Herpesviruses: Types, Replication, and Diseases PDF

HERPESVIRIDAE HUMAN PAPILLOMAVIRIDAE  HERPESVIRIDAE Genome: linear dsDNA Icosahedral capsid of 162 capsomers surrounded by an amorphous tegument Spherical to pleomorphic envelope (150-200 nm in diameter) HERPESVIRIDAE o they are ubiquitous, except HH...

HERPESVIRIDAE HUMAN PAPILLOMAVIRIDAE  HERPESVIRIDAE Genome: linear dsDNA Icosahedral capsid of 162 capsomers surrounded by an amorphous tegument Spherical to pleomorphic envelope (150-200 nm in diameter) HERPESVIRIDAE o they are ubiquitous, except HHV-8. o they cause benign disease, but they can cause significant morbidity and mortality, especially in immunosuppressed people and some (EBV, HHV-8) are associated with human cancers. o they cause latent infection: the viral genome is maintained silently in the infected cell, replicating at each cell cycle HERPESVIRUS REPLICATION  HERPESVIRUS REPLICATION o The attachment of the viral glyproteins to host receptors mediates endocytosis of the virus into the host cell. o Fusion with the plasma membrane to release the nucleocapsid and the tegument proteins into the host cytoplasm. o The capsid is transported to the nuclear pore where viral DNA is released into the nucleus o Transcription/translation of immediate early genes (proteins important for the regulation of gene transcription), early genes (transcription factors and enzymes, including the DNA polymerase). o Replication of parental genome by a rolling circle mechanism. o Transcription/translation of late mRNAs (structural proteins) o Assembly of the virus in nuclear viral factories and budding through the inner lamella of the nuclear membrane which has been modified by the insertion of viral glycoproteins, throughout the Golgi and final release at the plasma membrane. LYTIC REPLICATION LATENT REPLICATION  LYTIC AND LATENT CYCLES Lytic cycle: HSV-1 replicates in epithelial cells, and the production of viral progeny leads to cell death Latent cycle: the viral DNA takes a circular (episomal) structure; genome generates only the latency-associated transcripts (LATs), that are not translated into proteins, but encode micro-RNAs that inhibit expression of important immediate early and other genes.  HERPES SIMPLEX VIRUS TYPE 1 and TYPE 2 HSV-1 and HSV-2 are two different types of herpesviruses, sharing many characteristics: DNA homology (50%), antigenic determinants, tissue tropism → they generally cause lytic infections of fibroblast and epithelial cells at the entry site, and latent infections of neurons, trigeminal ganglia for HSV-1 and sacral ganglia for HSV-2. HSV-1 is usually spread by oral contact or saliva-contaminated items. Infection is very common. HSV-2 is spread mainly by sexual contact or autoinoculation or from an infected mother to infant at birth. Neonatal infection usually results from the excretion of HSV-2 from the cervix during vaginal delivery, but can occur from an ascending in utero infection during a primary infection of the mother. Neonatal infection is a devastating and often fatal disease. HSV disseminates to the liver, lung, and other organs, as well as to the central nervous system (CNS) resulting in mental retardation, neurologic disability or death.  HERPES SIMPLEX VIRUS TYPE 1 and TYPE 2 In the classic manifestation, the lesion is a clear vesicle on an erythematous base and then progresses to pustular lesions, ulcers, and crusted lesions. The lesion generally heals without producing a scar. gingivostomatitis Lesions are at infection sites. HSV-1 tends to cause disease above the waist and HSV-2, which is more commonly transmitted via sexual contact, causes herpes labialis disease below the waist “cold sores – fever blisters”  Diagnosis and Therapy of HSV infection DIAGNOSIS: o Viral isolation from herpetic lesions, cerebral spinal fluid → apperance of characteristics cytopathic effects on cells o Genome detection from vesicle fluid, crusted lesions and cerebral spinal fluid o Serology is not useful except for epidemiology and to identify a primary infection THERAPY: o Nucleoside analogs (acyclovir, valcyclovir, famcyclovir) → inhibitors of viral DNA synthesis. They are capable of shortening the duration of clinical symptoms and suppressing viral reactivation o The drugs are ineffective against latent virus  VARICELLA-ZOSTER VIRUS (VZV) Varicella or chickenpox