🦠Virology Unit 9 – Human Viral Pathogens – RNA Viruses

Key RNA Virus Families

• Orthomyxoviridae includes influenza viruses (influenza A, B, and C) characterized by segmented negative-sense RNA genomes
• Paramyxoviridae consists of measles virus, mumps virus, and respiratory syncytial virus (RSV) with non-segmented negative-sense RNA genomes
• Rhabdoviridae comprises rabies virus and vesicular stomatitis virus (VSV) with bullet-shaped virions and negative-sense RNA genomes
• Filoviridae contains highly pathogenic viruses such as Ebola virus and Marburg virus with filamentous virions and negative-sense RNA genomes
• Coronaviridae includes SARS-CoV, MERS-CoV, and SARS-CoV-2 (COVID-19) with large positive-sense RNA genomes and crown-like appearance
• Flaviviridae encompasses dengue virus, Zika virus, and hepatitis C virus (HCV) with positive-sense RNA genomes and enveloped virions
• Togaviridae includes chikungunya virus and rubella virus with positive-sense RNA genomes and icosahedral capsids
• Retroviridae comprises human immunodeficiency virus (HIV) and human T-cell leukemia virus (HTLV) with positive-sense RNA genomes that undergo reverse transcription

Viral Structure and Genome Organization

• RNA viruses possess genomes composed of ribonucleic acid (RNA) that can be either single-stranded (ssRNA) or double-stranded (dsRNA)
• ssRNA viruses can have positive-sense (+ssRNA) or negative-sense (-ssRNA) genomes
  • Positive-sense RNA genomes can directly serve as mRNA for protein synthesis
  • Negative-sense RNA genomes require an RNA-dependent RNA polymerase (RdRp) for transcription into positive-sense RNA
• Genome organization varies among RNA virus families
  • Some viruses have segmented genomes (influenza viruses) while others have non-segmented genomes (measles virus)
  • Genome size ranges from ~7 kb (picornaviruses) to ~30 kb (coronaviruses)
• Viral genomes encode structural proteins (capsid and envelope proteins) and non-structural proteins (polymerases, proteases, and accessory proteins)
• Virions can be enveloped (influenza virus) or non-enveloped (poliovirus) depending on the presence or absence of a lipid bilayer
• Capsid symmetry can be icosahedral (flaviviruses), helical (rhabdoviruses), or complex (poxviruses)
• Some RNA viruses have unique structural features such as matrix proteins (paramyxoviruses) or surface glycoproteins (coronaviruses)

Replication Strategies

• RNA virus replication occurs in the cytoplasm of infected cells and involves the synthesis of viral proteins and genome amplification
• Positive-sense RNA viruses (flaviviruses) can directly translate their genome into viral proteins using host cell ribosomes
  • Viral polyproteins are processed by viral and host proteases to produce individual proteins
  • Viral RdRp synthesizes negative-sense RNA intermediates that serve as templates for new positive-sense genomes
• Negative-sense RNA viruses (influenza viruses) must first transcribe their genome into positive-sense RNA using viral RdRp
  • Positive-sense RNA is then translated into viral proteins and serves as a template for genome replication
• Retroviruses (HIV) employ a unique replication strategy involving reverse transcription of the RNA genome into DNA
  • Viral DNA integrates into the host cell genome and is transcribed into viral RNA by host cell machinery
• RNA virus replication is error-prone due to the lack of proofreading activity in viral RdRps
  • High mutation rates contribute to viral evolution and the emergence of new variants
• Replication complexes are often associated with intracellular membranes (endoplasmic reticulum or Golgi apparatus) to facilitate viral assembly
• Some RNA viruses undergo reassortment (influenza viruses) or recombination (coronaviruses) during co-infection, leading to the emergence of novel strains

Transmission and Host Range

• RNA viruses exhibit diverse transmission routes and host ranges depending on their evolutionary adaptations
• Respiratory transmission occurs through inhalation of virus-containing droplets or aerosols (influenza viruses, measles virus)
• Vector-borne transmission involves the transfer of viruses by arthropod vectors such as mosquitoes (dengue virus) or ticks (tick-borne encephalitis virus)
• Fecal-oral transmission occurs through ingestion of contaminated food or water (noroviruses, rotaviruses)
• Sexual transmission is a primary route for some retroviruses (HIV) and can also occur for other RNA viruses (Zika virus)
• Vertical transmission from mother to child can occur during pregnancy, delivery, or breastfeeding (rubella virus, Zika virus)
• Zoonotic transmission involves the transfer of viruses from animal reservoirs to humans (Ebola virus, SARS-CoV)
  • Intermediate hosts (palm civets for SARS-CoV) or amplifying hosts (horses for Hendra virus) can facilitate zoonotic transmission
• Host range is determined by the presence of specific receptors on host cells and the ability of viruses to overcome host defense mechanisms
  • Some RNA viruses have a narrow host range (measles virus) while others can infect multiple species (rabies virus)

