Viral Infections PDF 2024

PATHOLOGY | MODULE NO. 3.1.1 LE NO. 2 VIRAL INFECTIONS Dr. Jose Remulla | 10/10/2024...

PATHOLOGY | MODULE NO. 3.1.1 LE NO. 2 VIRAL INFECTIONS Dr. Jose Remulla | 10/10/2024 ○ SLAM - in cells of the immune system LECTURE OUTLINE Signaling Lymphocytic Activation Molecule On activated lymphocytes, dendritic cells, and I. ACUTE (TRANSIENT) INFECTIONS 1 monocytes Serves as initial receptor for viral infection A. MEASLES (RUBEOLA) 1 ○ Nectin-4 - present in all epithelial cells B. MUMPS 2 The virus replicates in epithelial cells & leukocytes C. POLIOMYELITIS 2 Enters the respiratory tract → disseminates into lymphoid tissues →viral replication → viremia (virus spreads throughout the body D. WEST NILE VIRUS 2 ○ Manifestations: conjunctivitis, skin rashes, pneumonia, in the E. VIRAL HEMORRHAGIC FEVER 2 urinary tract, small blood vessels, lymphatic system, and F. ZIKA VIRUS INFECTIONS G. DENGUE 3 3 ⭐ CNS (in severe cases) Rash - a classic manifestation of measles that develops due to intact T-cell mediated immunity. H. NOVEL CORONAVIRUS SARS-CoV-2 (COVID-19) 3 ○ Blotchy, reddish-brown rash on the face, trunk, & proximal II. LATENT (HERPESVIRUS) INFECTIONS 3 extremities A. VARICELLA-ZOSTER VIRUS (VZV) INFECTIONS 3 More severe in malnourished children ○ Manifestations: Croup, pneumonia, diarrhea, & protein-losing B. CYTOMEGALOVIRUS (CMV) INFECTIONS 4 enteropathy, keratitis, encephalitis, and hemorrhagic rashes III. CHRONIC PRODUCTIVE INFECTIONS 5 (“black measles”). A. HUMAN IMMUNODEFICIENCY VIRUS (HIV) 5 Can cause transient immunosuppression ○ Results in secondary bacterial & viral infections IV. TRANSFORMING VIRAL INFECTIONS 9 ○ That is why measles prevention is very important; A. EPSTEIN-BARR VIRUS (EBV) INFECTION 9 vaccination protects you from measles and other diseases. IV. REFERENCES VI. APPENDIX 11 12 ⭐ Late complication: Subacute Sclerosing Panencephalitis (SSPE) 📋 Happens years after getting infected CNS manifestations; are almost always fatal. LEGEND ⭐ 💬 📖 📋 ❌ Not included MORPHOLOGY ⭐ Koplik spots Important Lecture Book Previous trans in the exam ○ Characteristic finding ○ Ulcerated mucosal lesions near the opening of Stensen ducts. I. ACUTE (TRANSIENT) INFECTIONS ○ Marked by necrosis, neutrophilic exudate, and Caused by structurally heterogeneous viruses neovascularization on microscopy. All elicit effective immune responses that clear the infection Lymphoid tissues typically have: Specific viruses exhibit widely differing degrees of genetic ○ Marked follicular hyperplasia diversity ○ Large germinal centers ○ Some can reinfect the same individual with different genetic ○ variants of the same virus (e.g., influenza) Some can no longer reinfect the same person due to having ⭐ ○ Warthin-Finkeldey Cells Warthin-Finkeldey Cells ○ Scattered multi-nucleate giant cells only 1 genetic serotype (e.g., mumps, measles) ○ Found in lymphoid tissues, lungs, & sputum ○ Some can infect people only once due to having only 1 genetic serotype. A. MEASLES (RUBEOLA) Single-stranded RNA virus of the Paramyxovirus group. The leading cause of vaccine-preventable death and illness worldwide, usually in developing countries with poor sanitation & nutrition. Affects multiple organs 📖 Presentation ranges from mild or self-limiting to severe disease. Produces severe disease if the person has T-cell defects (e.g., HIV infection, leukemias) Diagnosis is usually made clinically or by serologic & antigen testing. PATHOGENESIS ⭐ Has 💬 only 1 serotype There’s only one type of antigenic composition in the virus, meaning once you develop an immune response and antibodies, you’re already immune for life. Figure 1. Measles giant cells in the lungs [Robbins & Cotran] Transmitted via respiratory droplets Note the glassy eosinophilic intranuclear inclusions. Viral hemagglutinin binds to 3 cell surface receptors to infect cells ○ CD46 - on all nucleated cells PATHOLOGY | VIRAL INFECTIONS | Bernabe, Catalan, Co, Farochilen, Favila, Reyes 1 of 12  B. MUMPS 📖 Bulbar poliomyelitis (Brainstem) ⭐ Acute systemic viral infection with pain & swelling of salivary Complications of the polio vaccine: ○ The live attenuated vaccine may mutate & revert to wild-type 💬 glands. Also a paramyxovirus (like measles). Salivary gland pain and swelling is a classic manifestation due to the desquamation of ductal epithelial cells (they die virulent infectious forms and cause outbreaks. NOT RECOMMENDED in areas with LOW incidence/prevalence. and slough off leading to obstruction of salivary glands RECOMMENDED only in HIGH prevalence areas to help causing the pain and swelling), subsequent edema, and spread immunity faster. inflammation When incidence/prevalence drops → vaccination ⭐ May also involve the CNS, testis, ovary, and pancreas. Aseptic Meningitis Most common extra-salivary gland complication (15%) programs should shift to the inactivated vaccine. Diagnosis: made by viral culture, PCR, or serology. Aseptic - bacteriologic studies won’t find any organism Has 2 surface glycoproteins: D. WEST NILE VIRUS ○ One with hemagglutinin & neuraminidase activities Presentation ranges from mild, self-limited infection or severe ○ One with cell fusion & cytolytic activities neuroinvasive disease. Transmitted via respiratory droplets. An arthropod-borne virus (arbovirus) of the Flavivirus group, which Enters the upper respiratory tract → spreads to draining lymph also includes viruses that cause dengue fever and yellow fever. nodes → replicates in T cells → Vascular dissemination to Distribution in the Old World (Africa, Middle East, Europe, salivary & other glands Southeast Asia, and Australia) Vaccine-preventable disease ○ MMR vaccine for Measles, Mumps, and Rubella Diagnosis: mostly clinical, also include serology, viral culture, & 📖Transmitted by: mosquitoes to birds and to mammals. Infected birds develop prolonged viremia and are the major reservoir for the virus. PCR Humans are incidental hosts. ○ Acquire the infection from a mosquito bite. MORPHOLOGY ○ Less common: human-to-human transmission by blood transfusion, organ transplantation, breastfeeding, or Mumps Parotitis transplacental spread. ○ Bilateral in 70% of cases Replicates in skin dendritic cells → migrate to lymph nodes → ○ Enlarged glands with a doughy consistency viral replication → enter the bloodstream (hematogenous spread). ○ Moist, glistening, and reddish-brown (on cross-section) ○ Some enter the CNS by breaching the BBB and infect ○ Edematous interstitium with many macrophages, neurons. lymphocytes, & plasma cells, and compressed acini & ducts ○ Chemokine receptor CCR5 contributes to CNS resistance to (on microscopy) infection. ○ Neutrophils & necrotic debris may fill up ductal lumens Manifestations: Mostly asymptomatic; 20% present with fever, Plugging of lumens leads to subsequent inflammation headache, myalgia, fatigue, anorexia, and nausea. Mumps Orchitis ○ May have maculopapular rash. ○ Common manifestation in males ○ CNS complications occur in about 1 in 150 infections ○ Marked testicular swelling ○ Meningitis, encephalitis, meningoencephalitis (10% mortality ○ Caused by edema, mononuclear cell infiltration, and focal rate) hemorrhages ○ Rare complications: hepatitis, myocarditis, pancreatitis ○ Parenchymal swelling compromises blood supply and Diagnosis: usually by serology, viral culture, & PCR. causes areas of infarction. ○ Testicular damage can lead to scarring, atrophy, and sterility (if severe). MORPHOLOGY Mumps Pancreatitis Perivascular & leptomeningeal chronic inflammation ○ Infection and damage of acinar cells may release digestive Microglial nodules enzymes → cause parenchymal & fat necrosis and Neuronophagia (involving temporal lobes & brainstem) neutrophilic infiltration Mumps Encephalitis E. VIRAL HEMORRHAGIC FEVER ○ Associated with perivenous demyelination & mononuclear Severe life-threatening multisystem syndrome cuffing. Leads to shock and widespread hemorrhage from vascular C. POLIOMYELITIS Acute systematic viral infection. 