1. Immunodefisiensi
(HIV sebagai Role Model)
Ricky Herlianto
Jopi Chandra Sindhutomo
Jason Julianus
Alfredo Bambang
(2012-060-152)
(2012-060-153)
(2012-060-172)
(2012-060-193)

2. Definisi
• Penyakit immunodefisiensi didefinisikan
sebagai kegagalan, kerusakan atau
kemunduran fungsi dari satu atau lebih
komponen dalam sistem imun yang pada
akhirnya dapat menyebabkan penyakit
atau kelainan yang serius

3. Jenis Immunodefisiensi




Secara umum terdapat 2 jenis immunodefisiensi
immunodefisiensi primer (congenital)
Immunodefisiensi sekunder (didapat / acquired)
Immunodefisiensi baik primer maupun sekunder
dapat meningkatkan kerentanan terhadap infeksi,
terkena kanker dan juga dapat mencetuskan
penyakit autoimun.

4. Immunodefisiensi Primer


Penyakit immunodefisiensi primer disebabkan
karena adanya kelainan genetik
Ada berbagai jenis kelainan immunodefisiensi
primer, contohnya
 kelainan
pada sistem imun innate
 defisiensi antibody
 defisiensi sel T

11. Terapi



Transplantasi antibody, sumsum tulang atau stem
cell
enzyme replacement.
Saat ini juga berkembang gene therapy dengan
menggunakan virus yang telah dimodifikasi.(1)(5)

12. Immunodefisiensi Sekunder

14. HIV/AIDS

15. Pendahuluan


HIV termasuk dalam keluarga lentivirus, dan
merupakan suatu retrovirus.(2)
Salah satu karakteristik unik dari lentivirus adalah
kemampuannya untuk menyebabkan efek sitopatik
dalam jangka pendek, dan infeksi yang latent
dalam jangka panjang

16. Pendahuluan


Terdapat dua tipe virus HIV, yaitu HIV-1 dan HIV-2.
HIV-1 paling banyak menyebabkan AIDS. HIV-2
menyebabkan AIDS yang progresinya lebih
lambat.(1)

17. Pendahuluan


Menurut penelitian, HIV-1 kemungkinan berasal
dari virus yang menyerang simpanse
(Pantroglodytes), yang banyak terdapat di Afrika
Pusat.
Di sisi lain, HIV-2, dengan gen 40-60% homolog
dengan HIV-1, datang dari sooty mangabey
(Cercocebus atys), yang banyak terdapat di Africa
Barat dari Senegal sampai Pantai Gading

18. Filogenetik HIV

20. A phylogenetic tree based on
the complete genomes of
primate immunodeficiency
viruses. The scale (0.10)
indicates a 10% difference at
the nucleotide level.

21. Epidemiologi HIV

24. Struktur HIV

27. Genom HIV

31. Mekanisme Masuknya HIV dan
Siklus Kehidupan HIV

37. Tahapan Infeksi HIV

39. Infeksi HIV


Infeksi HIV dibagi menjadi tiga fase, yaitu
infeksi awal atau akut
 Pada
infeksi akut, infeksi terjadi di jaringan mukosa,
yang merupakan reservoir untuk sel T dan tempat
dimana sebagian besar sel T memori berdiam. Dalam
2 minggu, jumlah sel T CD4 berkurang drastis.(1)(5)


transisi dari infeksi akut ke infeksi kronis
infeksi lanjutan atau kronis

42. Fase Transisi



Fase transisi dimulai dengan sel dendritik yang
memfagosit virus dan membawanya ke nodus
limfatikus. Di nodus limfatikus, sel dendritik
mentransfer virus HIV kepada sel T CD4.
Fase transisi diakhiri dengan bekerjanya sistem imun
humoral dan selular, yang menyebabkan jumlah
virus di plasma berkurang dalam waktu 12 minggu
menjadi jauh lebih rendah (berakhirnya viremia).
Selama fase transisi, ada kemungkinan terjadi
peningkatan jumlah sel T CD4 karena diferensiasi
dari progenitor.(1)

43. Fase Infeksi Kronis dan Clinical Latency


Pada fase infeksi kronis, penderita asimptomatik
atau hanya mendapat gejala ringan. Hal ini karena
jumlah virus HIV di plasma menurun secara drastis
Fase clinical latency dapat berlangsung selama
bertahun-tahun. Dengan berjalannya waktu,
penderita juga akan menjadi lebih mudah terinfeksi
penyakit karena berkurangnya sel T CD4 secara
bertahap

44. Pathogenesis HIV

45. Untuk lebih
jelasnya,
gambarnya dapat
dilihat di file pdf
asli poster nature
reviews
immunology
*dilampirkan
pada slide paling
akhir (slide versi
PDF)

