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The immune response to HIV Supplement to Nature Publishing Group Nina Bhardwaj, Florian Hladik and Susan Moir Since HIV was discovered as the causative agent of AIDS almost 30 years ago, HIV infection has become a devastating pandemic, with millions of individuals becoming infected and dying from HIV-related disease 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 essential component of the Breaching the mucosal barrier Donor virus population Stratified squamous epithelium Vagina or ectocervix Inserted HIV genome Endocervix HIV virion Infected intraepithelial CD4+ T cell Impermeable tight junctions between cells CD1a+ Langerhans cell Langerin Advanced disease HIV penetration and infection A few hours Increased number of immature transitional B cells CCR5 HIV uptake by DC-SIGN blocks DC maturation APOBEC3G Conventional DC Lack of effective antiviral immunity CD8+ T cell response 1 week NK cell Type I IFNs NK cell activation Draining lymphatic vessels Early infection HIV-specific B cell and antibody response CD8 TCR T cell + MHC class I Follicular B cell Clonal expansion of HIV-specific CD8+ T cells IL-10 HIV-bearing DC TReg cell Activated mature B cell Increased B cell apoptosis and GC destruction Inadequate CD4+ T cell help Exhausted memory B cell Increased in association with HIV viraemia Follicular DC Decreased number of resting memory B cells and splenic marginal zone B cells Inadequate CD4+ T cell help T cell zone Medulla Follicular hyperplasia Short-lived plasmablast B cell follicle Decreased class-switch recombination (Nef-mediated) Paucity of HIVspecific IgA at mucosal sites Increased turnover and polyclonal activation of B cells TFH cell MHC class II Naive mature B cell Immune activation (pro-inflammatory cytokines) Subcapsular sinus macrophage CD4+ T cell CTLA4 Infected memory T cell HIV virions and HIV-bearing cells CD8 T cell Inhibition of viral replication Decreased response to antigens Amplification in draining lymph nodes + IL-12, IL-15, IL-18 pDC CD4+ HIV-bearing stromal DC TRIM5 CYPA Chronic infection Local amplification of initial founder virus(es) in a single focus of CD4+ T cells Internalized virion DC dysfunction SAMHD1 Type I IFNs IL-7 T cell-attracting chemokines DC-SIGN CD4 IL-10 CD4+ T cell lymphopenia Transcytosis of HIV virions Infected CD4+ T cell Subepithelial DC Stroma CYPA and TRIM5 recognize HIV capsid The B cell response to HIV Tear in the mucosal epithelium Monocyte SAMHD1 and APOBEC3G restrict HIV replication Columnar epithelium CD1a The DC response to HIV HIV uptake by langerin leads to virus degradation Document #29290 | Version 1.1.0 HIV-infected donor cell Lack of tight junctions between cells Mucus layer adaptive immune system — CD4+ T helper cells. This Poster summarizes how HIV establishes infection at mucosal surfaces, the ensuing immune response to the virus involving DCs, B cells and T cells, and how HIV subverts this response to establish a chronic infection. Based on a clearer understanding of HIV infection and the response to it, the field has now entered an era of renewed optimism for the development of a successful vaccine. Decreased natural immunity to secondary pathogens Hypergammaglobulinaemia Poor antibody response CD4 TReg cell differentiation promoted by IDO IDO Viral RNA pDC Systemic infection 2–4 weeks TRAIL TLR7 IFN-induced T cell apoptosis Few high-affinity broadly neutralizing antibodies Efferent lymphatic HIV reservoirs in gutassociated and other lymphoid tissues Weeks Months gp120 gp41 Years gp41 gp120 Several years gp120 CD4binding site The T cell response to HIV T cell-attracting chemokines Galectin 9 TRAIL-induced T cell apoptosis TReg cell • Non-neutralizing • Lack of viral control Suppression + TIM3 of CD8 T cell response • Neutralizing, but limited breadth • Virus acquires escape mutations • Neutralizing with wider breadth • ~20% of infected individuals • Affinity matured, broadly neutralizing • ~1% of infected individuals HIV-specific CD8+ T cell Cytokines and other soluble factors Chemokine-mediated recruitment of new CD4+ T cells for HIV to infect TCR MHC class I Viral replication Several months T cell-escape mutations in HIV • First Env and Nef • Later Gag and Pol Viral spread Broadly neutralizing HIV-specific antibodies • ↓ MHC class I binding • ↓ TCR recognition • ↓ Epitope processing Several years Cell Isolation Solutions