💬 dysregulation & damage shock means there is hypoperfusion which lowers the blood pressure. Range of manifestations from mild self-limiting to severe or Caused by 4 different genera of enveloped RNA viruses: paralytic disease. ○ Arenaviridae, Filoviridae, Bunyaviridae, Flaviviridae Spherical, unencapsulated RNA virus of Enterovirus genus. Produce a spectrum of disease presentations ranging from: 📖 Has 3 stereotypes, all covered by available vaccines: Salk - killed vaccine; inactivated injected vaccine ○ Mild disease – fever, headache, myalgia, rash, neutropenia, and thrombocytopenia 📖 recommended in low-prevalence areas. Sabin - live attenuated oral vaccines recommended in high-prevalence areas. ○ Severe, life-threatening disease – sudden hemodynamic deterioration & shock Starts in animal or insect host during their life cycles Transmission: Fecal-oral - areas with poor hygiene or sanitation. Humans are incidental hosts The virus binds to CD155 (epithelial adhesion molecule) to enter ○ Transmitted by infected rodents, mosquitoes, or ticks the cell → virus is ingested & replicates in the mucosa of the Some viruses with person-to-person mode of transmission: pharynx & gut → spreads into tonsils & Peyer patches (of the ○ Ebola, Marburg, Lassa ileum) → spreads through lymphatics to lymph nodes and eventually in the blood. MORPHOLOGY 💬 Presentations: transient viremia & fever Mostly a mild illness, but there are neurologic manifestations, Hemorrhagic manifestations: ○ Thrombocytopenia or platelet dysfunction 📖 📋 including paralysis, in about 1% Spinal poliomyelitis (infects the spinal cord) Common; presents with paralysis; (+) shrinkage of ○ ○ Endothelial cell damage Cytokine-induced DIC (disseminated intravascular affected limbs due to denervation paralysis coagulation) PATHOLOGY | VIRAL INFECTIONS | Bernabe, Catalan, Co, Farochilen, Favila, Reyes 2 of 12  💬there is an increased risk of thrombi because of the consumption of coagulation factors in DIC G. DENGUE Flavivirus, mostly in tropical & subtropical regions ○ Deficiency of clotting factors (due to liver injury) Vector: Aedes mosquito Spectrum of manifestations: F. ZIKA VIRUS INFECTIONS ○ Less severe: fever, headache, macular rash, severe myalgias Flavivirus discovered in 1947 (breakbone fever) Recent outbreaks: ○ Severe: dengue hemorrhagic fever, bleeding, liver failure, ○ State of Yap (2007) altered consciousness, organ failure, and plasma leakage ○ ○ French Polynesia (2013-2014) Brazil (2015) Transmitted by mosquitoes (Aedes aegypti) ⭐ ○ (leading to shock & respiratory distress) Antibody-dependent enhancement There are 4 serotypes of dengue virus Manifestations: ○ Previous infections increase severity of reinfection with a ○ Microcephaly in babies different serotype ○ 💬Fever, myalgia, arthralgia, conjunctivitis, maculopapular rash these are non-specific symptoms of Zika Virus Neurologic: Guillain-Barre Syndrome (GBS) ○ 📖 Enhanced uptake of virus into macrophages via Fc receptors Increases infectivity of virus & contribute to severe dengue Found in degenerating neurons/glial cells and chorionic villi in the placenta H. NOVEL CORONAVIRUS SARS-CoV-2 (COVID-19) Viral RNA detectable in the brain tissue First detected in Wuhan, China (December 2019) ○ Likely from a seafood & animal market MORPHOLOGY ○ Suspected animal-to-human transmission Cerebral calcification, cerebral atrophy, ventricular enlargements, Spread into a worldwide pandemic by the end of March 2020 and hypoplastic cerebral structures (most common adverse ○ Lots of human-to-human transmission outcomes) Clinical manifestations range from mild to severe respiratory Ocular abnormalities: pigment mottling, chorioretinal atrophy, and illness optic nerve abnormalities ○ People with comorbidities are more vulnerable to severe Common findings in newborn (autopsy series): disease (e.g., DM, COPD, heart failure, cancer) ○ Microcephaly, ventriculomegaly, congenital joint contractures (arthrogryposis), and pulmonary hypoplasia HISTOPATHOLOGY Diffuse alveolar damage & mononuclear cell inflammation ○ Non-specific, typical of severe lung damage & reactive changes II. LATENT (HERPESVIRUS) INFECTIONS Term – definition ○ Terminologies A. VARICELLA-ZOSTER VIRUS (VZV) INFECTIONS Term – definition ○ Terminologies 💬 Diagnosis: by viral culture, PCR, or viral antigen ( or antibodies) detection from scrapings of scabs or crusted lesions MORPHOLOGY Chickenpox ○ Rash occurs ~ 2 weeks after respiratory infection ○ Lesions appear in multiple waves centrifugally from the torso to