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The immune response to HIV

Nina Bhardwaj, Florian Hladik and Susan Moir


Supplement to Nature Publishing Group

Since HIV was discovered as the causative agent of adaptive immune system — CD4+ T helper cells. This
AIDS almost 30 years ago, HIV infection has become Poster summarizes how HIV establishes infection at
a devastating pandemic, with millions of individuals mucosal surfaces, the ensuing immune response to
becoming infected and dying from HIV-related the virus involving DCs, B cells and T cells, and how
disease every year. A global research effort over the HIV subverts this response to establish a chronic
past three decades has discovered more about HIV infection. Based on a clearer understanding of HIV
than perhaps any other pathogen. Immunologists infection and the response to it, the field has now
continue to be intrigued by the capacity of HIV to entered an era of renewed optimism for the
effectively knock out an essential component of the development of a successful vaccine. Document #29290 | Version 1.1.0

Inserted Vagina or ectocervix Endocervix


Breaching the mucosal barrier HIV genome
Donor virus population
HIV-infected
Lack of tight donor cell
Stratified Mucus junctions
squamous layer HIV virion
between cells
epithelium
Infected
intraepithelial
Impermeable
CD4+ T cell
tight junctions Columnar
between cells epithelium
CD1a The B cell
The DC CD1a+ response to HIV
response to HIV Langerhans cell
Langerin Tear in the
mucosal Advanced disease
epithelium
CD4+ T cell
Transcytosis lymphopenia
Monocyte of HIV virions
Infected
CD4+ T cell IL-7
Subepithelial Increased number of immature
DC transitional B cells
Stroma
HIV penetration and infection
T cell-attracting
DC-SIGN CD4 chemokines
A few hours
HIV uptake by
langerin leads to IL-10 CCR5
virus degradation HIV uptake by Chronic infection
Local amplification
DC-SIGN blocks Internalized of initial founder pDC
DC maturation virion virus(es) in a single
focus of CD4+ T cells Decreased
Infected CD4+ response to Decreased
HIV-bearing memory T cell antigens Naive class-switch
SAMHD1 and Draining
APOBEC3G stromal DC mature recombination
APOBEC3G lymphatic vessels
DC dysfunction B cell (Nef-mediated)
restrict HIV SAMHD1 Early infection
replication
TRIM5
Amplification in draining lymph nodes Immune activation Paucity of HIV-
CYPA and CYPA Conventional DC Lack of (pro-inflammatory specific IgA at
TRIM5 effective cytokines) mucosal sites
recognize antiviral
HIV capsid immunity HIV virions and
HIV-bearing cells Follicular
Subcapsular Increased turnover hyperplasia
CD8 +
and polyclonal
sinus macrophage Inadequate
T cell activation of B cells CD4+ T cell
IL-12, help
Type I IL-15,
IFNs Activated Exhausted
IL-18 CD8+ T cell TFH cell mature memory
CD4+ Increased B cell
response T cell B cell B cell
apoptosis and
HIV-specific B cell GC destruction Increased in
MHC and antibody
1 week CD8 TCR
+ class II association with
response HIV viraemia
T cell
Inhibition of NK cell Decreased number of
MHC
viral replication Follicular Short-lived resting memory B cells
class I
B cell plasmablast and splenic marginal
Clonal expansion Follicular DC zone B cells
CTLA4 IL-10
NK cell of HIV-specific HIV-bearing
DC B cell follicle Inadequate
activation CD8+ T cells CD4+ T cell
Type I help Decreased
IFNs T cell natural immunity
Poor antibody Hypergamma-
TReg cell zone to secondary
Medulla response globulinaemia
pathogens
CD4
Few high-affinity broadly
IDO TReg cell Efferent lymphatic neutralizing antibodies
Viral RNA differentiation Several
HIV reservoirs in gut- Weeks Months Years
promoted by IDO Systemic infection years gp120
pDC 2–4 weeks associated and other gp120 gp120
gp41 gp41
lymphoid tissues
TRAIL
TLR7 CD4-
binding
The T cell response to HIV site
IFN-induced T cell-attracting Galectin 9
T cell apoptosis TRAIL-induced TReg cell Suppression • Non-neutralizing • Neutralizing, but • Neutralizing with • Affinity matured,
chemokines
T cell apoptosis • Lack of viral limited breadth wider breadth broadly neutralizing
TIM3 of CD8 T cell
+

