Immunodefisiensi

(HIV sebagai Role Model)

Ricky Herlianto (2012-060-152)

Jopi Chandra Sindhutomo (2012-060-153)

Jason Julianus (2012-060-172)

Alfredo Bambang (2012-060-193)

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

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.

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

Terapi

Transplantasi antibody, sumsum tulang atau stem

cell

enzyme replacement.

Saat ini juga berkembang gene therapy dengan

menggunakan virus yang telah dimodifikasi.(1)(5)

Immunodefisiensi Sekunder

HIV/AIDS

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

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)

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

Filogenetik HIV

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

Epidemiologi HIV

Struktur HIV

Genom HIV

Mekanisme Masuknya HIV dan Siklus Kehidupan HIV

Tahapan Infeksi HIV

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

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)

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

Pathogenesis HIV

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

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

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

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

• 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

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)

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)

Terapi

REFERENSI • 1. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular immunology. 7th

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

Thank You For Your

Attention

Scientists Helping Scientists™ | WWW.STEMCELL.COM

SAMHD1

APOBEC3G

CYPA

TRIM5

TReg cell

HIV uptake by DC-SIGN blocksDC maturation

Lack ofeffective antiviralimmunity

DC dysfunction

SAMHD1 andAPOBEC3G restrict HIV replication

CD8+ T cellresponse

CD8+ T cell

IL-12, IL-15,IL-18

Type I IFNs

NK cell activation

Inhibition ofviral replication

Type IIFNs

CD4

CTLA4

TRAIL

IL-10

Monocyte

IDO

pDC

T cell-attractingchemokines

Viral spread

CYPA and TRIM5recognize HIV capsid

Conventional DC

TLR7

Viral RNA

HIV uptake by langerin leads to virus degradation

Chemokine-mediated recruitment of newCD4+ T cells for HIV to infect

NK cell

HIV-infecteddonor cell

Donor virus population

HIV virionMucuslayer

Stratifiedsquamousepithelium

Vagina or ectocervix Endocervix

Stroma

HIV-bearingstromal DC

Internalizedvirion

CD4DC-SIGN

CCR5

Infected CD4+ memory T cell

Inserted HIV genome

Tear in themucosalepithelium

HIV penetration and infection

Subepithelial DC

Lack of tight junctions between cells

InfectedintraepithelialCD4+ T cell Impermeable

tight junctionsbetween cells

T cell-attractingchemokines

Local amplification of initial founder virus(es) in a single focus of CD4+ T cells

CD1a+

Langerhans cell

pDC

Columnarepithelium

Transcytosisof HIV virions

CD1a

InfectedCD4+ T cell

Draininglymphatic vessels

A few hours

HIV-specificCD8+ T cell

TIM3

Galectin 9

TIM3LAG3 CTLA4

PD1

Upregulation of inhibitory receptors on CD8+ T cells

• ↓ MHC class I binding• ↓ TCR recognition• ↓ Epitope processing

CD4+ T cell depletion and immunodeficiency

Decreased T helper cell function

T cell-escape mutations in HIV• First Env and Nef• Later Gag and Pol

T cell exhaustion (loss of effector function and proliferative capacity)

Cytokines and other soluble factors

HIV-infected CD4+ T cell

TCRMHC class I Perforin and

granzymes

Perforin pore

Apoptosis

Viralreplication

CD8+ T cell response insufficient to clear infection

• Chronic infection• Repeated T cell activation

Suppression of CD8+ T cell response

TReg cell

Severalmonths

Decreased response to antigens

Chronic infection

Early infection

Advanced disease

Follicular hyperplasia

Decreased natural immunity to secondary pathogens

Poor antibodyresponse

Weeks Months Years Several years

CD4-bindingsite

Few high-affinity broadly neutralizing antibodies

Hypergamma-globulinaemia

Increased turnover and polyclonal activation of B cells

CD4+ T celllymphopenia

Naivemature B cell

Activatedmature B cell

Exhaustedmemory B cell

Short-livedplasmablast

• Non-neutralizing• Lack of viral

control

• Neutralizing, but limited breadth

• Virus acquires escape mutations

• Neutralizing with wider breadth

• ~20% of infected individuals

• Affinity matured, broadly neutralizing

• ~1% of infected individuals

gp41 gp41 gp120gp120gp120

IL-7

Decreased number of resting memory B cells and splenic marginal zone B cells

Increased B cell apoptosis and GC destruction

Immune activation(pro-inflammatorycytokines)

Inadequate CD4+ T cell help

Paucity of HIV-specific IgA at mucosal sites

Decreased class-switch recombination (Nef-mediated)

Inadequate CD4+ T cell help

Increased number of immature transitional B cells

Increased in association with HIV viraemia

Systemic infection

1 week

HIV-specific B cell and antibodyresponse

HIV reservoirs in gut-associated and other lymphoid tissues

Subcapsularsinus macrophage

CD4+ T cell

MHC class II

MHC class I

TCR

B cell follicle

Follicular DC

Follicular B cell

TFH cell

Medulla

Efferent lymphatic

HIV virions and HIV-bearing cells

CD8+ T cell

HIV-bearingDC

T cell zone

Severalyears

Clonal expansionof HIV-specificCD8+ T cells

2–4 weeks

IL-10

TReg celldifferentiationpromoted by IDO

TRAIL-inducedT cell apoptosis

IFN-inducedT cell apoptosis

Langerin

Supp

lem

ent

to N

atur

e Pu

blis

hing

Gro

up

The B cell response to HIVThe DC

response to HIV

The T cell response to HIV

Amplification in draining lymph nodes

Breaching the mucosal barrier

The immune response to HIVNina 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

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.

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.

• RoboSep™ (www.RoboSep.com) fully automates the immunomagnetic cell isolation process, reducing hands-on time, 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 immunodensity-based 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.

AbbreviationsAPOBEC3G, 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 non-integrin; 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.

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

AffiliationsNina Bhardwaj is at the NYU Langone Medical Center, Smilow Research Building, New York 10016, USA. e-mail: Nina.Bhardwaj@nyumc.org

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.

IMMUNOLOGY

Broadly neutralizing HIV-specific antibodies

Name of antibody

Source or approach

Target on HIV Properties

2G12 B cell immortalization

Carbohydrates on gp120

Unique heavy-chain domain swap

IgG1 b12 Phage-display library

CD4-binding site of gp120

Long heavy-chain CDR3; heavy-chain-dominant binding

2F5 and 4E10

B cell immortalization

Membrane-proximal external region of gp41

Autoreactive; bind host lipids

PG9 and PG16

Large screen; cultured clone

gp120 conformational epitope in variable loops (V1–V2)

Dependent on quaternary structure; long heavy-chain CDR3

VRC01 and NIH45-46

Large screen; single-cell sort

CD4-binding site of gp120

Highly mutated; mimic CD4 binding to gp120

PGT121 and PGT125

Large screen; cultured clone

gp120 V3 carbohydrate-dependent epitope

Diverse, with similarities to 2G12

10E8 Large screen; cultured clone

Membrane-proximal external region of gp41

Binds cell-surface epitopes

© 2012 Macmillan Publishers Limited. All rights reserved