the head & extremities ○ Each lesion progresses rapidly 💬 Macule → Vesicle → Rupture → Crusting Progresses from a macule then it becomes a fluid filled vesicle then it ruptures, becomes ulcerated, then it will scab/crust Vesicle ⭐ Fluid-filled lesion Resembles a “dewdrop on a rose petal” Most vesicles rupture leaving a superficially ulcerated skin which eventually crusts ○ Histopathology: intraepithelial vesicles with intranuclear 💬 inclusions at the base of vesicles Those infected with Herpes simplex or Varicella, the cells have a glassy, multinucleated appearance (the nuclei are pale) Figure 2. Morphology of Brain from a 2-month Child with Zika Virus Infection ([A] Subcortical band of degenerating cells with prominent calcifications. [B] Cortex with degenerating neurons [arrows]) PATHOLOGY | VIRAL INFECTIONS | Bernabe, Catalan, Co, Farochilen, Favila, Reyes 3 of 12  B. CYTOMEGALOVIRUS (CMV) INFECTIONS Produce variety of manifestations depending on age and immune status of the host Latently infects monocytes and their bone marrow progenitors ○ Reactivation when cell immunity is depressed Causes an asymptomatic or mononucleosis-like infection in healthy individuals Severe infections can occur in neonates and in the immunocompromised (especially those with HIV or AIDS) Transmission mechanisms: ○ Transplacental – from infection in a mother without protective antibodies (congenital CMV) ○ Neonatal – via cervical/vaginal secretions at birth or breastmilk from a mother with active infection (perinatal CMV) Figure 3. Skin Lesion of Chickenpox (Varicella-Zoster Virus) with Intraepithelial Vesicle ○ ○ Saliva – toddlers in daycare centers Genital route – common in people >15 years of age ( when they become sexually active) 💬 💬 (There is a fluid-filled cavity within the epidermis (does not reach the dermis). The ○ Iatrogenic – via blood transfusion or organ transplantation epidermis is still intact. There may be intranuclear inclusions at the base of the There’s a high incidence and prevalence of transmission in vesicle. These are viral cytopathic changes associated with Varicella Zoster.) CMV but since most people are not immunocompromised, they do not have severe manifestations Herpes Zoster (Shingles) Acute infection causes transient but severe immunosuppression ○ Reactivation of latent infection Can infect dendritic cells & impair antigen processing and T-cell ○ Virus traveling from the ganglion (DRG) to the skin stimulation Carried by sensory nerves Can evade immune defenses & NK cells Often associated with intense itching, burning, or sharp ○ Evade immune defenses by: 💬 pain due to radiculoneuritis Symptoms may be worse than chickenpox (even though it Downmodulating MHC class I & II molecules Producing homologues of TNF receptor, IL-10, & MHC ⭐ ○ just happens in the regional area) Ramsay Hunt Syndrome Severe version of Herpes Zoster ○ Class I molecules Evade NK cells by : Producing ligands that block activating receptors ○ Facial paralysis due to involvement of geniculate nucleus by Producing class I-like proteins that engage inhibitory the Herpes Zoster virus receptors Can involve the facial nerve which innervates the facial muscles Sensory Ganglia Morphology (viral cytopathic changes) MORPHOLOGY ○ Contains dense, predominantly mononuclear infiltrates (on 💬 microscopy) Mononuclear: the macrophages, lymphocytes and ⭐CellularResembles gigantism (40 µm) an Owl’s eye → large intranuclear inclusions with halo which spans half of the nuclear diameter ○ 💬 plasma cells Polymorphonuclear: neutrophils (inflammation) With herpetic intranuclear inclusions within neurons and Hence the name “cytomegalovirus” ○ (cyto – cell; mega – large) Smaller basophilic inclusions in the cytoplasm can also be seen 💬 their supporting cells Explains the multinucleated cells with a glassy nuclei Other manifestations (more severe): Parenchymal epithelial cells in the glands can also be infected Other organs that can be involved: ○ Neurons, alveolar macrophages, pneumocytes, renal tubular ○ Interstitial pneumonia, encephalitis, transverse myelitis, cells and glomerular endothelial cells vasculopathy, and necrotizing visceral lesions Disseminated