46. Awal

Infeksi HIV dimulai dari penerobosan virus melewati
sawar mukosa (mucosal barrier)
 melewati
celah antar sel
 melalui mikroabrasi atau sobekan pada epitel
 mekanisme transcytosis

Sel dendritik juga memegang peranan penting
dalam penerobosan virus melewati sawar mukosa

48. Infeksi Makrofag



Selain sel T CD4, terdapat juga sel-sel lain yang
juga diinfeksi oleh virus HIV seperti makrofag, sel
dendritik, dan sel folikular dendritik
Makrofag memiliki kadar CD4 yang rendah, tetapi
memiliki banyak proteoglikan heparan sulfat yang
disebut syndecan pada permukaannya
Syndecan juga dapat memediasi absorpsi virus HIV
dengan menempel ke gp120

49. Infeksi sel Dendritic


Sel dendritik memiliki kadar CD4, CXCR4, dan
CCR5 yang lebih rendah dari sel T CD4, sehingga
tidak terlalu rentan terhadap virus HIV
sel dendritik memiliki DC-SIGN pada
permukaannya yang berfungsi untuk
mengagregasikan virus pada permukaan, sehingga
saat berkontak dengan sel T CD4, virus HIV dapat
dengan mudah berpindah

50. • Sel dendritik bertanggungjawab
untuk menginisiasi respon imun
adaptif terhadap virus di nodus
limfatikus. Lebih jauh lagi, sel
dendritik dapat mengaktifasi sel
NK dengan sekresi IL-12, IL-15
dan IL-18.
• Sel dendritik memiliki SAMHD1
dan APOBEC3G yang dapat
menginhibisi replikasi virus HIV,
tetapi interaksi dari capsid HIV
dengan cyclophilin (CYPA) di sel
dendritik dapat menginduksi
terbentuknya interferon tipe 1
yang bersifat antiviral melalui
cryptic cytoplasmic sensor

55. Sel T


+
CD4
sebagai reservoir virus
infeksi dapat menyebabkan sel T CD4 menjadi
berhenti berproliferasi dan tidak aktif.
Dalam kondisi seperti itu, sel T CD4 disebut sebagai
latent reservoir, dan memiliki masa hidup yang
sangat panjang, dengan waktu paruh 44 bulan,
bahkan setelah 7 tahun penderita menjalani supresi
replikasi virus.(8)

56. Transmisi Virus HIV



Transmisi HIV dapat melalui berbagai cara. Cara
yang paling umum adalah melalui kontak seksual,
baik pada lawan jenis ataupun sesama jenis.
HIV pada anak-anak paling banyak ditransfer dari
ibunya, baik saat didalam rahim, saat melahirkan,
ataupun saat menyusui anaknya.
Metode lain yang juga sering terjadi adalah
pemakaian jarum suntik secara bersama-sama. (1)

59. Terapi

63. •
•
•
•
•
•
•
•
•
REFERENSI
Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular immunology. 7th
1.
Edition. United States of America: Elsevier; 2012.
2. Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Localzo J. Harrison’s
Principles of Internal Medicine. 18th edition. New York: McGrawHill; 2012.
3. Arason G, Jorgensen G, Ludviksson B. Primary Immunodeficiency and
Autoimmunity: Lessons From Human Diseases. Scand J Immunol. 2010;71:317–28.
4. Ballow M. Primary immunodeficiency disorders: Antibody deficiency. J Allergy
Clin Immunol. 2002 Apr;109(4):581–91.
5. Rich RR, Fleisher TA, Shearer WT, Schroeder HW, Frew AJ, Weyand CM. Clinical
Immunology Principles and Practice. 3rd edition. China: Elsevier; 2008.
6. Bhardwaj N, Hladik F, Moir S. The immune response to HIV. 2012 [cited 2013
Sep 2]; Available from:
http://web2.mendelu.cz/af_239_nanotech/data/up/mats/nri1201_hiv_references.
pdf
7. Levy JA. HIV pathogenesis: 25 years of progress and persistent challenges:
AIDS. 2009 Jan;23(2):147–60.
8. Stebbing J, Gazzard B, Douek DC. Where Does HIV Live? N Engl J Med.
2004;350(18):1872–80.
9. http://www.nature.com/nri/posters/hiv

64. Thank You
For Your
Attention

65. 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
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
CD8
T cell
+
HIV-specific B cell
and antibody
response
TCR
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
Scientists Helping Scientists™ | WWW.STEMCELL.COM
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
IDO
Viral RNA
pDC
Systemic infection
2–4 weeks
TRAIL
TLR7
IFN-induced
T cell apoptosis
Few high-affinity broadly
neutralizing antibodies
Efferent lymphatic
TReg cell
differentiation
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
• 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 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 immunodeficiency
PD1
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
• 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
15 minutes. 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 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
PG16
cultured clone epitope in variable
quaternary structure;
loops (V1–V2)
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,
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: 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.