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Transcript
HIV/AIDS Nester 5th ed Chapter 29 The Origin of HIV HIV most likely came from monkeys • 1995 a virus was discovered that was genetically half way between HIV and SIV Evaluation of the rate of genetic change of HIV shows that common ancestor arose between 1915 & 1941 - most likely 1931. Beginnings - continued HIV-1 came from chimpanzees. HIV-1 group M is worldwide. • It has a single origin - one man or one chimp. HIV-1 in the US evolved between 1960 and 1971 - most likely 1967. Alerts us to dangers of cross-species transmission Beginnings - continued HIV-2 came from sooty mangabeys. Similar structure to HIV-1 Antigenically distinct > 55% of the genome differs from HIV-1 Found in West Africa and India Transmission less efficient Disease progression is slower. Beginnings 1981 in San Francisco 5 previously healthy homosexual men had unusual health problems • unusual opportunistic infections • certain tumors • immunodeficiency This clustering of cases of a new disease led to an amazing public health story HIV/AIDS Epidemic two decades after the onset The Virus Retroviridae • Lentiviruses • • • • • • SS RNA Ten HIV subtypes (a-j) in group M Found in many diverse species - e.g. horse Immunosuppressive disease Neurological disease Tumors HIV Structure Figure 29.3a Surface glycoprotein (SU) - gp120 Transmembrane glycoprotein (TM) - gp41 Matrix protein (MA) - p17 Capsid protein (CA) - p24 HIV Structure HLA from host cell membrane Lipid envelope - host plasma membrane Two strands of ss RNA Reverse transcriptase (RT) Protease (PR) Integrase (IN) HIV Genome Figure 29.3b LTRs -host cells recognize long terminal repeats gag gene - yields MA, CA, NC pol gene - yields PR, RT, IN env gene - yields gp120 and gp41 Group antigen polymerase HIV Genome Figure 29.3c gag & pol transcript is cleaved by a viral protease • gag and pol split into 3 enzymes - PR, RT, IN • gag is split into p24, p17 and other proteins env- translated from a spliced mRNA • precursor processed by host protease HIV Genome Accessory genes - translated from spliced mRNA’s • Interact in different ways with host cell substances • Varies with cell type infected • HIV with defective nef might be a vaccine • tat might be a factor in Kaposi’s sarcoma • Vpr might be used to stop growth of tumor cells The Term AIDS Acquired immunodeficiency syndrome Term used first in 1982 by the CDC Used to define diseases that predict that someone would have low resistance to disease More than one immunodeficiency disease HIV disease caused by HIV is just one Symptoms of HIV Infection Incubation period is 6 days to 6 weeks The acute disease lasts about 6 weeks Most cases are asymptomatic Some cases are “flu-like and not severe • Often these mild symptoms are ignored Symptoms of HIV Infection Some cases have • Fever, headache, sore throat, muscle aches, enlarged lymph nodes, and a generalized rash • CNS disturbances like moodiness, confusion, seizures, paralysis and encephalitis Asymptomatic period follows • Usually lasts years Transmission can occur all during this time Symptoms of HIV Infection PGL - persistent (or chronic) glandular lymphadenopathy • Can lasts from acute disease through AIDS LAV - lymphadenopathy syndrome • Occurs at the end of the asymptomatic period Symptoms of HIV Infection ARC - AIDS related complex • Characterized by less severe opportunistic infections AIDS - severe immunodeficiency Table 29.1- AIDS defining conditions Pathogenesis Figure 29.4 • Intestinal epithelium • Brain cells • Dendritic and other APC’s (antigen presenting cells) • CD4 (T-helper) lymphocytes • CD8 (T-cytotoxic) lymphocytes • CD4+ macrophages Impairment of chemotaxis, phagocytosis and antigen presentation Cytokines of TH regulate cytotoxic action of Tc cells, immunoglobulin production HIV cellular targets Pathogenesis Cells with CD4+ markers • • • • • Helper T-lymphocytes Monocytes Tissue macrophages Dendritic cells of lymph nodes B-lymphocytes (especially if infected with EBV) Pathogenesis Cells without CD4+ markers • • • • • • • Epithelial cells of intestine and vagina Neurons Astrocytes Oligodendroglia Microglia Bone marrow stem cells Capillary endothelial cells Pathogenesis Virus replication • Attachment - Figure 29.5 Receptor on cell • Ligand on virus • Co-receptors - cytokine receptors – CCR5 on macrophages – CXCR-4 on