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Acquired Immunodeficiency Syndrome

(AIDS)
History
1950s: Blood samples from Africa have HIV
antibodies.
1976: First known AIDS patient died.
1980: First human retrovirus isolated
(HTLV-1).
1981: First reports of Acquired Immunodeficiency Syndrome in Los Angeles.
1983: Virus first isolated in France (LAV).
1984: Virus isolated in the U.S. (called
HTLV-III and AIDS-Related Virus, ARV).
1985: Development and implementation of
antibody test to screen blood donors.

Acquired Immunodeficiency Syndrome


(AIDS)
History (Continued)
1986: Consensus name Human
Immunodeficiency Virus (HIV-1).
Related virus (HIV-2) identified.
1992: AIDS becomes the leading cause of
death among adults ages 25-44 in the
U.S.
1997: Mortality rates of AIDS starts to
decline due to the introduction of new
drug cocktails.
2001: World Health Organization predicts
up to 40 million infected individuals.
More than 22 million have already died.

AIDS: A Leading Cause of Death


Among People Aged 25-44 years in
U.S.

Deaths per 100,000 people aged 25-44 years

Overview of HIV
-Infect and kills CD4 lymphocytes
- Loss cell mediated immunity opportunistic infect.
- Other (macrofag , monosit) that have protein CD4
on their surface can be infected also
- HIV-1 and HIV-2 cause AID

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
5

Classification of HIV
HIV class: Lentivirus

Retrovirus: single stranded RNA transcribed to double


stranded DNA by reverse transcriptase
Integrates into host genome
High potential for genetic diversity
Can lie dormant within a cell for many years,
especially in resting (memory) CD4+ T4 lymphocytes

HIV type (distinguished genetically)

HIV-1 -> worldwide pandemic (current ~ 40 M


people)
HIV-2 -> isolated in West Africa; causes AIDS much
more slowly than HIV-1 but otherwise clinically
similar

HIV at Surface
of CD4
Lymphocyte

Courtesy of CDC

Virulogy of HIV
-Is of one the two HTLV
- Two identical ss (+)RNA surrounded by envelop (lipid
bilayer) containing viirus-specifict glycoprotein
(gp 120 and gp 41)
-Genom complex
1. encode structural protein : gag , pol, env
2. tat , rev (replication) ; nef , vif , vpr and vpu
(as accessory gene)

gag
5

LTR

P24,

gag
pol
env
VIF
TAT
VPU
REV
NEF
LTR

pol
PROT
INT

POL

env
H
VIF

gp120
TAT

gp41
VPU

LTR

REV

: internal core protein as group-specifict antigen


: polymerase protein ( riverse transriptase)
: envelope glycoprotein
: viral infectivity factor
: transactivating protein
: viral protein U
: regulator of expression of virion protein
: negtive regulatory factor
: long terminal repeat

3
NEF

gene
gag

protein encode by gene

tat
rev

p24 , p7
p17
riverse trancriptase
protease (PROT)
integrase (INT)
gp 120
gp 41
TAT
REV

nef

Nef

pol
env

Fungtion of protein
nucleocapsid
matrix protein
transcribec RNA DNA
cleaves precursor polipeptide
integrates viral DNA host DNA
attachment to CD4 protein
fussion with host cell
activation of transcription v. gene
transport mRNA from nucleus
to cytplama
decrease CD4 & MHC I protein
on surface infected cellls, induce
death of uninfected CTL, I importand for pathogenesis SIV

gene

protein encode by gene

vif

Vif

vpr

Vpr

Vpu

Vpu

Fungtion of protein

Enhance infectivity by inhibit


APOBEC3G ,enzyme that
cause hypermutation of
retroviral DNA
transport viral core from
cytplasma in nondividing cells
enhance virion release from
cells

Notes : - Apolipoprotein B RNA editing enzymes

Structure of the Human


gp120
Immunodeficiency Virus HIV is agp 41
Retrovirus
gp24

P17 Matrix
protein

Lipid bilayer

Several important antigen of HIV


1. gp 120 and gp 41 (type specific glycoprotein)
gp120 interact with CD4 protein second protein
chemokine reseptors. gp 41 mediates fussion of
viral envelope and cell membrane.
Ab against gp120 neutralize innfectivity of HIV
2. Group specific antigen gp24
located in the core is not know. Ab against this
antigent not neutralize of HIV infectivity

Life Cycle of HIV


1. Attachment: Virus binds to surface
molecule (CD4) of T helper cells and
macrophages.
Coreceptors: Required for HIV infection.
CXCR4 and CCR5 mutants are resistant to
infection.

