HIV IMMUNE

2017
Klasifikasi HIV

 HIV termasuk dalam family retrovirus genus lentivirus

 Retrovirus mempunyai ciri ciri
 Dikelilingi oleh membran lipid
 Mengandung 2 copy RNA
 Mempunyai variable genetik yg banyak
 Menyerang semua vertebra
 Mempunyai kemampuan replikasi unik
Klasifikasi HIV (lanjutan)

 Lentivirus mempunyai ciri

 Menyebabkan kronik infeksi
 Kemampuan replikasi yg persistent
 Menyerang CNS
 Long period clinical latent
Transmission
• Modes of infection
• Sexual transmission at genital or colonic mucosa
• Blood transfusion
• Mother to infant
• Accidental occupational exposure
How HIV Enters Cells
• gp120 env protein binds to CD4 molecule
• CD4 found on T-cells macrophages, and microglial cells
• Binding to CD4 is not sufficient for entry
• gp120 env protein binds to co-receptor
• Chemokine receptors:
• CCR5 and CXCR4 receptors
• Binding of virus to cell surface results in fusion of viral envelope with cell
membrane
• Viral core is released into cell cytoplasm
HIV and Cellular
HIV
HIV Receptors
Receptors
Receptors

Copyright © 1996 Massachusetts Medical Society. All rights reserved.

Virus Tropism

Virus M-tropik T-tropik

Target sel •Monosit Tcell line
•Makrofag
• microglia
• Sel T primer
Co-reseptor CCR5 CXCR4
Stadium Acut •Lanjut
• resisten
Transmisi HIV
 HIV masuk ke dalam tubuh
dengan 2 cara
 Penetrasi permukaan mukosa
 Inokulasi langsung melalui
darah
 Masuk sebagai virus bebas atau
sel yg terinfeksi HIV

 HIV dapat ditranmisikan dari

virus ke sel atau sel ke sel
Viral-host Dynamics
 About 1010 (10 billion) virions are produced daily
 Average life-span of an HIV virion in plasma is ~6 hours
 Average life-span of an HIV-infected CD4 lymphocytes is ~1.6
days
 HIV can lie dormant within a cell for many years, especially in
resting (memory) CD4 cells, unlike other retroviruses
1. HIV (retrovirus) enters cell
2. Reverse Transcriptase makes
DNA copy of RNA
3. Viral DNA forms provirus with
host DNA

Viral DNA makes mRNA

mRNA makes HIV proteins
HIV proteins become HIV capsid
mRNA is collected inside of HIV
capsid forming new HIV
New HIV leaves cell and wraps
itself in host membrane
(envelope)
HIV entering and leaving a human cell
 Sistim Kekebalan Normal
 Melindungi tubuh dengan mengenali antigen pada bakteri/
virus
 Terdiri dari dari Organ lymphoid
 Semua komponen penting untuk produksi dan pematangan
limfosit
 Sel T dan Sel B diproduksi oleh stem sel di sumsum tulang
 Innate vs adaptive immunity

In response to pathogens, vertebrate immune systems

use two interconnected systems:
• Innate immunity
• Adaptive immunity
The major cells of innate immunity
Big eaters/Always hungry

Antigen Presenting Cells (APCs)

Proteins eaten by APCs are broken down to small pieces (peptides),
which are loaded on special receptors (MHCs) and transported to the
cell surface. Peptide+MHC complex can be recognized by a T cell and that
interaction can lead to an adaptive immune response.
 Fagosit
 Fagosit terdiri atas monosit dan makrofag
 Fungsi :menelan dan mencerna sel yang membawa partikel antigen.
 memulai respon imun dengan mempresentasikan antigen kepada
limfosit, dan penting sebagai regulasi respon imun dan inflamasi
 Innate immune system vs HIV

Innate responses against HIV HIV counter-attack

• Rapid and first line of defense • The virus can infect members of
against the virus the innate immune system
• Innate cells can act as depot
• Alert and activate the adaptive
and effectively transmit virus
immune response
• Inhibition of function via viral
• Release pro-inflammatory factor release and/or improper
signals immune signals
• Clearance of infected cells
• Internalize and process the
virus to present to T cells to
initiate the adaptive response
 Role of Cytokine Dysregulation in
Pathogenesis of HIV
 HIV is associated with increased expression of pro-inflammatory
cytokines
TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma

