus interactions. Trends Biochem Sci 27:122–126.
  4. Sieczkarski SB, Whittaker GR (2002) Dissecting virus entry via endocytosis. J Gen Virol 83:1535–1545.
  5. Mellman I. (1996) Endocytosis and molecular sorting. Annu Rev Cell Dev Biol 12:575–625.
  6. Burkard C, Verheije MH, Wicht O et al. (2014) Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathog 10:e1004502.
  7. Wang D, Guo H, Chang J et al. (2018) Andrographolide prevents EV-D68 replication by inhibiting the acidification of virus-containing endocytic vesicles. Front Microbiol 9:2407.
  8. Schmid M, Speiseder T, Dobner T et al. (2014) DNA virus replication compartments. J Virol 88:1404–1420.
  9. Goulding J. Virus replication. In: Bitesized Immunology. British Society for Immunology. Accessed 8 July 2020.
  10. Douam F, Hrebikova G, Soto Albrecht YE et al. (2017) Single-cell tracking of flavivirus RNA uncovers species-specific interactions with the immune system dictating disease outcome. Nat Commun 8:14781.
  11. Choi KH (2012) Viral Polymerases. Adv Exp Med Biol 726:267–304.
  12. Amorim MJ, Bruce EA, Read EK et al. (2011) A Rab11- and microtubule-dependent mechanism for cytoplasmic transport of influenza A virus viral RNA. J Virol 85:4143–4156.
  13. Zamora JLR, Aguilar HC (2018) Flow virometry as a tool to study viruses. Methods 134–135:87–97.
  14. Lippé R (2018) Flow virometry: A powerful tool to functionally characterize viruses. J Virol 92:e01765-17.
  15. Cossarizza A, De Biasi S, Guaraldi G et al. (2020) SARS-CoV-2, the virus that causes COVID-19: Cytometry and the new challenge for global health. Cytometry A 97:340–343.

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Viral Life Cycle Overview - US (2024)


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