Supplement to Nature Publishing Group

The immune response to HIV

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

IMMUNOLOGY
Breaching the mucosal barrier

Donor virus population

Stratied
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
eective
antiviral
immunity

CD8+ T cell
response
1 week
NK cell

Type I
IFNs

NK cell
activation

Draining
lymphatic vessels

Early infection

CD8
T cell

HIV-specic B cell
and antibody
response

TCR

MHC
class I

Follicular
B cell

Clonal expansion
of HIV-specic
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 HIVspecic IgA at
mucosal sites

Increased turnover
and polyclonal
activation of B cells

TFH cell
MHC
class II

Naive
mature
B cell

Immune activation
(pro-inammatory
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 amplication
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

Scientists Helping Scientists | WWW.STEMCELL.COM

HIV-infected
donor cell

Lack of tight
junctions
between cells

Mucus
layer

adaptive immune system CD4+ Thelper 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
IDO
Viral RNA
pDC

Systemic infection

24 weeks

TRAIL
TLR7
IFN-induced
T cell apoptosis

Few high-anity broadly

neutralizing antibodies

Eerent lymphatic

TReg cell
dierentiation
promoted by IDO

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

Anity matured,
broadly neutralizing
~1% of infected
individuals

HIV-specic
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 cell-based 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 25 minutes. Cells are immediately ready
for downstream functional assays.

Name of
antibody
2G12

Perforin and
granzymes
Perforin
pore
Apoptosis
LAG3 TIM3 CTLA4

HIV-infected
CD4+ T cell

CD4+ T cell depletion

and immunodeciency

PD1

Decreased T helper
cell function

CD8+ T cell response

insucient to clear infection
Chronic infection
Repeated T cell activation

Upregulation of inhibitory
receptors on CD8+ T cells

RoboSep (www.RoboSep.com) fully automates the immunomagnetic

cell isolation process, reducing hands-on time, minimizing human
exposure to potentially hazardous samples and eliminating crosscontamination, 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
15minutes. The SepMate-50 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.

T cell exhaustion (loss

of eector 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
PG16
cultured clone epitope in variable
quaternary structure;
loops (V1V2)
long heavy-chain CDR3
VRC01 and Large screen;
CD4-binding site of
Highly mutated; mimic
NIH45-46 single-cell sort gp120
CD4 binding to gp120
PGT121
Large screen;
gp120 V3
Diverse, with
and
cultured clone carbohydratesimilarities to 2G12
PGT125
dependent epitope
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,
Tcell 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: Nina.Bhardwaj@nyumc.org

Acknowledgements
N.B. thanks D. Frleta for his review and contributions to the poster.

2012 Macmillan Publishers Limited. All rights reserved

Florian Hladik is at the Department of OBGYN, University of Washington,

Seattle, Washington 98195, USA. e-mail: fhladik@fhcrc.org
Susan Moir is at the Laboratory of Immunoregulation, NIAID/NIH,
Bethesda, Maryland 20892, USA. e-mail: smoir@niaid.nih.gov
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.