 HIV results in disruption and loss of immunoregulatory cytokines

IL-2, IL-12
Necessary for modulating effective cell-mediated immune responses
(CTLs and NK cells)
 Sel T
 Ada 2 fungsi: regulasi sistem imun dan membunuh sel-sel yang
membawa target antigen spesifik.
 Setiap sel T memiliki penanda permukaan, seperti CD3, CD4, CD8 yg
membedakan antar sel
 CD4+ merupakan sel pembantu yang mengaktivasi sel B, killer cells, dan
makrofag saat ada antigen spesifik.
 CD8+ membunuh sel yang terinfeksi virus atau bakteri, juga sel-sel
kanker
Role of Cellular Activation in Pathogenesis of
HIV
• HIV induces immune activation
• Which may seem paradoxical because HIV ultimately results in severe
immunosuppression

• Activated T-cells support HIV replication

• Intercurrent infections are associated with transient increases in viremia
• Accounts for why TB worsens underlying HIV disease
 Sel B
 mengenali antigen spesifik dan menghasilkan antibodi spesifik
 Antibodi bekerja dengan membungkus antigen lalu memicu sistim
komplemen
 Membungkus antigen & membuat antigen rentan thd fagosit
 Ada 5 Kelas :G,A,M,D,E
 CD4 T cells vs HIV
CD4 T cells responses against HIV
• Orchestrate adaptive immune
response
• Activated by innate immune system
• Facilitate CD8 T cell (killer) and
B cell activation
• Provide signals and growth factors
for proper immune responses
HIV counter-attack
• Infects CD4 T cells
• Causes depletion of the CD4
T cell population and thereby
removes the “brains” of the
immune response
• Uses surviving CD4 T cells
as a reservoir (latent HIV)
Adaptive immune response
Overview of Adaptive Immune
Response Extracellular
APC infection
Intracellular
infection Free antigen
MHC I presentation
of endogenous
antigen MHC II
presentation of
exogenous antigen

Naïve Naïve
T8 cell B-Cell
Naïve T4
helper cell

Humoral
Cell-mediated Th1 Th2 (plasma cells /
(CTLs) antibodies)
 General Principles of
Viral-host Interactions
• Host: mounts HIV-specific immune responses
• Cellular (cell-mediated) - most important
• Humoral (antibody-mediated)

• Virus: subverts the immune system

• Infects CD4 cells that control normal immune responses
• Integrates into host DNA
• High rate of mutation
• Hides in tissue not readily accessible to immune system
Cellular Immune Responses to HIV
• CD8 Cytotoxic T lymphocyte (CTL)

• Derived from naïve T8 cells, which recognize viral antigens in context of

MHC class I presentation

• Directly destroy infected cell

• Activity augmented by Th1 response

Cellular Immune Responses to HIV
 CD4 Helper T Lymphocyte (Th)
Plays an important role in cell-mediated response
Recognizes viral antigens by an antigen presenting cell (APC)
○ Utilizes major histocompatibility complex (MHC) class II
Differentiated according to the type of “help”
○ Th1 - activate Tc (CD8) lymphocytes, promoting cell-mediated immunity
○ Th2 - activate B lymphocytes, promoting antibody mediated immunity
 CD8 T cells vs HIV
CD8 T cells responses against HIV
• Killer arm of the immune system
• Seek, identify and destroy
infected cells
• Control virus in the initial months
of infection
HIV counter-attack
• Virus mutates and escapes
• Chronic inflammation leads
to exhaustion
• Lack of CD4 T cells:
a. Insufficient signals to
activate more killer cells
b. Defective memory
c. Impaired function
 B cells vs HIV