CMV Particularly in immunosuppressed people. ○ Presents with focal necrosis with minimal inflammation in any organ Figure 4. Dorsal Root Ganglion with Varicella-Zoster Virus Infection (Note the ganglion cell necrosis & associated inflammation. The inflammation is from a lot of lymphocytes & some plasma cells — definition of ‘mononuclear’.) Figure 5. Cytomegalovirus (Distinct nuclear and ill-defined cytoplasmic inclusions in the lung.) PATHOLOGY | VIRAL INFECTIONS | Bernabe, Catalan, Co, Farochilen, Favila, Reyes 4 of 12  CONGENITAL CMV III. CHRONIC PRODUCTIVE INFECTIONS Congenital infection is mostly asymptomatic (95% of cases) Body’s immune system is unable to eliminate the virus Cytomegalic Inclusion Disease Leads to persistent viremia due to continued replication ○ Can occur in young patients if the virus is acquired from a High mutation rates → allow escape from the immune system mother with primary infection 2 main examples: ○ Affected infants may suffer: ○ Human Immunodeficiency Virus & Hepatitis B virus Intrauterine growth retardation, jaundice, hepatosplenomegaly, anemia, thrombocytopenia, and A. HUMAN IMMUNODEFICIENCY VIRUS (HIV) encephalitis Causative agent of Acquired Immune Deficiency Syndrome ○ In fatal cases, brain is smaller than normal (microcephaly) (AIDS) and have calcifications ○ Characterized by profound immunosuppression 💬 Manifests as intellectual disability, hearing loss, and ○ Leads to opportunistic infections, secondary neoplasms other neurologic impairments ( due to opportunistic viruses), and neurologic ○ Milder disease can present with interstitial pneumonitis, manifestations 💬 hepatitis, or a hematologic disorder ○ Spread globally, with African countries as the worst-hit Diagnosis: made by viral culture or PCR in urine or saliva places ( extremely high incidence of prevalence) PERINATAL CMV EPIDEMIOLOGY Infection acquired during passage through birth canal or from breastfeeding HIGH-RISK GROUPS Can be asymptomatic due to protective anti-CMV antibodies from the mother 💬 💬 Gay and bisexual men ( in the US & other developed nations) This is slowly changing, don’t discriminate between sexual Many infants may excrete the virus in the urine or saliva despite having no symptoms orientations. As long as people are sexually active with their partners ⭐️ CMV MONONUCLEOSIS 💬 Intravenous drug users Due to sharing of needles Mostly asymptomatic in healthy young children and adults Hemophiliacs Commonly manifests as an infectious mononucleosis-like illness (in immunocompetent hosts beyond the neonatal period) ○ With fever, atypical lymphocytosis, lymphadenopathy, and 💬 Recipients of blood and blood products which may be tainted Decreasing because of better donor screening and testing of blood products hepatitis (marked by hepatomegaly & abnormal liver function Heterosexual intercourse tests) ○ Still the most common mode of transmission worldwide Diagnosis: made by serology ○ Due to contact with high-risk individuals Virus can persist throughout life, hiding in leukocytes Babies born to HIV-infected mothers ○ CMV can also cause latent infection through different mechanisms MAJOR ROUTES OF TRANSMISSION CMV IN IMMUNOSUPPRESSED INDIVIDUALS 📋 Transmission occurs under conditions facilitating exchange of blood or body fluids containing virus or virus-infected cells May be a primary infection or reactivation of a latent infection ○ 3 major routes: sexual, parenteral, & mother-to-infant 💬 Used to be the most common opportunistic viral infection in AIDS transmission 💬 Occurs when the patient has very low CD4+ T-cell count Sexual Transmission Usually, it can present with a retinal infection ○ Dominant mode of transmission worldwide Can also be caused by solid-organ transplantation ○ Infect blood vessels or dendritic cells in mucosa Serious (even life-threatening) disseminated CMV infections in immunosuppressed people primarily affects the lungs ○ 💬 Transmission is enhanced by presence of other sexually transmitted diseases ( due to recruitment of leukocytes near areas (mucosal surfaces) where transmission occurs, (pneumonitis) and GI tract (colitis) ○ Pneumonitis which increases the chance of WBCs to come in