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Pathogenesis of HIV
- 1. Pathogenesis of HIV PRESENTER: DR MWAURA UINIVERSITY OF NAIROBI
- 2. Scope ◦ Definitions ◦ Epidemiology ◦ History ◦ Viral Properties & Life Cycle ◦ Immune System Overview Objectives ◦ Understand morphology of HIV ◦ Understand process HIV infection and progression to AIDS
- 3. Definitions HIV – Human Immunodeficiency Virus Retrovirus /Lentivirus Positive sense SS RNA virus AIDS – Acquired Immunodeficiency syndrome Severe immune suppression leading to OIs & Neoplasms due to HIV infection HIV + CD4+ <200/ml or HIV + AIDS defining OI
- 4. EPI: Global (2018) 37.9 million 36.2 million 18.8 million 17.4 million 1.7 million 1.7 million 160 000 1.6 million – – – – 770 000 670 000 100 000 Source: UNAIDS/WHO estimâtes People living with HIV New Infections HIV-related deaths
- 5. Kenya 2018
- 6. Origin of HIV HIV 1 – SIVcpz, HIV 2 - SIVsmm Hunter/Bush meat?? Around 1920s in Congo. Phylogenetic studies instrumental in tracking origin & evolution HIV 1 - 4 distinct cross over from chimpanzees -Corresponds sub groups = M, N, O, P
- 7. History/Timeline 1900s – A form of SIV transmitted to humans from Chimps in the Congo (DRC) 1920s ––HIV was circulating in Kinshasa 1959 – 1st Known case (from preserved blood Samples) 1960s – HIV 2 tramsmitted to humans from Sooty Mangabey monkeys in Guinea-Bissau 1966- 1st case in Americas – Haiti 1969- Robert Rayford died of HIV ** 1976 – Arvid Noe dies 1977 – Danish Physician Grethe Rask died of AIDS 1978 – Senhor Jose – Died of HIV 2 1980 – A cluster of Pnemocystis Penumonia cases reported to CDC 1982 – 121 people had died of HIV
- 8. Timeline….ctd 1982 – terry Higgins died of AIDS in UK 1982- Term AIDS coined 1983 – PCR developed 1984 – Retrovirus discovered by Luc Montegnor & Robert Gallo 1986 – HIV name adopted
- 9. HIV 1 Diversity M, N, O, P M- 11 subtypes Subtype C – southern Africa, Eastern Africa, India, Nepal, and parts of China Recombinants- Gives rise to new subtype Most diversity – Central Africa – Supports origin theory Founder Effect – Eg White SA Homosexuals- Type B
- 10. Morphology of HIV Components ◦ 2 Identical Positive ssRNA strands ◦ Viral Enzymes – Integrase, Protease, RT ◦ Viral Capsid – outer Matrix P17 ,Major Capsid P24, Nuclear Protein (P7) ◦ Lipid Envelope ◦ Envelope Glycoproteins GP 160 GP 120, GP 41 Size : 120nm Diameter Shape: Icosahedral Symmetry Genes: gag, pol, env
- 11. HIV Virion
- 13. CD4 Cells Syn: T Helper, T lymphocytes Central role in activation of cellular & Humoral immune systems Express CD4 antigen (a GP)on their cell membrane CD4 is a co-receptor of the T cell receptor (TCR) and assists the latter in communicating with antigen-presenting cells. Bind to APC’s MHC II antigens.. Highly specific Causes activation of tyrosine kinase which leads to activation of molecular processes of activated T cells Eg Secretion of IL 2
- 15. HIV Life Cycle 1. Fusion –GP 120/41 to CD4 & CXCR4 +CCR5 2. Entry – Into Host Cell 3. Reverse transcription- From RNA to DNA - RT 4. Integration- Into Host genome - Integrase 5. Replication – Using host cell resources 6. Assembly – Viral components move towards cell membrane, 7. Budding- pinching off cell membrane to form virion envelope, proteases cleaves polyproteins forms mature virion
- 16. HIV Life Cycle
- 17. Step 1 & 2: Fusion & Entry 1.Attachment of GP 120 to CD4 on T Cells 2.Conformational change in GP120- allows attachment to Co-receptors CCR5/ CXCR4 3.GP 41 unfolds, attaching to cell membrane 4.GP41 then fold back on itself… pulling the viral membrane towards the cell membrane 5.Then the two membranes fuse 6.Allows injection of Viral capsid into cell cytoplasm
- 19. Step 3: Reverse Transcription Viral capsid lysed by cytoplasmic enzymes freeing viral RNA and enzymes Two catalytic domains – Ribonuclease H domain moves along , reads and makes a DNA strand from the RNA which is then destroyed. Polymerase domain makes another complimentary DNA(cDNA) strand to form a double strand. In quiescent T cells, HIV cDNA may remain in the cytoplasm in a linear episomal form
- 20. Step 4: Integration In actively dividing T cells, Viral cDNA and Integrase migrates to the nucleus Integrase slices cellular DNA allowing the viral DNA to attach into host genome forming provirus. Once DNA is integrated… its permanent May remain dormant until activated….Latency Activation – Antigens /Cytokines upregulates several transcription factors, including NF-κB, which moves from the cytosol into the nucleus. NF-κB binds to regulatory sequences including genes for cytokines and other immune mediators, promoting their transcription. The long-terminal-repeat sequences that flank the HIV genome also contain NF-κB binding sites, so binding of NF-κB activates viral gene expression Activation by other pathogens or HIV itself leads to viral RNA production – A vicious cycle.