Pathogenesis and Disease

• RNA viruses cause a wide range of diseases in humans, ranging from mild respiratory infections to severe hemorrhagic fevers
• Pathogenesis involves the interaction between viral factors and host immune responses
  • Viral entry into host cells is mediated by specific receptors (ACE2 for SARS-CoV-2) and can be facilitated by viral surface proteins (hemagglutinin for influenza viruses)
  • Viral replication in target tissues leads to cell damage and the release of inflammatory mediators
• Disease severity depends on factors such as viral load, virulence, and host immune status
  • High viral loads and efficient replication can lead to more severe disease (Ebola virus)
  • Virulence factors such as immunomodulatory proteins (NS1 in dengue virus) can enhance pathogenicity
• Tissue tropism determines the sites of viral replication and the associated clinical manifestations
  • Respiratory viruses (influenza viruses) primarily infect the respiratory tract, causing symptoms such as cough and pneumonia
  • Neurotropic viruses (rabies virus) infect the central nervous system, leading to encephalitis and neurological symptoms
• Viral infections can trigger systemic inflammatory responses (cytokine storm in severe COVID-19) that contribute to disease pathogenesis
• Chronic infections can occur with some RNA viruses (hepatitis C virus) and may lead to long-term complications such as cirrhosis and liver cancer
• Co-infections with multiple viruses (HIV and hepatitis B virus) or with bacteria (influenza virus and Streptococcus pneumoniae) can exacerbate disease severity

Immune Response and Evasion Mechanisms

• The immune system plays a crucial role in controlling RNA virus infections through innate and adaptive immune responses
• Innate immune responses are the first line of defense against viral infections
  • Pattern recognition receptors (Toll-like receptors) detect viral components and activate antiviral signaling pathways
  • Type I interferons (IFN-α/β) are produced by infected cells and stimulate an antiviral state in neighboring cells
  • Natural killer (NK) cells recognize and eliminate virus-infected cells through cytotoxic mechanisms
• Adaptive immune responses involve the activation of virus-specific T cells and B cells
  • CD8+ T cells (cytotoxic T lymphocytes) kill virus-infected cells through the release of perforin and granzymes
  • CD4+ T cells (helper T cells) support the activation and differentiation of B cells and CD8+ T cells
  • B cells produce virus-specific antibodies that neutralize viral particles and facilitate their clearance
• RNA viruses have evolved various mechanisms to evade or suppress immune responses
  • Antigenic drift (influenza viruses) and antigenic shift (influenza A viruses) allow viruses to escape pre-existing immunity
  • Viral proteins can interfere with interferon signaling (NS1 protein of influenza viruses) or inhibit apoptosis (Bcl-2 homologs in herpesviruses)
  • Some viruses (HIV) directly infect and deplete immune cells, compromising the overall immune response
• Persistent infections can occur when viruses establish a balance with the host immune system
  • Viral latency (herpes simplex virus) involves the maintenance of the viral genome in a non-replicative state
  • Chronic infections (hepatitis C virus) are characterized by ongoing viral replication and inflammation

Diagnosis and Detection Methods

• Accurate diagnosis of RNA virus infections is essential for appropriate treatment and disease control measures
• Clinical diagnosis is based on the presence of characteristic symptoms and epidemiological risk factors
  • Fever, cough, and respiratory distress are common in respiratory virus infections (influenza, COVID-19)
  • Rash, arthralgia, and conjunctivitis are associated with arboviral infections (dengue, Zika)
• Laboratory diagnosis relies on the detection of viral components or virus-specific immune responses
  • Reverse transcription-polymerase chain reaction (RT-PCR) is the gold standard for detecting viral RNA in clinical samples
    • Real-time RT-PCR allows for quantitative assessment of viral load and monitoring of treatment response
  • Antigen detection tests (rapid influenza diagnostic tests) provide quick results but have lower sensitivity compared to RT-PCR
  • Serological tests detect virus-specific antibodies (IgM and IgG) in patient sera
    • IgM antibodies indicate recent infection while IgG antibodies suggest past exposure or vaccination
  • Virus isolation in cell culture is used for research purposes and to characterize viral properties
• Molecular epidemiology techniques (genome sequencing) are used to track the spread of viral strains and identify mutations
  • Phylogenetic analysis helps to understand the evolutionary relationships among viral isolates
• Syndromic surveillance systems monitor the incidence of specific clinical syndromes (influenza-like illness) to detect outbreaks and guide public health responses