Herpes Zoster or shingles Primary infection Reactivation Common childhood VZV establishes a infection latent infection in sensory ganglia Mild febrile illness Vesicular rash along the associated with a entire dermatome generalized associated with a very vesicular rash painful post-herpetic neuralgia VARICELLA-ZOSTER VIRUS (VZV) When immune responses weaken, VZV reactivates by travelling anterograde towards nerve endings, replicates in keratinocytes and epithelial cells causing the formation of polykaryocytes, leading ultimately to a dermatomal rash. very painful post-herpetic neuralgia  VARICELLA-ZOSTER VIRUS (VZV) DIFFERENT CLINICAL MANIFESTATIONS FOR PRIMARY INFECTION AND REACTIVATION ATTENTION! skin lesions can release infectious virus  Diagnosis and Therapy of VZV DIAGNOSIS o Viral isolation from lesions, cerebral spinal fluid is performed only in selected cases (neurological sequelae) o Genome detection in clinical specimens o Serology is used to screen population THERAPY o Nucleoside analogs (acyclovir, valcyclovir, famcyclovir) → these drugs are effective in reducing fever and skin lesions if treatment is begun within 3 days of onset of infection, prior to the eruption of lesions. Moreover, they reduce viral dissemination in immunocompromised patients o Passive immunization of high-titer VZV immunoglobulin can be administered in immunocompromised patients VACCINE Two vaccines are licensed for use: Varivax® is the single-antigen varicella vaccine; ProQuad® is a combination measles, mumps, rubella, and varicella (MMRV) vaccine. Both vaccines contain live, attenuated varicella-zoster virus derived from the Oka strain.  CYTOMEGALOVIRUS o Ubiquitous (10-15% of children are infected before age of 5 years; 50–90% seroprevalence in adults) o Infects only humans o The predominant targets are fibroblasts, epithelial cells, endothelial cells, macrophages o It remains latent in myeloid stem cells, monocytes, lymphocytes, the stromal cells of the bone marrow, kidneys, heart and lungs. While CMV infection is usually asymptomatic, severe disease can result from primary infection or viral reactivation from latency in immune compromised hosts →interstitial pneumonia, gastroenteritis, retinitis, organ transplant rejection, death CMV is also a leading cause of congenital disease. Upon in utero infection, the child can exhibit microcephaly or severe sequelae, or both, including hearing loss, mental retardation, and learning disabilities  CYTOMEGALOVIRUS CMV uses several routes to spread with population: o Horizontal transmission occurs through organ transplantation of an infected organ or contact with infected bodily secretions (saliva, tears, urine, semen, stool, vaginal and cervical secretions)  CYTOMEGALOVIRUS CMV uses several routes to spread with population: o Vertical transmission occurs through transplacental (maternal blood) and intrapartum transmission, through breast feeding (maternal milk or colostrum) from an infected mother to the child Disease signs include small size, thrombocytopenia, microcephaly, intracerebral calcification, jaundice, hepatosplenomegaly, and rash (cytomegalic inclusion disease). Vision or hearing loss and mental retardation are common consequences of congenital CMV infection. The risk for serious birth defects is extremely high for infants born to mothers who had primary CMV infections during their pregnancies.  CYTOMEGALOVIRUS In immunocompromised subjects, almost every organ can be affected by CMV: o Liver → hepatitis o Lungs → pneumonia o Central nervous system → meningoencephalitis o Gastrointestinal tract → esophagitis, colitis o Kidneys o Eyes → retinitis  Diagnosis of CMV infection VIRAL ISOLATION CMV is grown in fibroblast cell cultures and normally must be maintained for weeks because the characteristic cytopathic effect develops slowly → not suitable MOLECULAR DIAGNOSIS o Detection of the viral genome, using PCR in cells of a biopsy, blood, bronchoalveolar lavage, urine sample, saliva, CSF o Useful in case of congenital infection and infection/reactivation in immunocompromised patients SEROLOGY o Seroconversion is usually an excellent marker for primary CMV infection. Titers of IgM are high during primary infection, however, IgM antibody may also develop during the reactivation of CMV and is therefore not a dependable indicator of primary infection