response control • Virus acquires • ~20% of infected • ~1% of infected


escape mutations individuals individuals
HIV-specific
CD8+ T cell
Cytokines Broadly neutralizing HIV-specific antibodies
and other
soluble TCR Name of Source or Target on HIV Properties
Chemokine-mediated factors MHC antibody approach
recruitment of new class I Perforin and 2G12 B cell Carbohydrates on Unique heavy-chain
CD4+ T cells for HIV granzymes
immortalization gp120 domain swap
to infect Viral
Several IgG1 b12 Phage-display CD4-binding site of
Long heavy-chain
months replication
Perforin library gp120 CDR3; heavy-chain-
pore dominant binding
T cell-escape Apoptosis 2F5 and B cell Membrane-proximal Autoreactive; bind host
mutations in HIV 4E10 immortalization external region of gp41 lipids
Viral spread
• First Env and Nef LAG3 TIM3 CTLA4 PG9 and Large screen; gp120 conformational Dependent on
• Later Gag and Pol HIV-infected PG16 cultured clone epitope in variable quaternary structure;
CD4+ T cell CD4+ T cell depletion PD1
and immunodeficiency loops (V1–V2) long heavy-chain CDR3
VRC01 and Large screen; CD4-binding site of Highly mutated; mimic
• ↓ MHC class I binding NIH45-46 single-cell sort gp120 CD4 binding to gp120
CD8+ T cell response Decreased T helper
• ↓ TCR recognition cell function PGT121 Large screen; gp120 V3 Diverse, with
insufficient to clear infection
• ↓ Epitope processing and cultured clone carbohydrate- similarities to 2G12
T cell exhaustion (loss PGT125 dependent epitope
Several • Chronic infection of effector function and 10E8 Large screen; Membrane-proximal Binds cell-surface
years • Repeated T cell activation
Upregulation of inhibitory proliferative capacity) cultured clone external region of gp41 epitopes
receptors on CD8+ T cells

Cell Isolation Solutions for HIV Research minimizing human exposure to potentially hazardous samples and Abbreviations Affiliations
From STEMCELL Technologies eliminating cross-contamination, making it the method of choice APOBEC3G, apolipoprotein B mRNA editing, catalytic polypeptide-like 3G; Nina Bhardwaj is at the NYU Langone Medical Center, Smilow Research
for HIV research labs. CCR5, CC-chemokine receptor 5; CDR3, complementarity-determining Building, New York 10016, USA. e-mail: Nina.Bhardwaj@nyumc.org
STEMCELL Technologies offers a complete portfolio of fast and easy • RosetteSep™ (www.RosetteSep.com) is a unique immunodensity- region 3; CTLA4, cytotoxic T lymphocyte antigen 4; CYPA, cyclophilin A; Florian Hladik is at the Department of OBGYN, University of Washington,
cell isolation solutions for HIV research, allowing viable, functional based cell isolation system for one-step enrichment of untouched DC, dendritic cell; DC-SIGN, DC-specific ICAM3-grabbing non- Seattle, Washington 98195, USA. e-mail: fhladik@fhcrc.org
cells to be isolated from virtually any sample source for use in cell- human cells directly from whole blood during density gradient integrin; GC, germinal centre; IDO, indoleamine 2,3-dioxygenase;
based models and assays. STEMCELL Technologies’ products are used centrifugation. IFN, interferon; IL, interleukin; LAG3, lymphocyte activation gene 3; Susan Moir is at the Laboratory of Immunoregulation, NIAID/NIH,
by leading HIV research groups worldwide, including the National • SepMate™ (www.SepMate.com) allows hassle-free PBMC isolation NK, natural killer; PD1, programmed cell death protein 1; PDC, Bethesda, Maryland 20892, USA. e-mail: smoir@niaid.nih.gov
Institute of Allergy and Infectious Disease and the Ragon Institute. in just 15 minutes. The SepMate™ tube contains a unique insert plasmacytoid DC; SAMHD1, SAM domain- and HD domain-containing The authors declare no competing financial interests.
that prevents mixing between the blood and density medium, protein 1; TCR, T cell receptor; TFH cell, T follicular helper cell; TIM3,
• EasySep™ (www.EasySep.com) is a fast, easy and column-free allowing all density gradient centrifugation steps to be carried out T cell immunoglobulin domain- and mucin domain-containing protein 3; Edited by Kirsty Minton; copyedited by Isabel Woodman;
immunomagnetic cell separation system for isolating highly quickly and consistently. TLR7, Toll-like receptor 7; TRAIL, TNF-related apoptosis-inducing ligand; designed by Simon Bradbrook.
purified immune cells in as little as 8 minutes. Cells are TReg cell, regulatory T cell; TRIM5, tripartite motif-containing protein 5. © 2012 Nature Publishing Group. All rights reserved.
immediately ready for downstream functional assays. To learn more about our specialized cell isolation products for http://www.nature.com/nri/posters/hiv
• RoboSep™ (www.RoboSep.com) fully automates the HIV research, or to request a sample or demonstration, visit Acknowledgements
immunomagnetic cell isolation process, reducing hands-on time, www.stemcell.com/HIV. N.B. thanks D. Frleta for his review and contributions to the poster. Supplementary text and further reading available online.

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