contact with Interstitial mononuclear infiltrate with foci of necrosis HIV, thus spreading the virus throughout the body faster) Accompanied by typical enlarged cells with inclusions Parenteral Transmission – occurs in 3 groups of individuals: Can progress to full blown ARDS (acute respiratory ○ Intravenous drug users (sharing needles, etc.) ○ distress syndrome) Colitis ○ ○ 💬 Hemophiliacs who received factor VIII & IX concentrates Due to unsafe blood products Recipients of standard blood transfusion Extensive intestinal necrosis and ulceration Can present morphologically with pseudomembranes Mother-to-Infant Transmission 💬 💬 and severe diarrhea ○ Transplacental spread in utero Similar to Clostridium difficile infection ○ During delivery (via an infected birth canal) There may also be retinitis but that is already in persons with ○ After birth (via ingestion of breast milk) 💬 severe AIDS Other concerns regarding routes of transmission: Diagnosis: histopathologic ( biopsy and use special ○ NO transmission via insect bites immunohistochemistry tests to detect the virus in the tissues), ○ NO transmission via casual contact (i.e., kissing & touching) viral culture, serology, antigen detection, PCR ○ Needlestick injuries present smaller risk ○ Infected blood spillage on non-intact skin ETIOLOGY Non-transforming human retrovirus from the Lentivirus family 2 genetically different but related variants of HIV: ○ ○ 💬 HIV-1 – present in the US, Europe, & Central Africa Mostly worldwide HIV-2 – present in West Africa & India Spherical virion with cone-shaped core surrounded by a lipid envelope PATHOLOGY | VIRAL INFECTIONS | Bernabe, Catalan, Co, Farochilen, Favila, Reyes 5 of 12  ⭐ Contents of the virus core: ○ P24 – major capsid protein (most abundant, detected via PATHOGENESIS OF HIV INFECTION AND AIDS ELISA (immunologic test for HIV)) ○ p7/p9 – nucleocapsid protein HIV mainly targets the immune system & central nervous system ○ ○ 2 copies of RNA genome 3 enzymes (protease, reverse transcriptase, integrase) 📖 Profound immunodeficiency affecting cell-mediated immunity Hallmark of AIDS Infects CD4+ cells, macrophages, & dendritic cells upon entering 💬 Enzymes that are important in the virology of HIV Targets of anti-retroviral medications Viral core is surrounded by matrix protein (p17) that lies the mucosal tissues and the blood Infection becomes established in lymphoid tissues → where the underneath the virion envelope virus become latent for long periods gp120 & gp41 – 2 proteins on the viral envelope involved in ○ Active viral replication (exhaust the lymphocytes) → leads to infection development of AIDS LIFE CYCLE OF HIV INFECTION OF CELLS BY HIV Initial step: infect cells by the binding of gp120 to CD4 as a receptor Leads to conformational change in gp120 → allows binds to chemokine receptors (CCR5 or CXCR4) ○ CCR5 – more of macrophages/monocytes ○ CXCR4 – more of T-lymphocytes Binding to the coreceptors induce conformational change in gp41 → exposure of fusion peptide (hydrophobic region at the tip of gp41) ○ This allows the HIV to fuse with the target cell VIRAL REPLICATION Once internalized, virus undergoes reverse transcription wherein RNA genome creates complementary dsDNA (aka proviral DNA or cDNA) ○ cDNA is linear in quiescent T-cells Figure 6. Structure of the HIV Virion ○ Becomes circular and enters the nucleus, and integrates into (The viral particle is covered by a lipid bilayer derived from the host cell and studded with viral glycoproteins gp41 and gp120.) 💬 the host genome (in dividing T-cells) Since HIV is a RNA virus it uses reverse transcription to create dsDNA which it uses to hijack the host’s cell machinery to HIV-1 RNA genome has 3 genes: gag, pol, & env genes (typical of retroviruses) create more copies of itself ○ gag & pol – large precursor proteins cleaved by viral After integration, the virus may remain quiescent for years (a ○ protease Accessory genes (tat, rev, vif, nef, vpr, & vpu) 💬 form of latent infection) Once the patient gets infected they may feel illness for a while then they recover. But behind the scenes the immune system Regulates the synthesis & assembly of infectious viral particles