T-lymphocytes • Penetration • Uncoating Attachment and entry of HIV into a host Steps in HIV replication Pathogenesis Virus replication - Figure 29.6 • RT makes a ds DNA from RNA in cytoplasm • Circularizes and integrates randomly - provirus • Spliced mRNA segments - from tat, rev, and nef genes • New genome RNA is made • Synthesis of structural components • Assembly and release by budding Pathogenesis HIV variability • • • • • • High rate of error of the RT Two genome pieces - RT can transcribe both Some regions of genes are conserved Some regions are variable Some variants infect some cells better Some variants replicate faster or slower Surface glycoprotein gp120 Pathogenesis Destruction of cells by HIV • • • • • • • Virally induces cell lysis Attack by HIV specific CD8+ cells Natural killer cells ADCC Autoimmunity Fusion of infected and uninfected cells Apoptosis Pathogenesis Clinical features • See graph - in notes and book Figure29.8 • Immune system slowly fails • CD4+ cell counts used for prognosis • Normal 1000/microliter • < 200/microliter - symptoms of AIDS Natural history of HIV Pathogenesis Atypical case • People with virus levels that don’t fall • 10% cases • AIDS in a few years • People with a good immune response • 5% to 10% • Progress more slowly • Some will still be free of AIDS 20 years later Epidemiology - Global >33,400,000 cases worldwide Most cases in developing countries Africa - 67% Asia - 22% South America and Caribbean - 5% North America - 2.7% Europe - 1.5% Epidemiology - Global Global death toll 16.3 million #1 killer in Africa even passing malaria By the end of 2000, 10.4 million children under 15 will be orphans. India is fast becoming the single country with the most HIV cases. A new case occurs every 6 seconds Epidemiology - U.S. Number of cases - 890,000 Number of deaths - 420,000 30,000 new cases each year Epidemiology - U.S. Women - increase is alarming - Figure 29.9 Women who have sex with bisexual men or IV drug abusers > 80,000 HIV (+) women may leave 150,000 children In the United States rising percentage of AIDS cases in women Epidemiology - U.S. Women – Cont. 1/10 HIV (+) women will miscarry Live births 15-40% get AIDS unless mother is treated 3% of babies may clear infection w/out treatment Epidemiology – U.S. Age at Diagnosis Number of Cases 30000 25000 20000 15000 10000 5000 0 0 25 30 35 40 45 50 70 Epidemiology - U.S. State or Territory Rate per 100,000 Washington, D.C. 182 Puerto Rico 71 New York 68 Florida 58 New Jersey 56 Epidemiology - U.S. State or Territory Rate per 100,000 Wyoming 3.9 Montana 2.9 South Dakota 2.6 North Dakota 0.8 Epidemiology - U.S. Type of Transmission Injecting drug user Heterosexual transmission Sex with injecting drug user Sex with men of other risk Other/undetermined Transfusion recipient % 45 39 21 18 12 4 Transmission Blood • Drug addicts who share needles • Hemophiliacs who got Factor VIII pre-1985 • Post surgery patients pre-1985 Sexual • Homosexual and bisexual men • Heterosexual • HIV (+) mother (or risky behavior) to child Transmission Body fluids where HIV is found • • • • • • • Blood Semen Vaginal and cervical secretions Urine Feces Mother’s milk Saliva*, tears, sweat Transmission HIV is not spread by: • • • • • • • Touch or hugs Swimming in a chlorinated pool Food Sharing dishwasher, washing machine Giving blood or doing blood tests Bathrooms* Mosquitoes Transmission HIV’s environmental and chemical inactivation • HIV persists for a week in plasma removed from a patient • HIV is hard to inactivate in dried pus or blood • HIV is susceptible to high level disinfectants • HIV is susceptible to >= 560 C (1320 F) • For 30 minutes Prevention Office disinfection procedures • 10% bleach • Really the best but has draw backs • Should be used on any surface that won’t be harmed by repeated use of bleach. • Should be made up before each use. • Works better if warm water is used to make up the solution Prevention Office disinfection procedures • High level disinfectants destroy all viruses • Can be used on almost any surface • Fumes may be less bothersome than bleach • Need to read each container for proper mixing instructions • Need to check toxicity Prevention - Table 29.3 Abstinence from any risky behavior Reduce sex partners - know partners well Use latex barriers and water soluble lubricants Newer polyvinyl barriers are OK Treat HIV (+) persons