M34+HIV+and+AIDS_BAKSHI.pdf

Microbiology Lecture # 34HIV and AIDS in Compromised Patients Chandra Shekhar Bakshi, DVM, Ph.D.Professor of Pathology, Microbiology and ImmunologyNew York Medical [email protected] DisclosureI have no conflicts of interest to disclose for this course Learning Objectives•Introduction...

Microbiology Lecture # 34HIV and AIDS in Compromised Patients Chandra Shekhar Bakshi, DVM, Ph.D.Professor of Pathology, Microbiology and ImmunologyNew York Medical [email protected] DisclosureI have no conflicts of interest to disclose for this course Learning Objectives•Introduction to Retroviruses, HIV and AIDS•Virology and basic pathophysiology•Epidemiology •Clinical syndrome•Diagnosis•Tre at me nt , pro phylax is and co nt ro l The Central DogmaRetroviruses violate the Central Dogma David Baltimore and Howard Temin Simultaneously discovered Reverse Transcriptase (1975 Nobel Prize in Medicine or Physiology)David BaltimoreHoward Temin Retroviruses•ThefirstretrovirusisolatedwasRousSarcomaVirusofchicken•Thecancercausingretroviruses(oncornaviruseswerethensubsequentlyisolated)•Theoncovirusesaltercellulargrowthbyexpressinganaloguesofcell-growthcontrollinggenes-Oncogenes•RobertGalloetal.,isolatedthefirstretroviruscausingdiseaseinhumansin1981.(isolatedhumanT-celllymphotropicvirus1(HTLV-1) Retroviruses•UnusualnumbersofyoungHomosexualmen,Haitians,HeroinaddictsandHemophiliacs(4Hclub)werenotedtobedyingofnormallybenignopportunisticinfections.•TheirsymptomsweredesignatedasAcquiredImmunodeficiencySyndrome(AIDS)•HIVhavebeenacquiredbyhumansfromchimpanzeesandthenrapidlyspreadthroughhumanpopulationinAfrica French scientists reported that they have isolated a new virus which may cause AIDSScience (1983) May 20Scientists at NIH reported that they have isolated a retrovirus related to Human T-cell Leukemia Virus in AIDS patientsFrench scientist Luc Montagnierand Robert GalloAnd the Band Played On (Movie) Classification of RetrovirusesCytopathic RetrorvirusesTu m or-Forming VirusesHuman Immunodeficiency Viruses (HIV 1 and HIV 2) Human T-LymphotropicViruses (Types 1, 2 and 5)-HTLV 1 = Adult Acute T-cell Lymphocytic Leukemia-HTLV 2 = Atypical Hairy Cell Leukemia-HTLV 5 = Malignant CuteneousLymphoma THE BIOLOGY OF HIV, SIV, AND OTHER LENTIVIRUSES: Harrington and SwanstromClassification of Retroviruses HIV-1 HIV-2 Group MGroup PGroup NGroup O AKHGFBDCCRFsM= Main Group: Cause 99% of HIV-1 infections (B and C are most common in the USA)O= Outlier: Less than 1% infections in Africa (Cameroon and neighboring countries)N= RareP= Rare HIV Diversity8 Distinct Lineages Origins of HIV Viruses Paul M. Sharp, and Beatrice H. Hahn Cold Spring HarbPerspectMed 2011;1:a006841 HIVHIV -1HIV-2•Originated from Chimpanzees•Found worldwide and more common•Disease progression is very rapid•During progression HIV-1 has lower CD4 counts than HIV-2•Higher circulating viral load•Four major groups M, N, O and P•99% of HIV-1 cases involve Group M. Group B is more common in Japan, the Americas, Europe and Australia•Originated from Sooty Mangabeys•Found predominantly in West Africa and Europe (Portugal)•Disease progression is slow (longer asymptomatic period)•During progression the CD4 counts are higher•Circulating viral loads are lower •Enveloped spherical viruses•Contain two identical RNA strands, RNA Polymerase, integrase, and two tRNAbase-paired to the genome within the protein core•Envelope spikes are the Glycoproteins: •Gp120:Attachment protein•Gp41: Fusion proteinStructure Genomic Structure of Retroviruses-HIV HIV Virus Stability and TransmissionHIV is inactivated by:•Heat (Autoclaving, hot air oven)•2% Glutaraldehyde•Domestic bleachHIV Virus can survive:•Up to 15 days at room temperature•10-15 days at 370C•600C for several hours Co-receptors for HIVTime course of a typical HIV-1 infection with the appearance of host range variants Ronald Swanstrom, and John Coffin Cold Spring HarbPerspectMed 2012;2:a007443R5-Memory T-cell Tropic-Macrophage TropicX4 T-Cell Tropic The population of cells targeted by R5 HIV initiating the infection are Memory T-cells. These cells have a high expression of CD4 as well as CCR5 receptors. Since the circulating CD4 T-helper cells are not targeted by R5 virus, there is an equilibrium between the viral load and CD4 T-helper cells that results in a period of clinical latency.Later R5 virus changes its tropism because of the mutations in glycoproteinsand targets CD4 T-helper cells by recognizing CD4 and CXCR4 (X4) receptors. This virus is called as X4 or T-cell tropic virus. The T-tropic virus attacks