and the pathogenicity of the virus is trying to contain the virus which leads to AIDS. ○ High variability in regions of envelope glycoproteins Active Replication Immune system evasion ○ Transcribing proviral DNA Major reason why the virus cannot be contained ○ Formation of complete viral particles budding from the cell easily by the immune system membrane ○ Extensive virus production and budding kills the infected cell ○ Repeated budding disrupts the cell membrane → destroys cell permeability → destruction of cells HIV has difficulty in infecting naïve (resting) T cells ○ Naïve T cells contain APOBEC3G enzyme ○ APOBEC3G Active form of an enzyme Induce mutations (cytosine to uracil) in viral DNA Apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G ○ Exact mechanism that prevents replication is not understood Latently infected T-cells become activated by antigens or cytokines ○ Leads to upregulation of transcription factors (NF-KB) ○ Leads to transcription of proviral DNA → production of virions → eventual cell lysis TNF & other cytokines from macrophages further stimulate NF-KB activity in T cells Figure 7. The HIV Genome ○ Further perpetuating the response (See Appendix A) Subdivisions of HIV: ○ Major (M) – common worldwide, divided into clades A to K Clade B – most common in US and Western Europe Clade E – common in Thailand Clade C – fastest spreading worldwide ○ Outlier (O) ○ Neither M nor O (designated as N) PATHOLOGY | VIRAL INFECTIONS | Bernabe, Catalan, Co, Farochilen, Favila, Reyes 6 of 12  HIV with bound antibodies localize to these cells and infect them B-CELL FUNCTION IN HIV INFECTION Polyclonal B-cell activation 💬 ○ Induces B cells to proliferate instead of depleting cells B cells produces many copies that are not identical to each other (in contrast to monoclonal where the cells are identical to each other) ○ Histologically, there is germinal center B-cell hyperplasia ○ Bone marrow plasmacytosis (increased plasma cells) ○ Hypergammaglobulinemia and circulating immune complexes ○ May result from multiple mechanisms: Can be due to reactivation of CMV or EBV Viral gp41 promotes B-cell growth & differentiation HIV-infected macrophages produce IL-6 → stimulates 💬 B- cell proliferation Despite the increase of numerous of B cells, plasma cells and antibodies, they are not effective and they don’t do anything Figure 8. Life Cycle of HIV useful. They are functionally defective and cannot mount (See Appendix B.) good and effective antibody responses. MECHANISM OF T-CELL DEPLETION IN HIV INFECTION PATHOGENESIS OF CNS INVOLVEMENT 📖 Loss of infected CD4+ T cells is mainly due to direct cytopathic Neurons are NOT infected. effects of the replicating virus ○ ~100 billion new virus particles are produced each day 📋 Microglial cells and macrophages are the ones that are infected ( especially by M-tropic strains). Neuropathologic changes are not as severe as expected from About 1-2 billion CD4+ cells die everyday ○ Initially, the body can replace them, but eventually get clinical symptoms. exhausted and gets depleted ○ Sometimes there may be severe neurologic manifestations, Virus kills cells via disruption of membrane (budding), or inhibit but, exactly in the brain, there aren’t many pathological protein synthesis changes. Other mechanisms that kill CD4+ cells: ○ Activation-induced cell death (via apoptosis), includes non- NATURAL HISTORY OF HIV INFECTION ○ infected CD4+ T cells Progressive destruction of architecture and composition of 📖 📖 Virus typically enters through mucosal epithelia Subsequent pathologic and clinical manifestations of infection lymphoid tissues are divided into 3 phases: ○ Loss of CD4 cell precursors (can either be direct infection or 1. Acute retroviral syndrome infection of accessory cells) 2. Middle, chronic phase (most are asymptomatic) ○ Fusion of infected and uninfected cells to form giant cells 3. Clinical AIDS (“full-blown AIDS”) ○ Qualitative CD4 defects → evidenced by loss of TH1 responses ○ Selective loss of memory CD4 T-cells PRIMARY INFECTION, VIRUS DISSEMINATION, AND ACUTE RETROVIRAL SYNDROME HIV INFECTION OF NON-T CELLS Mucosal infection → infection of memory CD4+ T cells