with anti-viral drugs Prevention - Table 29.3 Expand all forms of education to all age groups • Persons older than 50 were not being informed • Persons >= 50 account for 15% of new cases in NY Don’t expose vagina, penis, anus or mouth to semen, blood, menstrual blood, vaginal secretions, urine or feces Prevention Perinatal transmission • Diagnosis and treatment of STD’s • Prenatal care and anti-viral therapy • Non-invasive pre and intrapartum care to reduce blood exposures • Mild anti-septic wash of vagina and newborn • minimize delivery time after membrane rupture • C-section if necessary Prevention Vaccines • Could be used in two ways • To immunize uninfected people • To boost immunity of HIV (+) individuals before their immune system is destroyed • Best hope of understanding natural clearance • African prostitutes with no disease • Newborns that clear the virus Prevention Vaccines must: • Induce IgA as well as IgG but no enhancing antibodies. • Stimulate cell mediated. • Get around HIV antigenic variability - use antigens that are stable. • Be safe - no reversion, no induction of tumors, no autoimmune disease, etc. Prevention Vaccines in phase I • Component vaccines • • • • Purified gp120 and gp160 Synthetic surface proteins Synthetic lipopeptide Naked DNA containing env genes Prevention Vaccines in phase I • Viral vaccines • Vaccinia + gag and env grown in cell culture – virus-like particles form with surface antigens of HIV • Canary pox virus with HIV env genes for surface antigen • Vaccinia + HIV env genes for surface antigens Prevention Vaccines in Phase III • Only gp120 vaccines • Thailand - gp120 from two HIV strains • North America - gp120 from two HIV strains • Two subtype B strains Tumors Kaposi’s sarcoma Lymphomas Carcinomas of anal or cervical epithelium Kaposi’s Sarcoma Malignant tumor of the endothelium of blood and lymphatic vessels • Rare tumor in elderly men of Mediterranean or Eastern European origin • In all ages of certain parts of tropical Africa • Tumor regresses if a women becomes pregnant • HHV-8 found in Kaposi’s tumors - ????? Kaposi’s sarcoma Lymphomas Usually B-cell tumors Can be T-cell tumors In 5-10 % of HIV patients EBV may be a cofactor • Burkitt’s lymphoma - 1000X more than in general public Hairy leukoplakia activation of latent Epstein-Barr virus infection Lymphomas of the Brain Usually rare • 25% of AIDS patients have them • EBV found in these tumors Cervical and Anal Carcinoma Associated with HPV types 16 and 18 HIV lowers immunity to these viruses are not kept in check A woman should be checked regularly for cervical cancer if she is HIV(+) Women and homosexual men should be checked regularly for anal cancer Opportunistic Infections Pneumocystosis Toxoplasmosis Cytomegalovirus disease Mycobacterial diseases Pneumocystis carinii Tiny fungus that causes severe lung disease Slow onset, shortness of breath, rapid breathing, dusky appearance 1-3 micrometer spores - inhaled, attach to alveolar sac walls, alveoli fill with fluid and mononuclear cells, alveolar wall thicken and scar, oxygen exchange is reduced Pentamidine Toxoplasma gondii Protozoan that causes toxoplasmosis 10% of healthy, exposed adults get sick Disease is like “infectious mono” Congenital disease is very severe • Disease of mother involves fetus - 50% • Most cases occur in last trimester • Retinitis, mental retardation, epilepsy Cytomegalovirus HHV-5 is latent in glands and kidneys Cytomegalic inclusion disease Congenital cytomegalo virus disease • hearing loss, mental retardation • congenital CMV in 1% of live births Probably an STD Severe disease in the immunocompromised Mycobacterial Infections Mycobacterium tuberculosis Mycobacterium avium complex (MAC) • avium and intracellulare • species that do not usually cause severe disease in people Mycobacterial Infections Elderly with chronic lung disease • chronic cough, productive sputum Children • chronically enlarged lymph nodes Immunocompromised • cough, sputum, sweats, weight loss, diarrhea Factors in Long Term Survival Strong CD8+ anti-viral response Relatively non-virulent virus strain Low amount of virus in plasma and PBMC No immunological decline Non-progressors represent 5% of the total HIV infected population Structure & function of lymph node is good Factors in Faster Progression of AIDS MHC (HLA) type Age - young, old Viruses • • • • EBV, CMV, HSV-1, HHV-6 