Retroviruses Notes

Chapter 2 Acyanotic Defects NOTES RETROVIRUSES MICROBE OVERVIEW ▪ RNA viruses ▫ Require DNA generation, integration into host DNA → produce viral progeny ▪ Large viral family ▫ Seven genera ▪ Target cells determined by viral glycoprotein spikes on cell membrane → recognized cell surface receptors, coreceptors → viral entry → provirus creation ▫ Viral reverse transcriptase takes singlestranded viral RNA genome → creates linear, double-stranded DNA virus → provirus ▪ Provirus integration (via integrase) into host-cell DNA → viral particle production ▫ Integration stability of provirus, transmission to host-cell progeny determines retroviral infection persistence in host organism Morphology ▪ Lipid-enveloped particles 80–100nm diameter ▪ Protein core ▫ Two linear, ⊕-sense, single-stranded RNA genomes (7–11 kb) ▫ Enzymes (gene locus) needed for viral replication (protease—pol gene, p10 locus; reverse transcriptase—pol gene, p66 locus; integrase—pol gene, p32 locus) TYPES Human endogenous retroviruses ▪ Proviral DNA/partial genomic sequences integrated into host-genome ▪ Constitutes up to 8% of human DNA ▪ Vertical transmission via germline cells ▪ Translated DNA does not lead to infectious viruses; may → functional proteins Human exogenous retroviruses ▪ Passed horizontally via exposure to blood, sexual secretions, breast milk HUMAN IMMUNOFEDICIENCY VIRUS osms.it/HIV-(AIDS) PATHOLOGY & CAUSES ▪ HIV: human immunodeficiency virus ▪ Member disease of Lentivirus genus of Retroviridae family ▫ Characterized by immune cell targeting, immunodeficiency Two pathogenicity targets ▪ Immune system ▫ Mucosal HIV virion infiltration → bloodstream spread → infection of T cells, dendritic cells, macrophages → latency (may be chronic, indolent) → active replication → symptom progression/emergence → further replication→ severe OSMOSIS.ORG 501

immunocompromise, progression to AIDS (acquired immune deficiency syndrome) ▫ HIV infection → targeting, infection of CD4+ cells (e.g. CD4+ T-lymphocytes, monocytes, macrophage) → replication, spread → ↓ CD4+ cells → immunodeficiency ▫ Co-receptor CCR5 important in early infection; persistence ▪ Central nervous system (CNS) ▫ HIV infection → macrophage/microglia infection → abnormal CNS cytokine milieu → neuronal cell death Structure ▪ 110nm diameter spherical virion ▪ Core surrounded by lipid bilayer envelope ▪ Lipid envelope ▫ External glycoprotein gp-120, anchored by gp-41 ▫ Binding sites for host-cell CD4+ receptor (co-receptors—chemokine receptors; especially CCR5, CXCR4) ▪ Core ▫ Two single-stranded RNA copies ▫ Two transfer RNA primers (host-cell origin) ▫ Multiple enzyme copies: reversetranscriptase (RT), integrase, ribonuclease H (RNAse H) ▫ Other proteins: vpr, vif, nef (important in early virion life-cycle) Genome ▪ 9kb ▪ Similar to other retroviruses (six genes—tat, rev, vpr, vpu, vif, nef) ▫ HIV-2 specific: Vpx gene (homologous to gene in simian immunodeficiency virus (SIV); not present in other lentiviruses) Life cycle ▪ Cell contact, fusion: gp-120, CD4+ receptor fusion → gp-120 conformational change → opened gp-120 recognition site → gp-120 binding to host-cell co-receptor (CCR5/CXCR4) → gp-41 conformational change → gp-41 hydrophobic domain exposed → virion lipid bilayer insertion into cell membrane → virus-host-cell membrane 502 OSMOSIS.ORG fusion → viral entry ▪ Viral genome replication: viral RNA transcribed by viral RT in host-cell cytoplasm → HIV provirus production (double-stranded complementary DNA transcript) → transport to nucleus → integrase insertion in cell DNA → viral DNA transcription → viral RNA, protein ▫ Host-cell activation (naive T cells) important factor in determining active vs. latent HIV replication ▫ Antigen/cytokine-mediated T cell activation → NF-KB (nuclear transcription factor) cell stress activation → ↑ NF-KB promoter-associated gene transcription (in HIV proviral DNA) → ↑ viral replication → viral RNA, protein aggregation in cytoplasm → viral protein cleavage (e.g. gag) → viral content assembly → ↑ virion production (↑↑ virion budding → cell death) ▪ Host-cell death: ↑ virion budding → ↑ host-cell plasma membrane permeability; ↑ viral replication → native protein synthesis interference → dysregulated cellular protein concentrations → cell death ▫ Non-cytopathic host-cell HIV infection: HIV infection → inflammasome pathway activation → pyroptosis (inflammatory cytokine, cellular content release) → immune cell recruitment → viral spread (likely plays large role in HIV infection spread) Transmission ▪ HIV-1, HIV-2 ▪ Three transmission modes ▫ Sexual: USA—biologically-male individuals engaging in same-sex sexual contact (MSM) particularly important transmission mode (highest disease incidence → homosexual biologicallymale individuals); global—majority of sexual transmission via heterosexual intercourse; co-existent sexuallytransmitted disease (genital ulceration especially) → ↑ transmission risk during intercourse ▫ Parenteral: non-iatrogenic, intravenous (IV) drug users (shared needles, syringes, other paraphernalia contaminated with HIV ⊕ blood); iatrogenic (hemophiliacs who received

