LIPID ENVELOPE OF VIRUSES AS A KEY DETERMINANT OF TROPISM, PATHOGENICITY, STABILITY, AND A TARGET FOR ANTIVIRAL THERAPY

ABSTRACT

Understanding the structure and composition of the viral supercapsid is crucial for elucidating mechanisms of viral entry, assembly, and immune evasion. Such knowledge enables the rational design of antiviral drugs and vaccines targeting envelope proteins and lipid components. Moreover, insights into supercapsid organization facilitate the development of viral vectors and nanocarriers for therapeutic delivery in biomedicine.

Keywords: lipid envelope, virus, supercapsid.

The study of the lipid envelope (supercapsid) of viruses is of fundamental importance for modern medical virology, epidemiology, and clinical practice. The presence or absence of a supercapsid largely determines the routes of viral transmission, their stability in the external environment, the efficacy of standard disinfectants, as well as specific patterns of pathogen spread within populations. Understanding the structure and functions of the supercapsid is directly linked to the development of preventive measures (vaccines and antiseptics) and therapies (membrane fusion inhibitors and other antiviral agents), which makes this topic particularly relevant in the context of the increasing incidence of viral infections and the risk of new pandemics.

The lipid envelope, or supercapsid, is the outer membrane of a number of viruses that surrounds the capsid and nucleic acid. It plays a key role in viral attachment and entry into the cell, in immune evasion, and in the stability of virions in the external environment [5].

In terms of origin, the supercapsid is derived from host-cell membranes. In the course of budding or release of virions, they acquire a lipid bilayer from:

- the plasma membrane (typical for orthomyxoviruses, retroviruses, many paramyxoviruses);

- the membranes of the Golgi apparatus and endoplasmic reticulum (for example, coronaviruses, some arenaviruses);

- the nuclear envelope (some herpesviruses) [1, 6].

However, lipid distribution in the virion is not a simple copy of the host membrane: viral proteins (glycoproteins and matrix proteins) can redistribute lipids, forming condensed domains (raft-like regions) that are optimal for viral assembly and membrane fusion [10].

Unlike cellular membranes, the viral lipid envelope is always densely “packed” with viral proteins and is largely devoid of most host membrane proteins. During budding, virus-specific components are selectively incorporated and concentrated, ensuring the functional specialization of the supercapsid [4].

Viral glycoproteins projecting from the lipid envelope in the form of spikes (peplomers) are the principal functional elements of the supercapsid. These are transmembrane proteins whose ectodomains are extensively glycosylated, while their cytoplasmic tails interact with matrix or capsid proteins [4].

The main functions of glycoproteins are:

- attachment to the host cell. Glycoproteins recognize specific cellular receptors (proteins, lipids, or glycoconjugates). For example, influenza virus hemagglutinin binds to sialic acid, while the spike (S) protein of coronaviruses binds to ACE2, DPP4, or other receptors depending on the virus species [9]. This determines the tissue and host tropism of the virus;

- initiation of entry and membrane fusion. Many glycoproteins are fusion proteins. After receptor engagement and/or endosomal acidification, they undergo conformational rearrangements that bring the viral and cellular membranes into close apposition, driving membrane fusion and formation of a fusion pore through which the nucleocapsid enters the cytoplasm;

- immunogenicity and antigenic variability. Peplomers are the main targets of neutralizing antibodies. The antigenic structure of glycoproteins determines the serotype and subtype of the virus (as in influenza virus – H and N) [7].

Immune evasion is promoted by:

- antigenic drift (accumulation of point mutations in glycoproteins);

- antigenic shift (a radical change in the glycoprotein set due to reassortment of genome segments or recombination);

- the “glycan shield” – dense glycosylation that masks conserved epitopes [2].

Accumulation of glycoproteins in defined membrane regions generates budding sites. Interactions of their cytoplasmic tails with matrix proteins or components of the nucleocapsid ensure the spatial organization of virion assembly [3, 10].

In many viruses, a layer of matrix (M) proteins is located between the lipid envelope and the capsid. These structural proteins link the membrane to the nucleocapsid and provide mechanical integrity to the virion.

The main properties and functions of matrix/membrane-associated proteins are:

- linkage of the capsid to the supercapsid. M proteins interact with the cytoplasmic tails of viral glycoproteins in the lipid envelope and with the capsid or nucleoprotein complex inside the virion. This “scaffold” stabilizes the particle and defines its morphology (spherical, pleomorphic, etc.);

- initiation and regulation of assembly and budding. For many enveloped viruses, expression of a single matrix protein in a cell system is sufficient to form virus-like particles, underscoring the key role of the M protein in morphogenesis. M proteins recuit components of the cellular sorting and membrane-deformation machinery (for example, elements of the ESCRT complex), thereby promoting membrane protrusion and scission [8];

- indirect influence on tropism and pathogenicity. Although direct receptor recognition is generally not mediated by M proteins, they affect glycoprotein localization, the efficiency of assembly and release of virions, and consequently the infectivity of viral particles and the severity of cytopathic effects;

- participation in immune evasion. In a number of viruses, matrix and related membrane-associated proteins interfere with interferon signaling pathways, with intracellular protein trafficking, and with antigen presentation, thereby enhancing virulence.

The presence or absence of a supercapsid has a profound impact on the biological properties of a virus:

- stability in the external environment. Enveloped viruses (influenza, HIV, coronaviruses, herpesviruses, etc.) are more sensitive than “naked” capsid viruses (picornaviruses, reoviruses) to organic solvents, detergents, desiccation, and temperature fluctuations;

- routes of transmission. Enveloped viruses are typically transmitted by aerosol, contact, parenteral, or sexual routes, whereas environmentally stable non-enveloped viruses more often utilize the fecal–oral route;

- targets for antiviral therapy and prophylaxis.

The lipid envelope and its proteins serve as targets for:

- detergent- and alcohol-based antiseptics that disrupt the membrane;

- antiviral drugs that block membrane fusion (fusion protein inhibitors);

- vaccines that are directed primarily against surface glycoproteins [2, 9].

Thus, the supercapsid is not a passive covering, but a highly specialized virus–host-derived structure. Its formation from host membranes in combination with virus-specific proteins underpins the key stages of the viral life cycle: from attachment and entry to assembly, egress, and evasion of the host immune response.

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