Adenoviruses HBV HTLV 1 & 2 Factors in Progression of HIV Infection Genetic factors like CCR5 and CXCR4 Chemokine receptor gene CCR5 • Homozygous wild type – normal progression • Heterozygous wild type/32bp deletion - delayed progression • Homozygous 32bp deletion - delayed progression • Deletion is found in Europeans - not sure why Factors in Faster Progression of AIDS Clinical • • • • Symptomatic Duration >14 days Neurological involvement Acquisition of HIV from an index case with late-stage HIV-1 disease Factors in Faster Progression of AIDS Virologic • Infection with SI viral strain • Persistent p24 antigenemia • Higher HIV RNA viremia following seroconversion Re-infection with HIV Doctors in Ottawa, Canada document a case of re-infection of a HIV (+) patient with a different strain of HIV. The patient had sex with another HIV (+) patient and picked up a new virulent strain.. Therapy stopped working. Person got progressively worse Re-infection with HIV The patient’s virus level increased without explanation. His immune system got weaker suddenly. This confirms what doctors have long suspected. Myth: two HIV(+) people having sex will not acquire each other’s virus. Factors in Faster Progression of AIDS Immunologic • Low antibody titer to p24 • High antibody titer to gp120 • Presence of specific anti-HIV-1 IgM and IgA after infection • Immunodeficiency at the time of infection • Persistently low CD4+ cell count Neurological abnormalities Abnormalities seen in 60% of AIDS patients Early • Acute encephalitis • Acute meningitis Late • HIV dementia • Vacuolar myelopathy Neurological abnormalities Continued • Chronic meningitis • Inflammatory demyelinating polyneuropathy • Distal sensory neuropathy • Stocking-glove impairment • Myopathy • Mononeuropathy multiplex Neurological abnormalities Seen in 90% at autopsy of AIDS patients Pathology • • • • • • • Gliosis of cerebral sub-cortical nuclei Focal necrosis of white and gray matter Perivascular inflammation Enlargement of oligodendrocyte nuclei Microglial nodules Multinucleated giant cells - CPE Demyelination of white matter AIDS Dementia Stage 0 - normal Stage 0.5 - sub-clinical or equivocal • Minimal or mild • No impairment of work or daily activities Stage 1 - mild • Unequivocal intellectual or motor impairment • Able to do all but the most demanding work AIDS Dementia Stage 2 - moderate • Cannot work or perform demanding tasks • Capable of self care • Ambulatory but may need one prop Stage 3 - severe • Major intellectual disability • Cannot walk unassisted AIDS Dementia Stage 4 - end stage • Nearly vegetative • Rudimentary cognition • Para- or quadriplegic HIV - AIDS Testing Culture in PBMC’s Antibody detection • ELISA • Western blot • PCR • RT or p24 • HIV Ab or p24 • HIV Ab or ds DNA • Transcribed DNA Treatment - Antiviral Compounds Nucleoside RT inhibitors • Chain terminators • Zidovudine (AZT) Tat antagonists • Inhibit the Tat gene which stimulates transcription of HIV Treatment - Antiviral Compounds Non-nucleoside RT inhibitors • Bind to the enzyme active site • HIV-1 only Protease inhibitors • Block maturation Guidelines for Treatment HAART • “Highly active antiretroviral therapy” • Cocktail of antiviral drugs • Each component hits a separate step in the virus replication cycle • Multiple drugs used at once helps prevent resistance Guidelines for Treatment Adult patients in earliest stages of disease • • • • • One HIV protease inhibitor Two nucleoside analog inhibitors of RT DO NOT use one drug at a time Monitor regularly for virus and CD4+ levels Change two drugs as soon as treatment appears to be failing Guidelines for Treatment Treatment should be aggressive • Goal is to reduce virus to undetectable levels These “cocktails” are expensive • About $15,000 a year Patients in more advanced disease • Three drug “cocktails” • Avoid any drug previously used in this patient Guidelines for Treatment For pregnant women • Zidovudine reduces transmission from mother to child with the following regimen • Newborn cases now down to 500 per year • • • • Begin treatment at 14-34 weeks gestation Continue throughout the pregnancy Step up IV doses during delivery Treat newborn within 12 hours and for 6 weeks Immune Based Therapies Improve immunity for prevention of opportunistic infections • • • • Passive immunization Active immunization Cytokines Cytokine antagonists