Chapter 93 Retroviruses HIV-contaminated factor VII, IX concentrates; HIV-contaminated blood transfusion recipients; health personnel—e.g. needle-stick injuries) ▫ Vertical, mother-to-infant: in utero, transplacental spread; infected birth canal → delivery → neonatal infection; neonatal HIV ⊕ breast milk ingestion ▪ HIV-2 only ▫ Believed to be zoonosis resulting from SIV cross-speciation infection ▫ Endemic areas correlate with those of sooty mangabey ▫ Less transmissible than HIV-1 Disease ▪ Acute retroviral syndrome ▪ AIDS AIDS ▪ Persistent fever (> one week); fatigue; weight loss; diarrhea; generalized lymphadenopathy (LAD); serious, opportunistic infection ▪ Secondary neoplasms ▪ Neuropsychiatric disease ▫ Delirium; major depression; mania; schizophrenia; post traumatic stress disorder; substance abuse, addiction (commonly HIV infection risk factor) ▫ Dementia (AKA AIDS dementia complex): cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, cerebral toxoplasmosis, cryptococcal meningitis, CNS lymphoma TYPES ▪ Likely related to SIV ▪ Two human virus types ▫ HIV-1, HIV-2 RISK FACTORS ▪ West Africa residence (HIV-2), homosexual/ bisexual biologically-male individuals (USA), IV drug users, hemophiliacs, blood (or component) transfusion recipients, maternal HIV infection COMPLICATIONS ▪ Opportunistic infections, secondary malignancies, AIDS, neuropsychiatric disease Figure 93.1 An esophaeal biopsy composed of squamous mucosa with candida hyphae. Esophageal candidiasis is a common opportunitic infection in individual with AIDS. SIGNS & SYMPTOMS Acute retroviral syndrome ▪ Self-resolving, flu-like syndrome; sore throat; myalgias; fever; weight loss; fatigue Chronic infection ▪ Variable ▫ Asymptomatic → minor infection ▫ Oral/vaginal candidiasis, herpes zoster, mycobacterial tuberculosis (especially Sub-Saharan Africa) Figure 93.2 The histological appearance of mycobacterium avium intracellulare. There are numerous organisms within the cell cytoplasm. OSMOSIS.ORG 503

504 OSMOSIS.ORG

Chapter 93 Retroviruses OSMOSIS.ORG 505

DIAGNOSIS TREATMENT LAB RESULTS MEDICATIONS Serology: enzyme-linked immunoassay (ELISA) ▪ IgG, IgM, p24 antibody testing ▫ Time to positivity: 15–45 days (P24 (viral core protein) earliest positive marker) ▫ May be combined for HIV-1, HIV-2, p24 immunoassay in diagnostic, screening purposes Highly active antiretroviral therapy (HAART) ▪ Antiretroviral drug combination regimen ▫ Early initiation → ↓ morbidity, ↓ mortality, ↓ transmission risk (regardless of CD4+ count) ▪ Six distinct drug classes ▫ Combination of three drug types used for effective viral load management, combat particular drug class resistance development ▪ Protease inhibitor preferred initial agent ▫ Resistance testing results → narrow therapy ▪ Complications ▫ Immune reconstitution inflammatory syndrome ▫ ↓ in clinical state (symptom return experienced during active viremic phase), despite ↑ CD4+ levels ▫ Believed to be due to reinvigorated host response to high antigenic burden of persistent microbes, remaining viral load ▪ ⊕ Viral RNA level test (> 100,000 copies/ mL) ▫ May be used in indeterminate HIV-1/ HIV-2/ p24 immunoassay ▪ Leukopenia ▫ ↓↓ CD4+ count ▫ CD4+:CD8 ratio < 1 OTHER DIAGNOSTICS ▪ ▪ ▪ ▪ 506 OSMOSIS.ORG Flu-like illness Opportunistic infection Needlestick injury with HIV ⊕ individual Unprotected sex with partner of unknown/ HIV ⊕ status Pre-exposure prophylaxis ▪ Daily tenofovir use can very effectively ↓ transmission

Chapter 93 Retroviruses OSMOSIS.ORG 507

OTHER INTERVENTIONS Monitoring ▪ HIV RNA testing two, four, eight weeks after ART initiation ▫ Continue testing every two weeks until levels below detection limits ▫ Drug resistance testing at 24 weeks if ↑ in RNA viral level/no ↓ in RNA levels ▪ Once viral suppression achieved → repeat testing for RNA levels 3–6 months Screening ▪ One-time for individuals 13–75 years old ▪ Pregnant individuals (even in negative prior pregnancy screening) ▪ Annual/more frequent for high-risk individuals ▫ MSM (USA) ▫ IV drug users ▫ Sex partners of HIV unknown status, HIV ⊕, bisexual, individuals who inject drugs ▪ Blood factor screening ▫ Plasma/recombinant factor hemophiliac recipients 508 OSMOSIS.ORG Opportunistic infection prophylaxis ▪ Determined by CD4+ count ▪ Situational avoidance advised (e.g. cat litter, Toxoplasma exposure) Pre-exposure prophylaxis ▪ Indications ▫ High-risk sexual behavior/drug use ▫ Reliable individual to adhere to daily medication regimen

