A virus enters a host cell through a highly coordinated sequence of molecular events, beginning with attachment to the cell surface and ending with delivery of the viral genome into the cell’s interior. The process is not a single step but a cascade: the virus first grabs onto general molecules on the outside of the cell, then locks onto a specific receptor, and finally either fuses its membrane with the cell’s or tricks the cell into swallowing it whole. Each virus has evolved its own variation on this theme, but the underlying logic is remarkably consistent across viral families.
The Initial Grab
Before a virus can do anything useful, it has to physically stick to the surface of a cell. This first contact is often nonspecific, meaning the virus latches onto molecules that are found on many different cell types rather than hunting for one exact target. One of the most common molecules involved in this initial grab is heparan sulfate, a sugar chain that decorates the outer surface of most animal cells. Research on grass carp reovirus showed that enzymatically stripping heparan sulfate from cell surfaces significantly reduced both viral attachment and infection, confirming the molecule’s role as an early landing pad.1iScience. Cell surface heparan sulfate serves as an attachment receptor for grass carp reovirus The same principle applies to retroviruses: even envelope protein-free retroviral particles can attach to cells through heparan sulfate interactions.2PubMed. Cell surface heparan sulfate is a receptor for attachment of envelope protein-free retrovirus-like particles and VSV-G pseudotyped MLV-derived retrovirus vectors to target cells
This initial attachment is loose and reversible. Think of it as a handshake rather than a handcuff. The virus slows down and stays near the cell surface long enough to search for a more specific receptor, but it is not yet committed to entry. Many viruses exploit other general-purpose molecules at this stage too, including sialylated glycans (sugar chains capped with sialic acid), cell adhesion molecules from the immunoglobulin superfamily, and integrins.3PubMed Central. Virus-Receptor Interactions: The Key to Cellular Invasion The variety of attachment factors helps explain why so many different viruses can land on so many different cell types, even if they cannot always get inside.
Riding Filopodia to the Entry Site
Cells are not smooth spheres. Their surfaces bristle with thin, finger-like projections called filopodia, and some viruses have learned to use these as highways. After binding to a filopodium, certain viruses undergo a rapid, directed sliding movement toward the cell body, a behavior researchers have called “surfing.” This movement is powered by the actin filaments inside the filopodium and depends on a motor protein called myosin II.4PubMed Central. Actin- and myosin-driven movement of viruses along filopodia precedes their entry into cells
Single-particle tracking of SARS-CoV-2 virus-like particles revealed two distinct patterns of filopodia use. In one, the particle surfs along the filopodium toward the cell body, much like the behavior observed in other viruses. In the other, filopodia actively reach out and grab particles, pulling them inward.5Science Bulletin. Single particle tracking reveals SARS-CoV-2 regulating and utilizing dynamic filopodia for viral invasion Both strategies solve the same problem: getting the virus off a distant protrusion and down to the cell body where the actual entry machinery sits, rather than letting it drift randomly across the plasma membrane.
Finding the Right Lock
The loose initial attachment is just the beginning. For a virus to actually enter, it needs to bind a specific receptor protein that acts as the real key to the door. This is where things get selective. Which receptor a virus targets determines which tissues, organs, and even species it can infect. SARS-CoV-2, for example, primarily uses the ACE2 receptor and a host protease called TMPRSS2 to get into cells. As the virus has evolved, mutations in its spike protein have altered receptor binding strength and opened the possibility of using alternative receptors, which helps explain shifts in how the virus spreads and which tissues it damages.6PubMed Central. Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants
Many viruses go a step further and require a second receptor, called a co-receptor, before they can actually fuse with the cell. HIV provides the textbook example. The virus first binds CD4 on the surface of T cells, but that alone does not trigger entry. A second interaction with a co-receptor, either CXCR4 or CCR5 depending on the viral strain, is needed to induce the structural changes in the viral envelope protein that drive membrane fusion.7Cell. The Cell Biology of Viral Entry – Section: Conformational Changes Induced by Receptors and Low pH In a biophysical model of this process, the primary receptor tethers the viral membrane to the cell membrane, while subsequent co-receptor binding is what actually enables fusion to proceed.8PubMed Central. Mechanisms of receptor/coreceptor-mediated entry of enveloped viruses The requirement for a co-receptor is one reason HIV is so selective about which cells it infects and why the same virus can behave differently depending on which co-receptor it uses.
Two Roads In
Once a virus has locked onto the right receptor, it faces a fundamental physical barrier: the cell membrane. Viruses have evolved two broad strategies to get past it, and the strategy depends largely on whether the virus itself is wrapped in a lipid membrane (enveloped) or is just a naked protein shell (non-enveloped).