Treatment and Prevention Strategies

• Treatment options for RNA virus infections are limited and mainly focus on supportive care and symptom management
• Antiviral drugs target specific viral proteins or processes to inhibit viral replication
  • Neuraminidase inhibitors (oseltamivir) are used for the treatment and prophylaxis of influenza
  • Protease inhibitors (lopinavir/ritonavir) and polymerase inhibitors (remdesivir) have been used for the treatment of COVID-19
  • Combination antiretroviral therapy (ART) is the standard of care for HIV infection and aims to suppress viral replication and prevent disease progression
• Monoclonal antibodies (palivizumab for RSV) can provide passive immunization and are used for the prevention of severe disease in high-risk individuals
• Supportive care measures include oxygen supplementation, fluid management, and treatment of secondary bacterial infections
• Prevention strategies aim to reduce the risk of viral transmission and protect susceptible populations
  • Vaccines are the most effective means of preventing RNA virus infections
    • Inactivated vaccines (influenza), live-attenuated vaccines (measles), and recombinant vaccines (HPV) are available for various RNA viruses
    • Vaccine development is challenging for viruses with high mutation rates (HIV) or multiple serotypes (dengue)
  • Non-pharmaceutical interventions (hand hygiene, respiratory etiquette, social distancing) are important for reducing the spread of respiratory viruses
  • Vector control measures (insecticide-treated bed nets) are used to prevent the transmission of arboviruses
  • Safe sex practices (condom use) and harm reduction strategies (needle exchange programs) are effective in preventing the sexual and blood-borne transmission of HIV and hepatitis C virus

Notable RNA Virus Outbreaks

• RNA viruses have been responsible for several significant outbreaks and pandemics throughout history
• 1918 influenza pandemic (Spanish flu) caused by an H1N1 influenza A virus resulted in an estimated 50 million deaths worldwide
  • High mortality was observed in young adults, possibly due to an overactive immune response (cytokine storm)
• HIV/AIDS pandemic has claimed over 35 million lives since its emergence in the early 1980s
  • HIV originated from cross-species transmission of simian immunodeficiency viruses (SIVs) from non-human primates to humans
  • The development of antiretroviral therapy has significantly improved the prognosis of HIV-infected individuals
• 2002-2004 SARS outbreak caused by SARS-CoV affected over 8,000 people in 29 countries
  • The outbreak was characterized by severe respiratory illness and high case fatality rates (9.6%)
  • Nosocomial transmission played a significant role in the spread of SARS within healthcare settings
• 2009 H1N1 influenza pandemic (swine flu) caused by a novel reassortant influenza A virus of swine origin
  • The virus exhibited efficient human-to-human transmission and spread rapidly across the globe
  • Younger age groups were disproportionately affected, possibly due to the presence of pre-existing immunity in older adults
• 2014-2016 Ebola virus disease outbreak in West Africa was the largest and most complex Ebola outbreak since the virus was first discovered in 1976
  • The outbreak resulted in over 28,000 cases and 11,000 deaths in Guinea, Liberia, and Sierra Leone
  • Factors such as weak healthcare systems, cultural practices (traditional burials), and community mistrust hampered outbreak control efforts
• 2015-2016 Zika virus epidemic in the Americas was associated with an increased incidence of microcephaly and other congenital abnormalities
  • The virus was primarily transmitted by Aedes mosquitoes, with sexual and vertical transmission also documented
  • The outbreak highlighted the neurotropic potential of Zika virus and its impact on fetal development
• COVID-19 pandemic caused by SARS-CoV-2 has resulted in over 500 million cases and 6 million deaths worldwide (as of April 2023)
  • The rapid global spread of the virus has led to unprecedented public health measures and societal disruptions
  • The development and deployment of effective vaccines have been crucial in mitigating the impact of the pandemic