and kills the CD4 T-helper cells, and thus there is a drastic reduction in the number of circulating T-cells which results in AIDs..Simultaneously, another variant of R5 virus evolves, which now can target macrophages. (R5 Macrophage-tropic)However, macrophages have low expression of CD4 receptors but also express CCR5 receptor. Thus, during AIDs the circulating virus can target:1. Memory T-cells (CD4HighCXCR5High): R5 T-cell tropic virus that initiates the infection2. CD4 T-helper cells (CD4HighCXCR4High): X4 T-cell tropic variant that is evolved during the period of clinical latency3. Macrophage-tropic virus (CD4LowCCR5High): R5 Macrophage-tropic Variant that is evolved during the period of clinical latency123 Replication of RetrovirusesTa ke n f r o m M i c r o b i o l o g y b y B a u m a n Course of HIV-1 InfectionTa ke n f r o m DeVitaet al., AIDS: Etiology, treatment and Prevention, 4thEd. 1997 Clinical Characteristics•50-90% of infections are asymptomatic•Symptoms generally appear 5-30 days after exposure which include:-Fever, fatigue, malaise, arthralgias, headache, nausea, vomiting, diarrhea-Lymphadenopathy, pharyngitis, rash, weight loss, mucocutaneousulcerations, aseptic meningitis-Leucopenia, thrombocytopenia, elevated liver enzymes-Median duration is 14 days Acquired Immunodeficiency Syndrome•Called Gay Related Immunodeficiency Syndrome (GRID)•AIDS is not a disease but a syndrome•AID Syndrome : Certain opportunistic or rare infections that occur in the presence of antibodies against HIV and a CD4 white blood cell count 50-200 cells/microliterof blood The course of AIDSTa ke n f r o m M i c r o b i o l o g y b y B a u m a n AIDS•ProtozoalDiseases: Pnumocyctis, To x o p l a s m a, Isospora, Cryptosporidium, Microsporidia•Bacterial Diseases: Mycobacteria, Treponema•Fungal: Candida, Cryptococcus, Histoplasma•Viral: CMV, HSV, JC•Malignancies: EBV Lymphoma, Kaposi’s sarcoma, anogenitalcarcinoma•Neurological Symptoms: Aseptic meningitis, PML, myelopathies, neuropathy and AIDS dementia complex Diseases associated with AIDSHerpesKaposi’s sarcomahttp://www.microbiologybook.org/lecture/images/natural-history.gif200-500 Prompt testing HIV is essential for:-Early initiation of antiviral therapy-Identification of carriers-Following the course of disease and confirm the diagnosis of AIDs-Evaluation of `the efficacy of treatment –Diagnosis•Patient has one or more rare diseases, antibodies against HIV, fewer than 200 CD4 lymphocytes per microliterof blood, unexplained weight loss, fatigue, and fever•Serological diagnosis involves detecting antibodies against HIV–ELISA, agglutination test, and Western Blot–Positive test does not indicate presence of AIDS–Definitive diagnosis by PCR (Greater than 75,000 copiesof viral RNA/ml)•Signs and symptoms vary according to the diseases present•Long-term non-progressorsappear not to develop AIDS–May be due to defective virionsor lack of effective coreceptorsfor the virus http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6224a2.htm?s_cid=mm6224a2_eNew HIV diagnostic testing algorithm —United States, 2011–2013First generation-Viral LysatesSecond generation: Synthetic peptides/recombinant antigensThird generation: Immunoassays that will detect both IgMand IgG Tre at me ntTa ke n f r o m M i c r o b i o l o g y b y B a u m a n Anti-Retroviral therapy•Zidovudine•Lamivudin•Navirapin•Indinavir•Atazanavir•Ritonovir•HAART•AtriplaEfavirenz/Te n o f o v i r/Emtricitabine(EFV/TDF/FTC) is a combination of three drugs in one pill allowing the HAART regimen as one pill once a day•CCR5 inhibitor (Maraviroc)•T-20 (Enfuvirtide)•Raltegravir Emtricitabine/Tenofovir (Truvada) for HIV ProphylaxisCoutinhoand Prasad, 2013 Intrapartum Anti-Retroviral Therapy/ProphylaxisNovember 2017 Update (DHHS Guidelines)“Intrapartum intravenous Zidovudin(IV ZDV) should be administered when a woman’s HIV RNA is 50 or more copies/mL” VaccineNo vaccine is currently availableIs an HIV Vaccine Possible?ProductTr ia lAntigensImmunityPopulationVax G e nrgp120Vax 0 0 3 / Vax 0 0 4EnvAb, CD4MSM and IVDUMerck rAd5Step/PhambiliGag/Pol/NefCD8, CD4MSMSanofi Alvac/rgp120RV144Env+ GagAb, CD4GeneralVRC DNA/rAd5HVTN505Env/Gag/Pol/NefAb, CD8, CD4MSMMSM= Men having sex with Men; IVDU = Intravenous Drug users Broadly Neutralizing Antibodies Initiated Human Clinical Trials for bnAbTreat m ent of H IV-1 Infection Alteration of Host Genes that Determine SusceptibilityCcr5-delta 32 mutation protects against HIV-1 Infection (4-16% European descent)Disruption of Ccr5 using CRISPR/CAS [email protected]: x 4814