Fusing Directly at the Cell Surface
Some enveloped viruses merge their membrane with the cell’s plasma membrane right at the surface, at neutral pH, without ever being swallowed into the cell. HIV does this. Early experiments showed that blocking the acidification of internal compartments did not stop HIV from getting in, and electron microscopy captured the virus fusing directly with the plasma membrane within minutes.9Cell. CD4 functions as the cell-surface receptor for human immunodeficiency virus (HIV); however, the mechanism of virus entry into susceptible cells is unknown Vaccinia virus does something similar: both its intracellular and extracellular forms fuse with host cells at neutral pH, pointing to the plasma membrane as the site of entry.10PubMed Central. Fusion of intra- and extracellular forms of vaccinia virus with the cell membrane For these viruses, the viral genome spills directly into the cytoplasm from the cell surface.
Hijacking Endocytosis
Many other viruses take the scenic route. Instead of fusing at the surface, they trick the cell into pulling them inside through endocytosis, the normal process cells use to engulf molecules from their surroundings. The most common version of this is clathrin-mediated endocytosis, where the cell membrane dimples inward around the virus, forming a clathrin-coated pit that pinches off into a small bubble called an endosome.
SARS-CoV-2, despite being able to fuse at the surface under certain conditions, frequently enters cells via clathrin-mediated endocytosis. When researchers knocked down clathrin heavy chain, the protein essential for building these pits, viral infectivity dropped.11PubMed Central. SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis The same pathway is used by human enterovirus 71, where blocking clathrin-related genes with targeted RNA silencing inhibited infection by more than 80%.12PubMed Central. The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71 Hepatitis C virus depends on the same route, with clathrin depletion blocking entry and subsequent fusion inside acidic endosomes.13PubMed Central. Hepatitis C virus entry depends on clathrin-mediated endocytosis
Clathrin is not the only game in town. Influenza A virus, for instance, can use macropinocytosis as an alternative entry pathway when the clathrin route is unavailable. Macropinocytosis is a less selective process in which the cell forms large, ruffled membrane extensions that engulf whatever fluid and particles happen to be nearby.14PubMed Central. Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway Newcastle disease virus uses both clathrin-mediated endocytosis and macropinocytosis side by side, essentially hedging its bets with two parallel entry routes.15PubMed Central. Newcastle disease virus employs macropinocytosis and Rab5a-dependent intracellular trafficking to infect DF-1 cells This redundancy makes biological sense: a virus that can enter through more than one door is harder for the host cell to lock out.
What Happens Inside the Endosome
For viruses that enter via endocytosis, the real action happens once they are trapped inside an endosome. As endosomes mature, their interior becomes increasingly acidic. This pH drop is a critical trigger. The falling pH causes viral fusion proteins to change shape, exposing hidden hydrophobic regions that jam into the endosomal membrane and pull the viral and cellular membranes together.16PubMed Central. Precise Triggering and Chemical Control of Single-Virus Fusion within Endosomes
Alphaviruses and flaviviruses are classic examples. Their surface proteins sit as dimers on the virus particle at neutral pH, but the acidic endosome triggers a dramatic rearrangement into trimers that drive membrane fusion.17PubMed Central. Dealing with low pH: entry and exit of alphaviruses and flaviviruses Some viruses need more than just low pH. The SARS coronavirus spike protein requires proteolytic cleavage at two distinct sites, working together to prime the protein for the fusion step. One cut separates the receptor-binding and fusion portions of the spike, while a second cut at a downstream position exposes the fusion machinery itself.18PubMed Central. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites Human parainfluenza virus 3 follows a similar logic: its fusion protein is synthesized as an inactive precursor and must be cleaved by host cell proteases to become functional.19PubMed Central. Human parainfluenza virus 3 fusion protein cleavage: a key determinant of infection and spread
This dual requirement for low pH and protease activity is one reason some viruses infect certain cell types more easily than others. A cell that lacks the right protease, or whose endosomes do not acidify quickly enough, may resist infection even if it has the correct surface receptor.
How Non-Enveloped Viruses Break Through
Non-enveloped viruses face a different problem. Without a lipid membrane of their own, they cannot fuse with the cell. Instead, they have to physically breach the cellular membrane to get their genome across. Human rhinovirus, the most common cause of the cold, accomplishes this with a small capsid protein called VP4. Once the virus binds its receptor and undergoes a conformational change, VP4 is released and inserts into the host cell membrane, forming a multimeric pore. The pore is size-selective, with dimensions consistent with allowing viral RNA to pass through while keeping larger molecules out.20PLOS Pathogens. Capsid Protein VP4 of Human Rhinovirus Induces Membrane Permeability by the Formation of a Size-Selective Multimeric Pore Rather than dissolving the membrane or tearing a hole in it, the virus builds a molecular tunnel custom-fitted for genome delivery.
Traveling to the Nucleus
Getting past the cell membrane is not the end of the journey for many viruses. Those that replicate in the nucleus, including herpesviruses, adenoviruses, and parvoviruses, still have to move their genome across the cytoplasm and through the nuclear envelope. The cytoplasm is a thick, crowded environment, and passive diffusion is far too slow for something the size of a viral particle. Viruses solve this by riding the cell’s own transport infrastructure.