Dendritic cells spread virus to lymph nodes → more CD4 cell Infection of macrophages & DCs is also important in the infection pathogenesis of HIV infection Viral replication in the lymph nodes → viremia and virus spreads Infected macrophages throughout the body and further spreading the infection elsewhere ○ vpr protein (vpr gene) allows HIV to infect terminally Antiviral humoral and cell-mediated immune responses: differentiated macrophages ○ Seroconversion (production of antibodies against the virus ○ Macrophages are a reservoir for the virus (because they are about 3–7 weeks after exposure); resistant to cytopathic effects despite lots of viral ○ Development of virus-specific CD8+ T cells to kill the infected replication) cells; and ○ May act as initial portals of infection (mostly in M-tropic ○ Drop to low viremia due to control by immune system strains) ○ This is what happens after you recover from the initial acute Uninfected macrophages can also have defects (that may have retroviral syndrome. You will feel well but, behind the scenes, important consequences for host defense): your body is working overnight to control the virus. ○ Impaired microbicidal activity Acute Retroviral Syndrome ○ Decreased chemotaxis ○ Occurs 3–6 weeks after infection ○ Decreased secretion of IL-1 ○ Resolves spontaneously in 2–4 weeks ○ Inappropriate TNF secretion ○ Sore throat, myalgia, fever, weight loss, fatigue (mild ○ Poor antigen-presenting capacity symptoms) - typical nonspecific/random illness 2 types of Dendritic Cells are also important targets for initiation ○ Not yet a “full-blown AIDS”; more flu-like illness at first & maintenance of HIV infection (mucosal & follicular DCs) HIV RNA levels – measure of viremia, used in initial management ○ Mucosal Dendritic Cells to see how effective the medication is Transport virus to the regional lymph nodes CDC classified 3 categories of HIV infection (based on CD4+ cell Have lectin-like receptors that presents HIV intact to counts and the clinical manifestations) - refer to Table 1 CD4 T-cell (thus promoting infection of T cells) ○ Follicular Dendritic Cells Found on the surfaces of their dendritic processes Have receptors for Fc portions of antibodies PATHOLOGY | VIRAL INFECTIONS | Bernabe, Catalan, Co, Farochilen, Favila, Reyes 7 of 12  INFECTIONS CDC CLASSIFICATION CATEGORIES OF HIV INFECTION Protozoal and Helminthic Infections Cryptosporidium or Cystoisospora (enteritis) Clinical Categories CD4+ T-Cell Categories Pneumocystis (pneumonia or disseminated infection) 1 2 3 Toxoplasma (pneumonia or CNS infection) ≥500 200–499 1 month), fatigue, weight loss, diarrhea, and Pneumocystis jirovecii Pneumonia (still controversial whether generalized lymph node enlargement fungal or parasitic; consensus right now is fungal) ○ Patient may look like a cancer patient because of severe ○ Occurs in 15–30% of untreated people cachexia. ○ Now lesser incidence/prevalence due to HAART Serious opportunistic infections, secondary neoplasms, and Candidiasis - most common fungal infection clinical neurologic disease (AKA AIDS-defining illnesses) may ○ Infection of the oral cavity, vagina, and, in severe cases, emerge esophagus AIDS develops after a chronic phase lasting 7–10 years without Cytomegalovirus infection treatment ○ Common in very low CD4+ T cell counts ○ But different variants of the virus may be rapid progressors ○ May cause disseminated disease, or may be limited to the (2–3 years) eye or GI tract ○ 7–10-year gap → long period of clinical latency where the ○ CMV chorioretinitis - occurs with CD4+ count < 50/μL virus is killing so many of your cells behind the scenes and ○ Esophagitis and colitis in 5–10% of cases your immune system is trying to catch up, but, once it gets Atypical mycobacterial infections exhausted, full-blown AIDS will develop ○ Usually due to Mycobacterium avium-intracellulare ○ ○ 📖 Long-term nonprogressors 5–15% of infected individuals Untreated individuals but remain asymptomatic (for >10 ○ Occurs late in the disease Tuberculosis ○ Causes 1/3 of deaths in HIV patients worldwide years) ○ Due to reactivation of latent infection ○ With stable CD4 counts & low viremia (