🦠Virology Unit 11 – Host–Virus Interactions and Immune Responses

Viral Entry and Host Cell Recognition

• Viruses initiate infection by binding to specific receptors on the host cell surface, enabling them to enter the cell
  • Viral attachment proteins (VAPs) on the virus surface recognize and bind to host cell receptors
  • Examples of host cell receptors include ACE2 for SARS-CoV-2 and CD4 for HIV
• After binding, viruses enter the host cell through various mechanisms such as receptor-mediated endocytosis or membrane fusion
• Some viruses, like influenza, require additional steps such as endosomal acidification to trigger conformational changes in viral proteins for successful entry
• Viral entry is a critical step in the viral life cycle and determines host cell tropism and tissue specificity
  • Tropism refers to the specific cell types or tissues a virus can infect based on the presence of compatible receptors
• Host cell recognition and entry mechanisms vary among different viruses, influencing their pathogenicity and transmission routes
  • For example, respiratory viruses typically enter through the respiratory tract, while enteric viruses enter through the gastrointestinal tract
• Understanding viral entry and host cell recognition is crucial for developing antiviral strategies that block these initial steps of infection

Viral Replication Strategies

• Once inside the host cell, viruses hijack cellular machinery to replicate their genome and produce new viral particles
• DNA viruses typically replicate in the nucleus, while RNA viruses replicate in the cytoplasm
  • DNA viruses, such as herpesviruses, utilize host cell DNA polymerases for replication
  • RNA viruses, like influenza and HIV, encode their own RNA-dependent RNA polymerase (RdRp) for replication
• Positive-sense RNA viruses, such as poliovirus, can directly use their genome as mRNA for translation of viral proteins
• Negative-sense RNA viruses, like measles and Ebola, must first transcribe their genome into positive-sense RNA using viral RNA-dependent RNA polymerase
• Retroviruses, such as HIV, use reverse transcriptase to convert their RNA genome into DNA, which then integrates into the host cell genome
• Viral replication strategies often involve the formation of replication complexes or factories, where viral components concentrate to facilitate efficient replication
• The replication process is error-prone for many RNA viruses, leading to high mutation rates and the generation of viral quasispecies
  • Quasispecies are a population of genetically related but distinct viral variants that can contribute to viral evolution and adaptation

Host Cell Defenses and Innate Immunity

• Host cells possess various intrinsic defense mechanisms to detect and restrict viral infections
• Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) recognize viral pathogen-associated molecular patterns (PAMPs)
  • PAMPs include viral nucleic acids, proteins, and other conserved molecular structures
• Activation of PRRs triggers signaling cascades that lead to the production of type I interferons (IFN-α/β) and proinflammatory cytokines
  • Type I interferons induce an antiviral state in infected and neighboring cells by upregulating interferon-stimulated genes (ISGs)
  • ISGs encode proteins with antiviral functions, such as PKR, OAS, and APOBEC3
• The complement system, a part of the innate immune response, can directly neutralize viruses and promote viral clearance
• Natural killer (NK) cells are innate lymphocytes that recognize and kill virus-infected cells through cytotoxic mechanisms
• Macrophages and dendritic cells play crucial roles in innate immunity by phagocytosing virus particles, producing cytokines, and presenting viral antigens to T cells
• Innate immune responses provide the first line of defense against viral infections and help to limit viral spread while activating adaptive immunity

Adaptive Immune Responses to Viral Infections

• Adaptive immunity, consisting of humoral and cell-mediated responses, provides specific and long-lasting protection against viral infections
• Humoral immunity involves the production of virus-specific antibodies by B cells
  • Neutralizing antibodies bind to viral surface proteins and prevent viral entry into host cells
  • Non-neutralizing antibodies can contribute to viral clearance through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement activation
• Cell-mediated immunity is mediated by T cells, which recognize viral antigens presented by MHC molecules on infected cells
  • CD8+ cytotoxic T lymphocytes (CTLs) directly kill virus-infected cells through the release of perforin and granzymes
  • CD4+ T helper cells secrete cytokines that support CTL and B cell responses and can also have direct antiviral effects
• Memory B and T cells generated during adaptive immune responses provide rapid and enhanced protection upon re-exposure to the same virus
• The specificity and diversity of adaptive immune responses are generated through somatic recombination of B cell and T cell receptor genes
• Viral infections can induce both systemic and mucosal adaptive immune responses, depending on the route of infection and the specific virus
• The interplay between innate and adaptive immunity is crucial for the effective control and clearance of viral infections

Viral Evasion Mechanisms

• Viruses have evolved various strategies to evade or subvert host immune responses, enabling their survival and persistence
• Antigenic drift and shift in influenza viruses allow them to escape pre-existing immunity by altering their surface glycoproteins (HA and NA)
  • Antigenic drift involves minor changes in HA and NA due to point mutations, while antigenic shift results from the reassortment of viral gene segments
• Some viruses, like HIV and hepatitis C virus (HCV), exhibit high mutation rates, generating viral variants that can escape antibody and T cell recognition
• Viruses can interfere with antigen presentation by downregulating MHC class I expression on infected cells, preventing their recognition by CTLs
  • For example, herpes simplex virus (HSV) produces the ICP47 protein that inhibits TAP-mediated peptide transport into the endoplasmic reticulum
• Certain viruses, such as cytomegalovirus (CMV), encode decoy MHC molecules that can bind and sequester viral peptides, preventing their presentation to T cells
• Viruses can also inhibit innate immune signaling pathways, such as the interferon response, by targeting key components of these pathways
  • For instance, the NS1 protein of influenza virus can block RIG-I signaling and interferon production
• Some viruses, like Epstein-Barr virus (EBV), establish latent infections where viral gene expression is minimized, allowing them to evade immune detection
• Understanding viral evasion mechanisms is essential for developing effective antiviral therapies and vaccines that can overcome these strategies