- 21. Step 5: Synthesis & Assembly mRNA transcribed from the viral DNA in the host gag, pol, and env genes, encode for precursor proteins tat, rev, vif, nef, vpr, and vpu, genes - regulate the synthesis and assembly of infectious viral particles and the pathogenicity of the virus Protease cleave polypeptides to active viral proteins Viral component aggregate together to form a virion particle
- 22. Step 6: Budding • Viral particle moves towards the cell membrane • Bulges through enveloping itself with a part of the cell membrane – forms viral lipid bilayer membrane • Process leads to death of T cell
- 23. Loss of T Cell Function 1. Direct i. Membrane defect due to viral particle shedding ii. Hijacked cellular protein synthesis 2. Indirect i. Chronic activation due to HIV or OIs ----> Apoptosis ii. HIV infection of cells in lymphoid organs (spleen, lymphnodes, tonsils) iii. Fusion of infected and uninfected cells, leading to formation of syncytia (giant cells) – Cell death within hours iv. Qualitative defects in T cell function eg Loss of memory CD4 cells NB: During clinical latency – balance between destruction and replenishment.
- 24. Mechanismof CD4 T cell depletion in HIV infection
- 25. HIV Latency Normally.. Activated CD4+ cells die quickly after HIV infection A few infected macrophages & Langerhan cells survive long enough and revert back to memory state..G0 Hide in safe havens – LN,Spleen, BM, CNS Persist as memory cells, with an altered pattern of gene expression enabling long-term survival and rapid responses after re exposure to antigen. Account for inability to cure HIV even with ART. Ongoing Research –activation of latent infected CD4 cells, then cleared by Cytopathic T cells
- 26. HIV Invasion Genital Mucosal route – Most common - 70% Esp. Squamous Non Keratinised epithelium Mechanism of Mucosal Invasion? Mucosal Entrapment, Trancytosis Mucosal tears greatly aids in access to target cells Dendritic Cells – Initial targets in the mucosa …then present to CD4 cells in LNs Dissemination through lymphatic Channels Multiplication in LNs leads to destruction of T cells as new virions are formed. New waves of invasion and destruction leads to progressive loss of CD4 cells.
- 28. HIV Invasion
- 29. Natural History of HIV InfectionLevels(SeparateScales) CD4+ T cell HIV viral loadCD8+ T cell Neutralizing Antibodies Years AIDS and DeathAcute Asymptomatic (clinical latency) 4 – 8 weeks Primary infection
- 30. HIV disease progression –Acute infection Primary infection of cells in blood or mucosa (HIV directly infects T cells and microphages oris carried to those cells by dendritic cells) Viral replication in the regional lymph nodes leads to Exponential viral growth and widespread dissemination Development of anti-viral responses and symptoms of acute infection occur Decrease in plasma viral load and symptoms of acute infection resolve
- 31. Immune Reaction to HIV Humoral + cell mediated responses used in partial control of viral replication ..but… this leads to destruction of infected CD4+ cells HIV specific CTLs kill infected cells Antibodies recognize HIV infected cells ..by surface ag …leads to Antibody dependent cell- mediated cytotoxicity Apoptosis of infected cells
- 32. HIV disease progression -- AIDS • Acquired Immune Deficiency Syndrome: • Catastrophic breakdown of host defenses, marked increase in viremia and clinical disease. • CD4+ cell count less than or equal to 200 per microliter • Clinical Features: • Opportunistic infection • Neoplasms • CNS involvement
- 33. Viral Load Set Point
- 34. References https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587276/ Cold Spring Harb Perspect Med 2011;1:a007096 https://www.nps.org.au/australian-prescriber/articles/hiv-fusion-inhibitors-a-review https://www.niaid.nih.gov/diseases-conditions/hiv-replication-cycle Setting the stage – HIV host invasion Florian Hladik1,2,3 and M. Juliana McElrath1,2,4,5
Editor's Notes
- AIDS defining OI TB PJP KS CMV retinitis Cervical Cancer
- Lowest Wajir – 0.5
- M Major O other N Neither M or o P Pending Identification of more ecases
- Phylogenetic Modelling, genetic studies Haitian Connection ** Molecular biology studies at Tulane University in 1987.
