Mechanisms of Action of Antiviral Agents

Viral infections are initiated when virions attach to host cells. Attachment is mediated by capsid- or envelope-related viral proteins that bind specific receptors on host cell membranes. For example, the HIV envelope contains glycoproteins that mediate binding of the virus to CD4+ T lymphocytes that express CCR5 and/or CXCR4 receptors. A currently available inhibitor of viral attachment blocks HIV-specific CCR5 receptors on CD4+ T cell membranes.10

Viral entry across host cell membranes into the cytoplasm is mediated by other viral proteins. For example, the HIV envelope contains a protein (gp41) which promotes fusion of the viral envelope with target host cell (CD4+ T lymphocyte) membranes. A currently available inhibitor of viral entry blocks gp41-mediated fusion of the HIV envelope with the plasma membrane of host CD4+ T lymphocytes.10

Viral entry is followed by uncoating. This step refers to the removal/degradation or structural modification of the nucleocapsid, which results in the release of the viral genome into host cell cytoplasm and, in the case of DNA genomes, transport into host cell nuclei. Currently available inhibitors of viral uncoating block M2 proton channel in influenza A viruses and prevent pH-dependent disassociation of viral matrix proteins from the viral RNA.10

Following uncoating, the viral nucleic acid becomes available for gene expression, i.e., the transcription of viral RNA or DNA genome into mRNA, translation of mRNA into viral proteins, and proteolytic cleavage of viral polyproteins into their individual protein units. Currently available inhibitors of viral gene expression block HCV-related NS3/4A protease, essential for the expression of functional HCV proteins.10

Genome replication requires the generation of ribo- or deoxyribonucleoside triphosphates. Most RNA viruses replicate their genomes in host cell cytoplasm and most DNA viruses replicate their genomes in the nucleus of host cells. Nucleoside analogues, which when phosphorylated by viral or cellular kinases are incorporated into the growing viral genome and inhibit polymerase activity.10 Non-nucleoside polymerase inhibitors directly inhibit RNA or DNA polymerases.10

The first step in HIV genome replication is reverse transcription, i.e., the viral RNA is first copied into DNA, which is then transcribed into mRNA. Reverse transcriptase inhibitors block the transcription of the HIV RNA genome into DNA.10 The life cycle of the HIV also includes the additional step of integration, a process that binds HIV DNA to host cell DNA. HIV integrase inhibitors block the integration of viral genome into host cell genome.10

The next step in the viral life cycle is assembly, the process in which the immature virions are formed. Assembly is followed by maturation. This is the stage in the viral life cycle in which the new virions become infectious. The process involves proteolytic cleavage of one or more capsid- or envelop-related proteins by viral or host cell proteases. Currently available inhibitors of viral maturation are inhibitors of HIV proteases.10

Most viruses egress from infected host cells by cell lysis or by budding through the cell membrane. However, some virions require the additional step of release. For example, influenza A and B viruses require viral neuraminidase to effect their release from the extracellular surface of host cell membranes. Currently available inhibitors of viral release or neuraminidase inhibitors prevent the detachment the new influenza A and B virions from host cells.10