Pathogenesis and Disease Manifestation

• Viral pathogenesis refers to the mechanisms by which viruses cause disease in the host
• The severity and manifestation of viral diseases depend on factors such as viral virulence, host immune status, and route of infection
• Viruses can cause direct damage to host cells through cytopathic effects, such as cell lysis or apoptosis
  • For example, poliovirus infection leads to the destruction of motor neurons, resulting in paralysis
• Indirect damage can occur through the host's immune response to the virus, leading to inflammation and tissue injury
  • In severe cases of influenza, the cytokine storm induced by the host's immune response can cause widespread lung damage and respiratory failure
• Viruses can exhibit tissue tropism, preferentially infecting specific cell types or organs
  • Hepatitis viruses primarily infect liver cells (hepatocytes), leading to liver inflammation and damage
  • Measles virus has a tropism for immune cells and respiratory epithelium, contributing to its immunosuppressive effects and characteristic rash
• Persistent viral infections, such as those caused by HIV and hepatitis B virus (HBV), can lead to long-term complications like immunodeficiency and chronic liver disease, respectively
• Some viruses, such as human papillomavirus (HPV) and Epstein-Barr virus (EBV), are associated with the development of certain cancers
• Understanding viral pathogenesis is crucial for developing targeted therapies and managing the clinical manifestations of viral diseases

Antiviral Therapies and Vaccines

• Antiviral therapies and vaccines are essential tools for preventing and treating viral infections
• Antiviral drugs target specific stages of the viral life cycle to inhibit viral replication
  • Nucleoside analogues, such as acyclovir for HSV and lamivudine for HBV, interfere with viral DNA synthesis
  • Protease inhibitors, like lopinavir for HIV, block viral protein maturation
  • Neuraminidase inhibitors, such as oseltamivir for influenza, prevent the release of new viral particles from infected cells
• Combination therapy, using multiple antiviral drugs with different mechanisms of action, is often used to improve efficacy and reduce the risk of drug resistance
• Vaccines stimulate the host's immune system to generate protective immunity against specific viruses
  • Live attenuated vaccines, such as those for measles and mumps, use weakened viral strains that can induce a strong immune response without causing disease
  • Inactivated vaccines, like the inactivated polio vaccine (IPV), use killed viral particles to elicit an immune response
  • Subunit vaccines, such as the hepatitis B vaccine, use specific viral proteins to induce immunity
• Novel vaccine technologies, such as mRNA vaccines and viral vector vaccines, have shown promise in the development of vaccines against emerging viruses like SARS-CoV-2
• Passive immunization, using preformed antibodies from convalescent plasma or monoclonal antibodies, can provide immediate protection against viral infections
• The development of effective antiviral therapies and vaccines requires a deep understanding of viral biology, host-virus interactions, and the immune response to viral infections

Emerging Topics in Host-Virus Interactions

• The field of host-virus interactions is constantly evolving, with new discoveries and technologies shaping our understanding of viral infections
• The role of the microbiome in modulating host-virus interactions is an emerging area of research
  • Studies have shown that the gut microbiome can influence the immune response to viral infections and the efficacy of antiviral therapies and vaccines
• The use of organoids, three-dimensional cell culture models that mimic organ structure and function, has revolutionized the study of host-virus interactions
  • Organoids allow researchers to investigate viral tropism, pathogenesis, and antiviral drug testing in a more physiologically relevant context
• Single-cell sequencing technologies have enabled the high-resolution analysis of host-virus interactions at the individual cell level
  • These technologies can reveal heterogeneity in viral infection and immune responses, providing insights into viral persistence and immune evasion
• The impact of host genetics on susceptibility to viral infections and disease outcomes is an active area of research
  • Genome-wide association studies (GWAS) have identified host genetic variants that influence the risk and severity of viral infections, such as HIV and hepatitis C
• The development of gene editing tools, like CRISPR-Cas9, has opened new avenues for studying host factors involved in viral replication and for developing novel antiviral therapies
  • CRISPR-based screens can identify host genes essential for viral infection, providing potential targets for antiviral drug development
• The ongoing COVID-19 pandemic has highlighted the importance of understanding zoonotic viral infections and the factors that contribute to their emergence and spread
  • Research on host-virus interactions in animal reservoirs and intermediate hosts is crucial for predicting and preventing future zoonotic outbreaks
• Studying the interplay between viruses and other pathogens, such as bacteria and fungi, can provide insights into the complex dynamics of co-infections and their impact on disease outcomes
• Investigating the role of extracellular vesicles, such as exosomes, in mediating host-virus interactions and viral pathogenesis is an emerging field with potential implications for antiviral therapies