- Who discovered HIV… settled by Presidents of France & US Terry Higgins Trust PCR developed by Kary Mullis
- From US to SA by homosexual spread Subtype C = Most prevalent
- Viral genes code for Gag- cone shaped icosahedral capsid Pol - viral enzymes Env – surface prot gp 120 , 41
- Lipid Bi layer- From Host CD4 cell Membrane
- Scanning electron micrograph of HIV-1 (in green) budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and budding of virions.
- CD- Cluster of Differentiation
- 10b virions produced/ day Importance = Each step can be targeted with drugs that block replication
- Trojan Horse technique
- Genetic Mutation of CCR5 – Immunity to HIV Berlin Pt, London Pt
- Relevance – Infusion Inhibitors enfuvirtide Resistance to Infection- Δ32 mutation of CCR5 gene … Berlin Pt. Timothy Ray Brown…Recent London Pt ? Why is BMT not widely used?
- NRTIs/ NNRTIs
- Nuclear Factor Kappa B= Transcription Factor Vicious cycle of Low immunity => Ois> Antigenic stimulation of Viral Replicaton > Immune suppression. Repeat Integrase Inhibitors
- VPU – present only in HIV 1 ===respon for higher virulence?
- Death of T cell – Membrane failure due to budding viral particles - Attacked by bodys immune system
- progressive destruction of the architecture and cellular composition of lymphoid tissues. Fusion – Role of GP 120 on cell surface of Infected cells.
- Integrated DNA in the HOST nucleus = Nothing much you can do about it.
- Direct Inoculation- Straight forward Mucosal Route – Most significant, Best studied CD4 cells – central coordinates and controls other lymphocytes VMMC
- 4 main phases Viral Latency Vs Clinical Latency Markers Of Progression and response to ART
- Acute Primary Infection Once HIV enters the body, the virus infects a large number of CD4+ T cells and replicates rapidly. During this acute phase of infection, the blood has a high number of HIV copies (viral load) that spread throughout the body, seeding in various organs, particularly the lymphoid organs such as the thymus, spleen, and lymph nodes. During this phase, the virus may integrate and hide in the cell’s genetic material. Shielded from the immune system, the virus lies dormant for an extended period of time. In the acute phase of infection, up to 70 percent of HIV-infected people suffer flu-like symptoms. The Immune System Strikes Back Two to 4 weeks after exposure to the virus, the immune system fights back with killer T cells (CD8+ T cells) and B-cell-produced antibodies. At this point, HIV levels in the blood are dramatically reduced. At the same time, CD4+ T cell counts rebound, and for some people the number rises to its original level.
- Candidiasis of bronchi, trachea, esophagus, or lungs Invasive cervical cancer Coccidioidomycosis Cryptococcosis Cryptosporidiosis, chronic intestinal (greater than 1 month's duration) Cytomegalovirus disease (particularly CMV retinitis) Encephalopathy, HIV-related Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, pneumonitis, or esophagitis Histoplasmosis Isosporiasis, chronic intestinal (greater than 1 month's duration) Kaposi's sarcomav Lymphoma, multiple forms Mycobacterium avium complex Tuberculosis Pneumocystis carinii pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV
- The HIV set point is the viral load of a person infected with HIV, which stabilizes after a period of acute HIV infection. The only effective way to lower the set point is through highly active antiretroviral therapy. The set point is not completely fixed and constant, but can be quite dynamic with significant fluctuations.