o Useful in diagnosis of maternal infection (prenatal screening), not useful in immunocompromised patients  Treatment of CMV infection Ganciclovir (GCV) Valganciclovir Cidofovir (CDV) Foscarnet (phosphonoformic acid) (FOS) These drugs are approved for the treatment of specific diseases resulting from CMV infections of immunosuppressed patients No treatment available to prevent or treat congenital infection  EPSTEIN-BARR VIRUS (EBV) EBV is ubiquitous (80-90% seropositive adults). More than 90% of EBV-infected people intermittently shed the virus for life, even when totally asymptomatic → saliva (oral route) It has a very limited host range (humans are the only known natural hosts) and tissue tropism defined by the primary receptor, C3d component of the complement system Susceptible cells are: o Epithelial cells of the oropharynx and nasopharynx o B cells EBV can cause lytic infections of epithelial cells and latent infection or immortalization of B cells.  EPSTEIN-BARR VIRUS (EBV) Infectious mononucleosis or kissing disease The triad of classic symptoms is lymphadenopathy, splenomegaly and exudative pharyngitis accompanied by high fever, malaise, and often hepatosplenomegaly  EPSTEIN-BARR VIRUS EBV is a recognized oncogenic agent Epstein-Barr Virus–Induced cancers: o Endemic Burkitt lymphoma o Hodgkin disease o Nasopharyngeal carcinoma o B-cell lymphomas in patients with immunodeficiencies Co-factors are necessary for the development of cancer: o malaria contributes in the development of Burkitt lymphoma (sub-Saharan Africa) o genetics/environmental component for development of nasopharyngeal carcinoma in China o HIV infection/immunosuppression  Laboratory diagnosis of EBV infection The diagnosis is usually serological o Paul-Bunnel test Heterophile antibody results from the nonspecific activation of B cells by EBV and the production of a wide repertoire of antibodies. These antibodies include IgM heterophile antibodies that recognize antigens on horse or sheep erythrocytes (Monospot test) o EBV-specific serologic tests EBV infection is indicated by the finding of the following: (1) the presence of anti-EBV IgM antibody ± anti-EBV IgG (2) the absence of EBNA IgG antibody Nucleic acid amplification tests are available to detect EBV infection in immunocompromised patients (peripheral blood) No effective treatment or vaccine are available for EBV disease  OTHER HUMAN HERPESVIRIDAE HHV-6 (HHV-6A and HHV-6B) and HHV-7 are members of the β-Herpesvirinae responsible for exanthem subitum, or roseola, one of the five classic childhood exanthems. HHV-6 and HHV-7 infections occur very early in life (age 6 to 24 months). The viruses infect lymphocytes and establish a latent infection in T cells and monocytes. The viruses replicate in the salivary glands, are shed, and are transmitted in saliva. The disease is characterized by the rapid onset of high fever of a few days’ duration, which is followed by a rash on the trunk and face, and then it spreads and lasts only 24 to 48 hours. Viruses may reactivate in transplant patients and contribute to the failure of the graft. They have also been associated with multiple sclerosis and chronic fatigue syndrome.  OTHER HUMAN HERPESVIRIDAE HHV-8 is member of the Ɣ-Herpesvirinae associated to Kaposi sarcoma (KS), primary effusion lymphoma (a rare type of B-cell lymphoma), and multicentric Castleman disease. The B cell is the primary target cell for HHV-8, but the virus also infects a limited number of endothelial cells, monocytes, and epithelial and sensory nerve cells. HHV-8 is more prevalent in certain geographic areas (Italy, Greece, Africa) and in patients with AIDS and is most likely transmitted by sexual route disease but may be spread by other means (blood exposure). Although KS mainly affects the skin, the mouth, and the lymph nodes, it can also involve the bowels and lungs  PAPILLOMAVIRIDAE Genome: dsDNA, circular L1 Icosahedral capsid (50-55 nm) L2 Nonenveloped virus HPVs are > 100 genotypes typed by DNA sequence omology, subdivided into 16 groups. They are categorized by the epithelial cells they infect (tissue tropism): o Cutaneous HPVs infect squamous epithelium of the skin (face, hands, feet)→warts o Mucosal HPVs infect mucous membranes of the respiratory tract including pharynx, nasal and oral cavities, and of the anal and genital regions →papillomas and condylomas Some types can cause benign tumors (papillomas or warts), some can lead to carcinomas of the epithelial cells (cervical cancer) PAPILLOMAVIRIDAE  PAPILLOMAVIRIDAE Proteins E6 and E7 p53 and pRB Upregulated growth of the epithelial cells pathways  PAPILLOMAVIRIDAE The virus accesses the basal cell layer through breaks in the skin  PAPILLOMAVIRIDAE Cutaneous Syndromes: o Nongenital cutaneous HPVs infections involve benign wart → the wart develops because of virus stimulation of cell growth and thickening of the basal and prickle layers (stratum spinosum), as well as the stratum granulosum (mainly HPV 1-4) o Epidermodysplasia verruciformis (EV) promotes chronic cutaneous infections → flat warts can develop in cutaneous benign and malignant skin lesions Flat warts HPV infection in EV subject  PAPILLOMAVIRIDAE Mucosal Syndromes: o Anal and genital infections can involve numerous warts → condyloma acuminata o Infections of mucous membranes in the upper respiratory tract can cause respiratory papillomatosis → laryngeal papilloma, oral papilloma (mainly HPV 6 and 11) Papillomatosis and genital warts are considered low-risk because they don’t tend to progress beyond warts condyloma acuminata  HPV AND CERVICAL CANCER HPV infection occurs with a break in the epithelium so that HPV can infect basal cells HPV infection is usually transient (90% infection clear within 3 years) Long-term persistence of high-risk genital HPV infection is the strongest predictor of cervical precancer and cancer development in women In most women, there is a 15- to 20-year gap between HPV infection and cancer development  Laboratory diagnosis of HPV infection o Warts are used to diagnose HPV particularly in cutaneous infections o Infections of mucous membranes required additional interventions to visualize epithelial cells o endoscope if the infection of the upper respiratory tract is suspected o regular pap or acetic acid tests if an infection of the genital tract is suspected o Definitive diagnosis cannot be made without genome detection: polymerase chain reaction (PCR), and real-time PCR analysis of cervical swabs and other tissue specimens are the methods of choice for establishing the diagnosis and typing of the HPV infection Papillomaviruses do not grow in cell cultures, and tests for HPV antibodies are not useful  SCREENING OF HPV-RELATED LESIONS Cervical cancer screening involves testing for: o pre-cancer → pre-cancerous lesions can easily be treated and cancer avoided o cancer → cancerous lesions at an early stage and treatment has a high potential for cure Screening is recommended for every woman from aged 30 and regularly afterwards. There are 3 different types of screening tests that are currently recommended by WHO: o HPV testing for high-risk HPV types (molecular testing) o visual inspection with Acetic Acid (VIA) o conventional (Pap) test and liquid-based cytology (LBC)  PAP-TEST Normal HPV HPV-lesions Koilocyte Koilocytes are enlarged cells with clear halos around shrunken nuclei  Treatment of HPV infection Removal of warts and precancerous lesions with: o Salicylic acid products o Liquid nitrogen cryotherapy o Laser or surgical removal Immune modifiers may be use to boost the immune system in case of frequent re- occurrences → immune stimulant therapy with injection of interferon or topical applications of imiquimod (cytokine inducer and a modifier of the innate immune response)  Prevention of HPV-related cancer: vaccine HPV vaccines are prepared from virus-like particles (VLPs) produced by recombinant technology; VLPs combine safety of subunit vaccines with efficacy of live attenuated vaccines VLPs are molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material. Purified L1 protein (capside protein) self-assembles to form empty shells that resemble HPV VLPs  Prevention of HPV-related cancer: vaccine Three different vaccines have been developed: o Quadrivalent HPV vaccine (Gardasil) targets HPV types 6, 11, 16, and 18 o 9-valent vaccine (Gardasil 9) targets the same HPV types as the quadrivalent vaccine (6, 11, 16, and 18) as well as types 31, 33, 45, 52, and 58 o Bivalent vaccine (Cervarix) targets HPV types 16 and 18. HPV vaccination should be initiated at age 11 or 12 years for both boys and girls. Continued cervical cancer screening of vaccinated patients is needed