HIV Infection PDF

Dr. Bimal Kumar Das 30/08/2022  Human Immunodeficiency Virus Acquired Immuno Deficiency Syndrome ( AIDS) was first recognized in the United States in the summer of 1981 Oldest know case from Kanshasa , Dem Republic of Congo, West Africa , 1959. Harald zur hausen, Fran...

Dr. Bimal Kumar Das 30/08/2022  Human Immunodeficiency Virus Acquired Immuno Deficiency Syndrome ( AIDS) was first recognized in the United States in the summer of 1981 Oldest know case from Kanshasa , Dem Republic of Congo, West Africa , 1959. Harald zur hausen, Françoise Barré-Sinoussi and Luc Montagnier ( Pasteur Institute) isolated the virus from lymph node cells of AIDS patients (1983) - AWARDED THE NOBLE PRIZE 2008  HIV transmission Infected body fluids – Sexual contact – Breast milk – Transplacental infection of fetus – Blood-contaminated needles – Organ transplants – Artificial insemination – Blood transfusion & needle prick injuries  Retrovirus Family : Retroviridae (subfamily of lentiviruses) Genus: HIV1, HIV2 and SIV Retroviridae characteristic: reverse transcribe their genome to form dsDNA ( integrates into host DNA) Chronic infection Latency Persistent replication CNS involvement  Viral Genome LTR: binds to host Vif : overcomes Vpu : promotes CD4 transcriptional factor APOBEC and prevents degradation n for initiation DNA degradation release of virus transcription Rev :promotes nuclear Nef : blocks apoptosis of Vpr : promotes G2 export of incomplete CD4 cells and inhibits cell arrest spliced viral RNA cellular activation The Origin of SIV and HIV Origins of human AIDS viruses. Old World monkeys are naturally infected with more than 40 different lentiviruses, termed simian immunodeficiency viruses (SIVs) with a suffix to denote their primate species of origin (e.g., SIVsmm from sooty mangabeys). Several of these SIVs have crossed the species barrier to great apes and humans, generating new pathogens (see text for details). Known examples of cross-species transmissions, as well as the resulting viruses, are highlighted in red.. Cold Spring Harb Perspect Med. 2011 Sep; 1(1): a006841. doi: 10.1101/cshperspect.a006841  Genetic Groups 3 genetic group : M (major) O (outlier) N (non O non M) P M group further divided into clades: A, B, C, D, F, G, H, J, K  HIV Types and Subtypes HIV--1 Group Group N Group O M A B C D F G H J K CRF s  HIV-1 Diversity Worldwide HIV-1 group M: - 9 subtypes (>30% difference) - several circulating recombinant forms Subtype A B C D F, G, H, J. K CRF01_AE CRF02_AG CRF03_AB other Hemelaar et al. 2004. WHO/UNAID HIV tropism for T or M cells CD4 + T cells/monocytes/macrophages dendritic/Langerhans cells  HIV affinity for CNS cell types Non CD4 Microglial cells Astrocytes cells Brain endothelial cells  HIV genome variability ( Quasi species) Reverse Transcriptase is error-prone : enormous potential for (mutations) In an infected person : not all virus are identical but closely related viruses 17  Summary of AIDS epidemic in India In India, children (< 15 years) account for 6.54% of the total PLHV and 12% (10.4 thousand) of total new infections. 18  National AIDS Control Organisation (NACO) HIV prevention in India The National AIDS Control Organisation (NACO) is the body responsible for formulating policy and implementing programs for the prevention and control of the HIV epidemic in India. The current program, NACP-V (2017-2024), AIDS free India…“ HIV and AIDS ( Prevention and Control) Bill in April, 2017…zero new infections, zero AIDS related deaths and zero discrimination…… PATHOGENESIS  Early events sexual transmission –mucosa- vaginal, rectal, urethral encounters mucosal dendritic cells upon encountering a susceptible CD4+ T cell replicates in CD4+ T cells Dissemination to lymph nodes and GALT Abundant CD4 and virus replicate floridly burst of viremia disseminated throughout the body Lancet , July 2014  Human Immunodeficiency Virus (HIV) http://www.rhodes.edu/biology/glindquester/viruses/pagespass/hiv/attachment.jpg Burton et al. 2005. PNAS 102:14943. Overview of HIV infection of a target cell (e.g. T cell) Gut: the veiled site of HIV pathogenesis IMMUNE PATHOGENESIS  Immune dysfunction ( destruction) Exhaustion of the T cell supply v direct killing by the virus v virus induced apoptosis v immunologic senescence v architectural destruction of lymphoid organs by fibrosis due to TGF-β This may correlate most closely with progression to AIDS HIV multiplies inside the cd4 cells and kills the cd4 cells leading to reduced immunity Cellular & humoral immune responses to HIV  Immune escape strategies Host weapon Viral defense mechanism Humoral immunity