B cell responses against HIV HIV counter-attack

• Directed by CD4 T cell to make
antibodies against HIV
• Antibodies neutralize the virus
to prevent spread
• Virus mutates at a very high rate
• Loss of CD4 T cells results in:
– Increase in numbers of
immature B cells
– Exhaustion
– Decreased memory
Humoral Immune Response to HIV
• Neutralization
• Antibodies bind to surface of virus to prevent attachment to target cell
• Antibody-dependent cell-mediated cytotoxicity (ADCC)
• Fc portion of antibody binds to NK cell
• Stimulates NK cell to destroy infected cell
 Infeksi menjalar ke seluruh
jaringan dalam 3 hari
 Infeksi menyebar ke
macrofag jaringan
mengaktifkan CD4 sel
dalam lymph node
 Masuk dalam peredaran
darah
 Masuk kedalam orgam
HIV induces strong cellular and humoral immune responses

CTL-cytotoxic T lymphocytes (CD8 killer T cells)

Cells Infected by HIV
 Numerous organ systems are infected by HIV:
Brain: macrophages and glial cells
Lymph nodes and thymus: lymphocytes and dendritic cells
Blood, semen, vaginal fluids: macrophages
Bone marrow: lymphocytes
Skin: langerhans cells
Colon, duodenum, rectum: chromaffin cells
Lung: alveolar macrophages
 General Principles of
Immune Dysfunction in HIV
 All elements of immune system are affected
 Advanced stages of HIV are associated with substantial disruption
of lymphoid tissue

Impaired ability to mount immune response to new antigen

Impaired ability to maintain memory responses
Susceptibility to opportunistic infections
Syncytium Formation
• Observed in HIV infection, most commonly in the brain
• Uninfected cells may then bind to infected cells due to viral gp 120
• This results in fusion of the cell membranes and subsequent
syncytium formation.
• These syncytia are highly unstable and die quickly
Why is HIV not cleared by the immune system?

 High mutation rate of HIV

 HIV latency

 Compromised immune function, primarily through the loss

of CD4 T helper cells
CD4 T cells are depleted in the course of HIV infection
Why are CD4 T cells depleted during the course of HIV infection?

1. HIV-infected CD4 T cells are targeted by the immune response

2. CD4 T cells are lost due to immune exhaustion
 Mechanisms of CD4
Depletion and Dysfunction
• Direct
• Elimination of HIV-infected cells by virus-specific immune responses
• Loss of plasma membrane integrity because of viral budding
• Indirect
• Syncytium formation
• Apoptosis
• Autoimmunity
Primary Infection

 70-80% symptomatic, 3-12 weeks after exposure

 Fever, rash, cervical lymphadenopathy, aseptic
meningitis, encephalitis, myelitis, polyneuritis
 Surge in viral RNA copies to >1 million
 Fall in CD4 count to 300-400
 Recovery in 7-14 days
Seroconversion
 Median 8 weeks after infection
 Level of viral load post sero-conversion
correlates with risk of progression of disease

 Asymptomatic Phase
 Remain well with no evidence of HIV disease
except for generalized lymphadenopathy
 Fall of CD4 count by about 50-150 cells per year
CD4 T-cell Count and Progression to AIDS

• Gradual reduction in number of circulating CD4

cells is inversely correlated with the viral load

• Any depletion in numbers of CD4 cells renders the

body susceptible to opportunistic infections
Kegagalan Sistim Imun dan Sistim pertahanan
Virus
 Sistim pertahanan diri dari Virus
 HIV provirus “Tidur”(laten)dalam sel yg
terinfeksi
 Virus berada diantara folikel dendrit
 Terjadi mutasi baik genotype maypun
fenotype akibat tekanan oleh
CTL&neutralizing antibodi
 Perubahan struktur envelop
 Kegagalan sistim imun
 Inadekuat imun respon secara kwalitatif
 Penghapusan CTL yg telah dikloning
 Akumulasi CTL jauh dari tempat replikasi virus
 Reservoar Anatomi dari HIV
 Menyebabkan
 ARV tidak dapat masuk dalam jumlah yg cukup
 Merupakan tantangan dalam eradikasi
 Sel reservoar dari HIV
 Hal ini melindungi HIV terhadap ARV walaupun konsentrasi
ARV dalam darah cukup
 Peran Aktivasi Imunitas
Infeksi Virus PMS Sifilis