Chapter 93 Retroviruses HUMAN T-LYMPHOTROPIC VIRUS osms.it/human_t-lymphotropic_virus PATHOLOGY & CAUSES ▪ Oncogenic retrovirus endemic to certain areas of world → T cell leukemia/lymphoma ▫ AKA HTLV-1 ▫ Genus: Deltaretrovirus ▪ Structure ▫ Enveloped, single-stranded RNA virus ▫ Only human pathogen of oncovirus subfamily ▪ Genome ▫ Contains retrovirus-consistent gag, pol, env, long terminal repeat (LTR) ▫ HTLV-1 specific: tax; encodes protein essential for viral replication; viral RNA transcription stimulation from 5’ LTR ▪ Transmission ▫ Usually via infected T cells (vs. virion particle) ▫ Breastmilk, sexual transmission, blood transfusion, tissue donation, IV drug use, zoonotic transmission (nonhuman primate source) ▪ Disease ▫ Adult T cell leukemia/lymphoma ▫ Myelopathy/tropical spastic paraparesis Targets CD4+ cells ▪ Unlike HIV life cycle, pathogenesis; largely unknown targeting, infection, replication mechanisms ▫ Tumor initiating cell appear to be CD4+ memory T cell with stem-cell-like properties ▪ Distinct from HIV ▫ HTLV-1 → proliferation of T cell population rather than killing of cells ▪ Integrated provirus → mitotic cell division → host cell replication ▫ Low replication rate ▫ Host cell DNA polymerase ensure high transcription fidelity (HTLV-1 genetically stable) Tax-specific oncogenic hallmarks ▪ Inr pro-growth signaling, cell survival ▫ Stimulates AKT (via PI3K), NF-KB, cyclin D2, ↓ CDK inhibitors → ↑ prosurvival, cell growth → polyclonal T cell expansion ▪ Inc genomic instability ▫ Interference with DNA-repair function ▫ Inhibition of cell cycle checkpoints (activated by DNA damage) RISK FACTORS ▪ Travel/residence in Japan, Caribbean basin, South America, Africa ▫ Sporadic incidence in USA COMPLICATIONS ▪ Mycosis fungoides ▫ Cutaneous T cell leukemia/lymphoma manifestation ▪ Uveitis ▪ Gastric cancer Rheumatologic, pulmonary disorders ▪ Chronic inflammatory arthropathy ▫ Shoulder, wrists, knees ▪ Sjögren syndrome ▪ Immune thrombocytopenia Infectious replication ▪ Integrated provirus re-expression → intracellular virion OSMOSIS.ORG 509

SIGNS & SYMPTOMS Adult T cell lymphotropic leukemia/lymphoma ▪ Skin lesions ▪ Generalized lymphadenopathy ▪ Hepatosplenomegaly Myelopathy/spastic paraparesis ▪ Insidious-onset lower extremity weakness, spasticity ▪ Hyperreflexia, ankle clonus present ▪ ⊕ extensor plantar responses ▪ Lumbar pain ▪ Others ▫ Back pain ▫ Detrusor instability → nocturia, urinary frequency, incontinence ▫ Minor sensory change: paresthesias, ↓ vibrational sense DIAGNOSIS DIAGNOSTIC IMAGING ▪ Lytic bone lesions MRI ▪ Tropical spastic paraparesis ▫ Cervical/thoracic cord atrophy ▫ Spinal cord white matter disease LAB RESULTS ▪ Leukopenia ▪ Hypercalcemia ▪ Histology is variable, with characteristic circulating tumor cells ▫ Medium-sized lymphocytes with condensed chromatin, bizarre hyperlobated nuclei (AKA clover leaf/ flower cells) 510 OSMOSIS.ORG ▪ ELISA ▫ Antibody against HTLV-1 virus detection ▪ Western blot ▫ Confirmatory testing for ELISA ▪ Polymerase chain reaction (PCR) ▫ Available for HTLV-1 ▫ Useful with ↑↑ suspicion (ELISA negative) ▪ Flow cytometry ▫ ↑ FoxP3 expression in leukocytes (↑ regulatory T cell-indicative) ▫ Otherwise immunophenotypically mature T lymphocytes OTHER DIAGNOSTICS ▪ Travel/residence in endemic area TREATMENT ▪ No therapy proven to benefit affected individuals MEDICATIONS ▪ Corticosteroid therapy may slow disease course ▪ Antiviral therapy ▫ NRTI zidovudine, IFN-alpha proven beneficial OTHER INTERVENTIONS Prevention ▪ Endemic area-avoidance when breastfeeding ▪ Blood donor screening ▪ Safe-sex practices ▪ Discourage needle sharing