for HIV Research From STEMCELL Technologies STEMCELL Technologies offers a complete portfolio of fast and easy cell isolation solutions for HIV research, allowing viable, functional cells to be isolated from virtually any sample source for use in cellbased models and assays. STEMCELL Technologies’ products are used by leading HIV research groups worldwide, including the National Institute of Allergy and Infectious Disease and the Ragon Institute. • EasySep™ (www.EasySep.com) is a fast, easy and column-free immunomagnetic cell separation system for isolating highly purified immune cells in as little as 8 minutes. Cells are immediately ready for downstream functional assays. • RoboSep™ (www.RoboSep.com) fully automates the immunomagnetic cell isolation process, reducing hands-on time, Name of antibody 2G12 Perforin and granzymes Perforin pore Apoptosis LAG3 TIM3 CTLA4 HIV-infected CD4+ T cell CD4+ T cell depletion and immunodeficiency Decreased T helper cell function CD8+ T cell response insufficient to clear infection • Chronic infection • Repeated T cell activation Upregulation of inhibitory receptors on CD8+ T cells minimizing human exposure to potentially hazardous samples and eliminating cross-contamination, making it the method of choice for HIV research labs. • RosetteSep™ (www.RosetteSep.com) is a unique immunodensitybased cell isolation system for one-step enrichment of untouched human cells directly from whole blood during density gradient centrifugation. • SepMate™ (www.SepMate.com) allows hassle-free PBMC isolation in just 15 minutes. The SepMate™ tube contains a unique insert that prevents mixing between the blood and density medium, allowing all density gradient centrifugation steps to be carried out quickly and consistently. To learn more about our specialized cell isolation products for HIV research, or to request a sample or demonstration, visit www.stemcell.com/HIV. PD1 T cell exhaustion (loss of effector function and proliferative capacity) Source or approach B cell immortalization Phage-display library Target on HIV Properties Carbohydrates on gp120 CD4-binding site of gp120 Unique heavy-chain domain swap IgG1 b12 Long heavy-chain CDR3; heavy-chaindominant binding 2F5 and B cell Membrane-proximal Autoreactive; bind host 4E10 immortalization external region of gp41 lipids PG9 and Large screen; gp120 conformational Dependent on quaternary structure; PG16 cultured clone epitope in variable long heavy-chain CDR3 loops (V1–V2) VRC01 and Large screen; CD4-binding site of Highly mutated; mimic NIH45-46 single-cell sort gp120 CD4 binding to gp120 Diverse, with Large screen; gp120 V3 PGT121 similarities to 2G12 cultured clone carbohydrateand dependent epitope PGT125 10E8 Large screen; Membrane-proximal Binds cell-surface cultured clone external region of gp41 epitopes Abbreviations Affiliations APOBEC3G, apolipoprotein B mRNA editing, catalytic polypeptide-like 3G; CCR5, CC-chemokine receptor 5; CDR3, complementarity-determining region 3; CTLA4, cytotoxic T lymphocyte antigen 4; CYPA, cyclophilin A; DC, dendritic cell; DC-SIGN, DC-specific ICAM3-grabbing nonintegrin; GC, germinal centre; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IL, interleukin; LAG3, lymphocyte activation gene 3; NK, natural killer; PD1, programmed cell death protein 1; PDC, plasmacytoid DC; SAMHD1, SAM domain- and HD domain-containing protein 1; TCR, T cell receptor; TFH cell, T follicular helper cell; TIM3, T cell immunoglobulin domain- and mucin domain-containing protein 3; TLR7, Toll-like receptor 7; TRAIL, TNF-related apoptosis-inducing ligand; TReg cell, regulatory T cell; TRIM5, tripartite motif-containing protein 5. Nina Bhardwaj is at the NYU Langone Medical Center, Smilow Research Building, New York 10016, USA. e-mail: [email protected] Acknowledgements N.B. thanks D. Frleta for his review and contributions to the poster. Florian Hladik is at the Department of OBGYN, University of Washington, Seattle, Washington 98195, USA. e-mail: [email protected] Susan Moir is at the Laboratory of Immunoregulation, NIAID/NIH, Bethesda, Maryland 20892, USA. e-mail: [email protected] The authors declare no competing financial interests. Edited by Kirsty Minton; copyedited by Isabel Woodman; designed by Simon Bradbrook. © 2012 Nature Publishing Group. All rights reserved. http://www.nature.com/nri/posters/hiv Supplementary text and further reading available online.