HSV, HHV-6
CMV, HBV Penyakit
Adenovirus
HTLV-1 Tropis
Dengue HF
Malaria

Infeksi
Bakteri
Vaksinasi Infeksi
TB
Sepsis Tetanus
Jamur
Influenza Cryptococcosis

HIV-NAT
 Variasi Virus
 HIV mempunyai variable genetik yg tinggi, yg disebabkan oleh
 Error pada reverse transcriptase
 Recombinasi
 Efek yg ditimbulkan:
 Menyebabkan tingginya mutan rate (1mutasi/genome/siklus replikasi)
 Virus dpt menghindar ARV
 Lari dari imun respon
 Merubah phenotype selama fase infeksi
Window Period: Untreated Clinical Course
Acute HIV syndrome
Primary antibody
Asymptomatic
HIV
infection viremia

--------------------------------------------PCR
P24
ELISA
Time from a to b is the window period
a b
0 2 3 4 years
Weeks since infection Source: S Conway and J.G Bartlett, 2003
Natural History of HIV

Fauci As, 1996

Laboratory Markers of HIV Infection
• Viral load
• Marker of HIV replication rate

• CD4 count
• Marker of immunologic damage
Diagnosis

 Antibody test, ELISA

 Western blot
 HIV RNA viral load
Management
 Treatment recommended when symptomatic or
CD4 count below 200
 Earlier if high viral load, rapidly falling CD4
count, hepatitis C co-infection

 Antiviral therapy
 Reverse transcriptase inhibitors
 Protease inhibitors
 Fusion inhibitors
 How HIV leads to Oportunistic infections
(Crowe, 1997)
Mechanisms
Functional abnormalities of the immune system engendered by HIV infection

Humoral effector mechanisms Cell-mediated effector mechanisms

Neutrophil B cell T cell Macrophage Natural kill cell
↓ Interferon
↓ Cytokine gamma
production

↓ Help to ↓ Antigen
B cell presentation

↓ killing of bacteria • Polycional activation ↓ Delayed-type ↓ Phagocytosis ↓ NK fuction

(e.g, Staphylococcus leads to hypergamma hypersensitivity (e.g., Candida albicans, (reduced
aureus) globulineamia, autoantibodies ↓ Cytotoxic T limphocyte Toxo gondii) interleukin-2)
• Neutropenia (through • Poor antibody responses function (e.g., reduced ↓ Chemataxis
drugs or infection) to vaccines (e.g., hepatitis B) responsesin vitro to ↓ Killing
• Absent IgM responses during CMV and influenza- (e.g., Toxo gondii)
resctivation of infection infected cells)
(e.g., Toxo gondii, CMV)
↓ Killing of encapsulated bacteria
(e.g., Pneumococcus,
Haemophilus influenzae)
HIV - OPPORTUNISTIC INFECTIONS
CD4 > 500/mm3 Acute HIV
Vaginal candidiasis
CD4 of 200-500/mm3 Bacterial pneumonias
Pulmonary tuberculosis
Oral thrush (candidiasis)
Oral hairy leukoplakia
Herpes Zoster
Kaposi’s sarcoma
CD4 < 200 Candida esophagitis
Toxoplasmosis
Cryptococcosis
Pneumocystis jiroveci pneumonia
CD4 < 50 Disseminated Mycobacterium avium complex
Take Home Message
• Infection with HIV usually occurs by sexual transmission, blood transfusion,
mother to infant or accidental exposure
• HIV targets the immune system and primarily infects CD4 positive
lymphocytes
• Immunodeficiency associated with HIV infections is mainly due to reduction in
CD4 positive helper lymphocyte numbers
• Increased viral load, significant reduction in CD4 lymphocytes and
opportunistic infections are the hallmarks of progression to AIDS
 Closing Comments

 APCs, B cells, CD4 and CD8 T cells work together to fight infection

 HIV perturbs APC function, and kills CD4 T cells

 This allows secondary “opportunistic” infections to occur,

leading to disease/death

 Vaccines have the potential to halt HIV infection, but thus far
an efficacious vaccine strategy has proven elusive

 A vaccine approach that takes into account all aspects of the immune
response will likely have the best chance of success
Thank you