Neutralizing antibodies Envelop protein variable loops Non neutralising antibodies Cellular immunity CD4 T cells CD8 T cells Enhanced apoptosis Mutation Escape to immuno- privilege area NK Cell with KIRs Mutations in variable loops of envelop protein Natural history of HIV infection 32 The pathway of HIV infection  Centre for Disease Control Classification This system classifies HIV infections based on CD4 count and clinical symptoms, Stage 1: CD4 count ≥ 500 cells/µl and no AIDS defining conditions Stage 2: CD4 count 200 to 500 cells/µl and no AIDS defining conditions Stage 3: CD4 count ≤ 200 cells/µl or AIDS defining conditions Unknown: if insufficient information is available to make any of the above classifications  Stage 1 - Primary Short, flu-like illness - occurs one to six weeks after infection Mild symptoms Infected person can infect other people  Stage 2 - Asymptomatic Lasts for an average of ten years This stage is free from symptoms There may be swollen glands The level of HIV in the blood drops to low levels HIV antibodies are detectable in the blood  Stage 3 - Symptomatic The immune system deteriorates Opportunistic infections and cancers start to appear.  Stage 4 - HIV ] AIDS The immune system weakens too much as CD4 cells decrease in number.  Factors determining rate of progression Characteristic of infecting virus Host genetic factor Anti viral immune response Environmental factors  Opportunistic Infections 99.9% (when combined with ELIZA) HIV rapid antibody test Screening test for HIV Simple to perform Absolute CD4 lymphocyte count Predictor of HIV progression Risk of opportunistic infections and AIDS when 95%; Sensitivity: 15-95%) Primarily used for viral detection with neonatal infection and with indeterminate serology p24 (Gag) antigen detection: positive before antibody, less sensitive than PCR, done in isolation or Ab/Ag Combo test HIV viral co-culture: complex, most sensitive  HIV-2 Tests Screening tests of HIV-1 do not always detect infection by HIV-2 Most cross reactions represent antibody induced by the core (p26) and/or pol antigens (p68, p34), because these are highly conserved between the two different viruses HIV-1/2 "combination tests," are available which incorporate antigens from both viruses Necessitates the use of highly specific ELISA (e.g., synthetic peptide- based), Western blot, radio-immunoprecipitation assays, or the polymerase chain reaction Antiretroviral Treatment  DHHS Antiretroviral Therapy Guidelines: October 2011 Preferred Regimens for ARV-Naïve Patients: Pill Burden Integrase Strand Transfer Inhibitor-Based Regimens (Integrase Strand Transfer Inhibitor + Two Nucleoside Reverse Transcriptase Inhibitors) Source: 2011 DHHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)  Why is there no cure for HIV? High mutation rate caused by RT The outer protein envelope (gp120) mutates, therefore the host’s immune system cannot recognize and destroy all HIV present HIV permanently incorporates into host DNA Development of drug resistant mutants  Issues in HIV Vaccine Development § Correlates of human protection unknown § HIV infection does not confer protective immunity § Reliance on natural history data and other studies § Lack of ideal animal model § No small animal model § Most research performed using macaques with SIV/SHIV § HIV-1 strain variability: subtypes A, B, C, D, E, F… § Difficult to do efficacy trials § Unfavorable market forces § ONLY CLINICAL TRIAL : RV-144 ( 2009) – A RECOMBINANT CANARY POX VECTOR VACCINE ( ALVAC-HIV)/PROTECTIVE EFFICACY -26- 31% THE END  CD4 Non CD4 monocytes/macrophages dendritic/Langerhans Replication Microglial cells Astrocytes cells cells Brain endothelial cells NK cells Adults and children estimated to be living with HIV 2013 Eastern Europe & Central Asia North America and Western and Central Europe 1.1 million 2.3 million [980 000– 1.3 million] [2.0 million – 3.0 million] Asia and the Pacific Middle East & North Africa 4.8 million Caribbean 230 000 [4.1 million – 5.5 million] 250 000 [160 000 – 330 000] [230 000 – 280 000] Sub-Saharan Africa Latin America 24.7 million 1.6 million [23.5 million – 26.1 million] [1.4 million – 2.1 million] Total: 35.0 million [33.2 million – 37.2 million] Progression of HIV to AIDS  Confirmatory test for HIV Infection Based on different antigen system (recombinant or synthetic peptides) or with different test principle making it more specific Western blot (WB) Immunoblot (IB) Indirect fluorescent antibody test (IFA) Radioimmunoprecipitation test (RIPA) q Do not produce biologic false-positive results q More laborious and more expensive than screening assays