2. Fusion: Viral envelope fuses with cell


membrane, releasing contents into the
cell.

HIV Life Cycle: Attachment


Requires CD4 Receptor plus a
Coreceptor

Life Cycle of HIV


3. Reverse Transcription: Viral RNA is
converted into DNA by unique enzyme reverse
transcriptase.
Reverse transcriptase

RNA ---------------------> DNA


Reverse transcriptase is the target of several
HIV drugs: AZT, ddI, and ddC.

HIV Life Cycle: Reverse


Transcriptase Converts RNA into
DNA

Life Cycle of HIV


4. Integration: Viral DNA is inserted into host cell
chromosome by unique enzyme integrase.
Integrated viral DNA may remain latent for years
and is called a provirus.
5. Replication: Viral DNA is transcribed and RNA
is translated, making viral proteins.
Viral genome is replicated.
6. Assembly: New viruses are made.
7. Release: New viruses bud through the cell
membrane.

HIV Life Cycle: Latent versus


Active Infection

HIV Life Cycle: Latent versus


Active Infection in Macrophages

HIV Immunology

Overview of Adaptive
Immune Response

Extracellular
infection

APC

Intracellular
infection
MHC I
presentation of
endogenous
antigen
Nave
cell

Free antigen

MHC II
presentation of
exogenous
antigen

T8

Nave
Cell

B-

Nave T4
helper
cell

Cell-mediated
(CTLs)
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Th1

Th2

Humoral
(plasma cells /
antibodies)

Diagram courtesy of Dr. Samuel Anderson

Cellular Immune Responses


to HIV
CD8 Cytotoxic T lymphocyte (CTL)
Critical for containment of HIV
Derived from nave T8 cells, which
recognize viral antigens in context of
MHC class I presentation
Directly destroy infected cell
Activity augmented by Th1 response

23

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
24

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
25

HIV Evasion Methods


Makes 10 billion copies/day -> rapid
mutation of HIV antigens
Integrates into host DNA
Depletes CD4 lymphocytes
Down-regulation of MHC-I process
Impairs Th1 response of CD4 helper T
lymphocyte
Infects cells in regions of the body
where antibodies penetrate poorly,
e.g., the central nervous system
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Pathogenesis of HIV

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 macriphages
28

General Mechanisms of HIV


Pathogenesis
Direct injury
Nervous (encephalopathy and peripheral
neuropathy)
Kidney (HIVAN = HIV-associated nephropathy)
Cardiac (HIV cardiomyopathy)
Endocrine (hypogonadism in both sexes)
GI tract (dysmotility and malabsorption)

Indirect injury
Opportunistic infections and tumors as a
consequence of immunosuppression
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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
Loss of containment of HIV replication
Susceptibility to opportunistic infections
30

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
Associated with up-regulation of HIV
replication

HIV results in disruption and loss of


immunoregulatory cytokines
IL-2, IL-12
Necessary for modulating effective cellmediated immune responses (CTLs and NK
cells)
31

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
Associated with up-regulation of HIV
replication

HIV results in disruption and loss of


immunoregulatory cytokines
IL-2, IL-12
Necessary for modulating effective cellmediated immune responses (CTLs and NK
cells)
32

Consequence of Cell-mediated
Immune Dysfunction
Inability to respond to intracellular
infections and malignancy
Mycobacteria, Salmonella, Legionella
Leishmania, Toxoplama,
Cryptosporidium, Microsporidium
PCP, Histoplamosis
HSV, VZV, JC virus, pox viruses
EBV-related lymphomas
33

Consequence of Cell-mediated
Immune Dysfunction
Inability to respond to intracellular
infections and malignancy
Mycobacteria, Salmonella, Legionella
Leishmania, Toxoplama,
Cryptosporidium, Microsporidium
PCP, Histoplamosis
HSV, VZV, JC virus, pox viruses
EBV-related lymphomas
34

Consequence of Cell-mediated
Immune Dysfunction
Inability to respond to intracellular
infections and malignancy
Mycobacteria, Salmonella, Legionella
Leishmania, Toxoplama,
Cryptosporidium, Microsporidium
PCP, Histoplamosis
HSV, VZV, JC virus, pox viruses
EBV-related lymphomas
35

Transmission
Modes of infection

Sexual transmission at genital or colonic mucosa


Blood transfusion
Mother to infant
Accidental occupational exposure

Viral tropism
Transmitted viruses is usually macrophage-tropic
Typically utilizes the chemokine receptor CCR5 to
gain cell entry
Patients homozygous for the CCR5 mutation are
relatively resistant to transmission

36

Early Phases of HIV Infection of


Mucosal Surfaces
Cell free

HIV
T-cell

Immature
Dendritic cell
Skin or
mucosa

Via lymphatics or
circulation
24
hours

1.

