? 2 a nature REVIEWS IMMUNOLOGY The immune response to HIV Nina Bhardwaj, Florian Hladik and Susan Moir ‘Since HIV was discovered the causative agent of ‘AIDS almost 30 years ago, HIV nection has become ‘2 devastating pandemic. with millons of individuals ‘becoming infected and dying from HIV-related clsease every year. A global research effort over the past three decades has discovered more about HIV than perhaps any other pathogen. Immunologists ‘continue to be intrigued by the capacity of HIV to ‘effectively knock out an essentiol component ofthe adaptive immune systern — CD4*Thelper cells. This Poster summarizes how HIV establishes infection at mucosal surfaces, the ensulng immune response to ‘the vrusinvoving DCs, B cells and Teall, and how HIV subverts this response to establish chronic Infection Based ona clearer understanding of HIV Infection andthe response tt the ildhas now ‘entered an eracf renewed optimism forthe evelopment ofa successful vaccine.Since HIV was dlscovered a the casative agent of ‘ontnue tbe intrigued by the capacity of HIV 10 ‘fectvly krack ot an essential component of the apie stem — CDT hepa als Tis Foster tumors how HV etablabes nection ot ‘mucosal sirfecesthe ensuing immune response to {hevirsinalvingDCs Bete and Teel ondhow iV sbverts narespanetestablsh a cron ‘section und on carer understanding o AVComplexities of HIV infection HIV primarily infects the CD4+ T-cells. Establishes Chronic Immune Activation. Thrives on CD4+ T-cell activation. Error prone HIV reverse transcription. Establishment of latent reservoir.Events that happen in an HIV infection “oo HIV-specific immune response ’ Massive viremia By oe { — ae Wide dissemination a to lymphoid organs “—— Establishment of Trapping of virus and Primary infection in GALT establishment of chronic, infection persistent infection Partial immunologic control of virus replication t : a Destruction of Accelerated virus Immune System replication eraeecied a aberrant cell signaling Rapid CD4+ T cell turnover Sauce: Longo Ot. Fauc AS, Kasper Ok Mouser St. Jameson i. osc: Hvrsans Principles of Internal Medicine, 18th Edition: wwn.accessmedicImmune escape Cellular Immunity CD8+ Tells Early Development of escape ‘mutants Late: Apoptosis ~ Expression of PDI molecule. Malfunctional CD8+ T cells. Humoral Immunity Neutralizing Antibodies Hypervariability of Primary sequence of the envelope. Extensive Glycosylation of the envelope. Conformational masking of the neutralizing epitopes. Mechanisms of CD4+ T cell depletion Loss of plasma membrane due to viral budding Accumulation of unintegrated viral DNA Apoptosis Aberrant intracellular signalling events.CD4+ T cells Extracellular bacteria iniricenaar piatagins — Autoimmunity Autoimmunity Staphylococcus, _ wont Streptococcus, Gx, be Pseudomonas, agith Ne Chlamydia, E.coli "egy ef M. tuberculosis Salmonelia T Follicular helper cells cope homeostasis Humoral Immunity & B cell Extracellular parasites Regulation of immune responses development ——— :// www. bloodjournal.ora/content/112/5 (adapted)Monocytes & Macrophages Dendritic cells Normal in Number. But functionally deficient. Crucial role in the establishment of HIV infection in the host. HIV is less cytopathic to monocytes. Main APCs for the HIV infection. Hence play a role of reservoir of infection. A target for vaccine. Increased cellular activation generates a large pool of monocytes/macrophages Natural Killer cells (NK) Normal in number. Abnormal CD56-/CD 16+ cells predominate. NK cell — Dendritic cell interaction.Innate responses against HIV 1. Rapid and first line of defense 1. against the virus 2. Identify and contain the 2. invader 3. Alert and activate the adaptive 3. immune response 4. Release pro-inflammatory signals 5. Clearance of infected cells 6. Internalize and process the virus to present to cell and T cells to initiate the adaptive response CD4 T cell responses against HIV 1. Orchestrate adaptive immune response 2. Activated by innate immune system 3. Facilitates killer T cell (CD8) and B cell activation 4. Release signals and growth factors for proper responses HIV counter-attack The virus can infect members of the innate immune system Innate cells can act as depot and effectively transmit virus Inhibition of function via viral factor release and/or improper immune signals B cell responses against HIV 1. Directed by CD4 T cell to make antibodies against HIV 2. Antibodies neutralize the virus to prevent spread HIV counter-attack 1. Infect CD4 T cells 2. Deplete the CD4T cell population removing the “brains” of the immune response Uses surviving CD4 T cells as reservoir 5 q b. HIV counter-attack 1. Early infection causes too much activation and overwhelms B cells: 1. Poor antibody responses 2. Loss of 8 cells, 3. Exhaustion 2. Virus mutates at a very high rate 3. Loss of CD4 T cells: 41. Increase immature 8 cells 2. Exhaustion 3. Decreased memory Frmaniy and We Coe ‘Use the immune stmt develop funeiona cue" ‘aes of matraly acer nun agains HN Development of therapeu vaccines is the nate lune semTake Home Message The primary immunopathogenic lesion in HIV infection involves CD4+ T cells. The dysregulated immune activation of the host serves to maintain the HIV persistence. HIV develops a latent reservoir in the host making the eradication of the virus difficult. HIV sets up an evolutionary race with the host B cells and till today has managed to win it.