Canine parvovirus, a well-studied model, enters cells by receptor-mediated endocytosis and eventually escapes from the endosome into the cytoplasm. From there, it hitches a ride on microtubules, the long protein filaments that serve as the cell’s internal railway. The motor protein dynein, which normally ferries cellular cargo toward the nucleus, carries viral capsids along these tracks. Disrupting microtubules or injecting antibodies against dynein sharply reduces the accumulation of viral capsids near the nucleus.21PubMed Central. Exploitation of microtubule cytoskeleton and dynein during parvoviral traffic toward the nucleus
Once at the nucleus, the virus faces one more barrier: the nuclear pore. Herpes simplex virus 1 has a particularly elegant solution. Its capsid docks at a nuclear pore complex, and the tightly packed DNA inside the capsid is under enormous internal pressure, roughly 18 atmospheres. When researchers applied external osmotic pressure to match that internal force, genome ejection was completely blocked, demonstrating that the pressurized DNA inside the capsid is what physically drives it through the nuclear pore and into the nucleus.22PubMed Central. Pressure-driven release of viral genome into a host nucleus is a mechanism leading to herpes infection This is the same basic principle as a pressurized spray can: the contents are under tension, and opening the valve lets them shoot out. Earlier osmotic suppression experiments had provided the first evidence that this high internal pressure, tens of atmospheres, exists in a human virus and is sufficient to power ejection of the entire genome.23PubMed Central. Herpes Virus Genome, the Pressure is On
Hiding from the Immune System During Entry
The proteins viruses use for attachment and entry are, by definition, exposed on the virus surface, which makes them obvious targets for the immune system. Antibodies that recognize these proteins can neutralize the virus before it ever touches a cell. To counteract this, many viruses coat their surface proteins with sugar molecules called glycans. These glycans are made by the host cell’s own machinery, so the immune system tends to ignore them, treating them as “self.”
The SARS-CoV-2 spike protein is a good example. Despite the glycans contributing only about 17% of the spike trimer’s total molecular weight, three-dimensional structural analysis showed that they shield roughly 40% of the protein surface from antibody recognition. The receptor binding domain, the part that must stay exposed to interact with ACE2, is a notable exception, which is why most effective neutralizing antibodies target that region. Interestingly, the degree of shielding was largely unchanged regardless of which specific glycan structures were attached, suggesting the shield works through brute physical coverage rather than any particular sugar chemistry.24Scientific Reports. Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition
Drugs That Target the Entry Process
Because entry is the first step of infection, it is an attractive target for antiviral drugs. If you can block a virus from getting into cells in the first place, you stop the entire replication cycle before it starts. One promising approach targets the fusion step directly. Class I fusion proteins, found on the surface of enveloped viruses including HIV, respiratory syncytial virus, SARS-CoV-2, Nipah virus, influenza, and Ebola virus, share conserved structural features. They all use heptad repeat regions to fold into a six-helix bundle that pulls the viral and cell membranes together. Peptide inhibitors designed to mimic one of these heptad repeat segments can jam the machinery by binding to the other segment first, preventing the bundle from forming and blocking fusion.25PubMed Central. Structure-Guided Design of Peptide Inhibitors Targeting Class I Viral Fusion Proteins
Enfuvirtide, an FDA-approved drug for HIV, works on exactly this principle. Maraviroc, another HIV drug, takes a different approach by blocking the CCR5 co-receptor so the virus cannot complete its receptor engagement. Monoclonal antibodies against the SARS-CoV-2 spike protein targeted the receptor binding domain to prevent ACE2 attachment. Each of these strategies intervenes at a different point in the entry process, from receptor binding to co-receptor engagement to membrane fusion, which underscores how many potential chokepoints the entry pathway offers for drug design.p>
An Ancient Evolutionary Connection
The molecular machinery viruses use to fuse membranes is not exclusive to viruses. Some of the same fusion proteins have been adopted by host organisms over evolutionary time. The most striking examples are the syncytins, proteins encoded by remnants of ancient retroviruses embedded in mammalian genomes. Syncytin-1 and syncytin-2 in humans are derived from retroviral envelope genes and are essential for the formation of the placenta, where they drive the fusion of cells into the syncytiotrophoblast layer that allows nutrient exchange between mother and fetus.
Structural studies have confirmed that the fusion domains of syncytins form six-helix bundles identical in architecture to those of class I viral fusion proteins.26Current Biology. Virus and eukaryote fusogen superfamilies – Section: Class I fusogen superfamily: the discovery of syncytins The machinery a virus evolved to break into cells was, millions of years ago, captured by the host genome and repurposed for one of the most critical processes in mammalian development. The evolutionary connection runs deep enough that researchers now group syncytins and class I viral fusion proteins into a single fusogen superfamily. It is a reminder that viral entry is not just a story of parasitism. The molecular tools viruses invented for forcing their way into cells have, in some cases, become tools that animal biology depends on.