HIV co-receptors,
CD4 + chemokine
receptor CC5
37

PEP

2.

Burst of HIV
replication
48 hours

Selective of
macrophagetropic HIV

3.

Mature Dendritic
cell in regional LN
undergoes a single
replication, which
transfers HIV to Tcell

Laboratory Markers of HIV


Infection
Viral load
Marker of HIV replication rate
Number of HIV RNA copies/mm3 plasma

CD4 count
Marker of immunologic damage
Number of CD4 T-lymphocytes
cells/mm3 plasma

38

AIDS Associated Disease


Categories
1. Gastrointestinal: Cause most of illness and death
of late AIDS.
Symptoms:
Diarrhea
Wasting (extreme weight loss)
Abdominal pain
Infections of the mouth and esophagus.
Pathogens: Candida albicans, cytomegalovirus,
Microsporidia, and Cryptosporidia.

AIDS Associated Disease Categories


2. Respiratory: 70% of AIDS patients develop
serious respiratory problems.
Partial list of respiratory problems associated with AIDS:
Bronchitis
Pneumonia
Tuberculosis
Lung cancer
Sinusitis
Pneumonitis

AIDS Associated Disease Categories


3. Neurological: Opportunistic diseases and
tumors of central nervous system.
Symptoms many include: Headaches, peripheral
nerve problems, and AIDS dementia complex
(Memory loss, motor problems, difficulty
concentration, and paralysis).

AIDS Associated Disease Categories


4. Skin Disorders: 90% of AIDS patients develop
skin or mucous membrane disorders.
Kaposis sarcoma
1/3 male AIDS patients develop KS
Most common type of cancer in AIDS patients

Herpes zoster (shingles)


Herpes simplex
Thrush
Invasive cervical carcinoma

5. Eye Infections: 50-75% patients develop eye


conditions.
CMV retinitis
Conjunctivitis
Dry eye syndrome

Drugs Against HIV


Reverse Transcriptase Inhibitors: Competitive
enzyme inhibitors. Example: AZT, ddI, ddC.
Protease Inhibitors: Inhibit the viral proteases.
Prevent viral maturation.
Problem with individual drug treatments:
Resistance.
Drug Cocktails: A combination of:
One or two reverse transcriptase inhibitors
One or two protease inhibitors.

Drug cocktails have been very effective in


suppressing HIV replication and prolonging the
life of HIV infected individuals, but long term
effectiveness is not clear.

Transmission of AIDS (Worldwide)


1. Sexual contact with infected individual: All
forms of sexual intercourse (homosexual and
heterosexual). 75% of transmission.
2. Sharing of unsterilized needles by
intravenous drug users and unsafe medical
practices: 5-10% of transmission.
3. Transfusions and Blood Products:
Hemophiliac population was decimated in
1980s. Risk is low today. 3-5% of
transmission.
4. Mother to Infant (Perinatal): 25% of
children become infected in utero, during
delivery, or by breast-feeding (with AZT only
3%). 5-10% of transmission.

Key Points
HIV is a retrovirus, capable of integrating into
host genome and establishing chronic infection
HIV can be classified into subgroups (clades)
which have characteristic geographic distribution
The important steps in the lifecycle of HIV include
cell entry, reverse transcription, integration, and
maturation/assembly
Cell-mediated immunity is critical for containment
of HIV infection and other intracellular infections
HIV evades host immunity by a variety of
mechanisms
45

Key Points (2)


HIV activates the immune system to
increase its own replication
CD4 count declines by both direct
and indirect mechanisms
HIV RNA set point predicts rate of
progression to AIDS
CD4 count decline is associated with
a predictable sequence of
opportunistic infections
46

Key Points (2)


HIV activates the immune system to
increase its own replication
CD4 count declines by both direct
and indirect mechanisms
HIV RNA set point predicts rate of
progression to AIDS
CD4 count decline is associated with
a predictable sequence of
opportunistic infections
47

Key Points (2)


HIV activates the immune system to
increase its own replication
CD4 count declines by both direct
and indirect mechanisms
HIV RNA set point predicts rate of
progression to AIDS
CD4 count decline is associated with
a predictable sequence of
opportunistic infections
48