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Mohammed El-Khateeb
HIV/AIDS
DVL-3
April 5th 2015
Overview
• History
• Organism
• Epidemiology
• Transmission
• Disease in Humans
• Disease in Animals
• Prevention and Control
HIV and AIDS History of an infectious agent
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In Los Angeles 1967-1978: only two cases of Pneumocystis carinii pneumonia
1979 - 5 cases of Pneumocystis carinii pneumonia
All Homosexual
 Dot-like intracystic bodies of
Pneumocystis carinii in lung
 Cytologic preparation from a
bronchoalveolar lavage – Giemsa stain
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Kaposi’s sarcoma rare (immunocompromization) , Elderly
1981 - 26 cases of Kaposi’s sarcoma
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Young
Male
San Francisco and New York
All Homosexuals
HIV and AIDS
•Two rare diseases in the gay community linked to
•IMMUNOSUPPRESSION
•OPPORTUNISTIC INFECTIONS
•Lymphadenopathy
•Hodgkin’s Lymphoma
Little in common but:
• Young
• White
• Male
• Large towns
• Homosexual community
• Gay-Related Immune Deficiency
• Acquired Immune Deficiency Syndrome (AIDS)
But not all gay men got the disease
Distinguishing characteristics
 Clusters of infected men
 Apparent concentration within sexually interactive
groups
 High numbers of sex partners
 Different ways of getting a similar syndrome [Blood
transfusions, Intravenous drug use, Hemophilia
(clotting factor)]))
 Suggests an infectious agent
A retrovirus causes AIDS
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In May 1983: doctors at the Institute Pasteur in France reported that they had
isolated a new virus, which they suggested might be the cause of AIDS. BarreSinoussi F. … and Montagnier L. (1983), 'Isolation of a T-Lymphotropic retrovirus froma
patient at risk for Acquired Immune Deficiency Syndrome (AIDS)', Science, May 20
In May 1983: doctors at the NIH in the US reported that a retrovirus virus related
to Human T cell Leukemia virus was present in patients with AS.
Gelman EP … and Gallo RC. (1983), “Proviral DNA of a retrovirus, human T-cell leukemia
virus, in two patients with’AIDS, Science, May 20
January 1985 It becomes clear that LAV and HTLV-III are the same virus and
The FDA licenses the first blood test for AIDS. (HIV-1)
 1986: HIV-2
discovered in
antigenicaly distinct
virus endemic in
West Africa.
Lentivirus
 All Retroviruses contain gag, pol, pro* and env
 Lentiviruses are more complex:
• Two regulatory genes: tat and rev
• Accessory genes:
• HIV-1 nef, vif, vpr, vpu
• HIV-2 and SIV lack vpu and have vpx
 *pro is sometimes contained within pol (HIV)
Diagram of Immunodeficiency Virus (HIV)
Retroviruses have stripped down genomes
So they make good use of what they have
How does HIV infect new
people
CD4 and CXCR4
CD4 & CCR5 found
on macrophages
Viral Replication
Transmission
• HIV can be transmitted via the exchange of a
variety of body fluids from infected individuals,
such as
• Individuals cannot become infected through
ordinary day-to-day contact such as kissing,
hugging, shaking hands, or sharing personal
objects, food or water.
How is HIV contracted?
DANGER
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Health Care Setting
Tattoos / Piercings
Blood Transfusions
Blood Products
Mother to Child
Oral Sex
Vaginal Sex
Anal Sex
Injecting Drugs
ALL CLEAR AHEAD
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Sneezing / Coughing
Sharing Glasses
Showers / Pools
Protected Sex
Insects
Kissing*
HIV in different body fluids
Blood
18,000
Semen
11,000
Vaginal
Fluid 7,000
Breast
Milk 4,000
Saliva 1
Average number of HIV particles in 1 ml of these body fluids
Immune Responses to Infection
Virion
Antigen Presenting
Cell (APC, Phagocyte)
Immune Responses to Infection
Virion
CD8+ T Cell
Killer
T
Cells
Antigen Presenting
Cell (APC, Phagocyte)
Kill
Infected
Cells
Immune Responses to Infection
Virion
CD8+ T Cell
Killer
T
Cells
Kill
Infected
Cells
Antigen Presenting
Cell (APC, Phagocyte)
B Cell
Antibodies
Coat
Pathogen
Immune Responses to Infection
Virion
CD8+ T Cell
Killer
T
Cells
CD4+ T Cell
T Helper
Cells
Antigen Presenting
Cell (APC, Phagocyte)
B Cell
Early Events in HIV Infections
Latent vs. active infection
In latent infection- retroviral genome is present but is not
transcribing viral genome or mRNA for structural proteins.
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HIV - Life History
Latency – Cellular – The problem of memory T4 cells
 Only activated T4 cells can replicate virus
 Most infected T4 cells are rapidly lyzed but are replaced
 Some T4 cells revert to resting state as memory cells which are
long-lived
 Memory T4 cells cannot replicate the virus unless they become
activated
Clinical Latency
 HIV infection is not manifested as disease for years
 During apparent clinical latency, virus is being replicated and
cleared
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Stages of HIV Infection
Course of HIV Infection
P24
antigen
Anti-HIV IgM
Window: 3-5 days
‘Sensitive’ Combo assays
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Mononucleosis-like, cold or flu-like symptoms
may occur 6 to 12 weeks after infection.
Lymphadenopathy
Fever
Rash
Headache
Fatigue
Diarrhea
Sore throat
Neurologic
manifestations.
 no symptoms
may be present
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HIV and AIDS
The cellular and immunological picture
The course of the disease
1. Acute Infection
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High virus titer
Mild symptoms
Fall in CD4+ cells but recovers
Rise in CD8+ cells but recovers
A high virus titer (up to 10 million viruses per ml blood)
Macrophages infected
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HIV and AIDS
2. A strong immune response
Virus almost disappears from circulation
• Good cytoxic T cell response
• Soluble antibodies appear later against both surface and internal
proteins
• Most virus at this stage comes from recently activated (dividing)
and infected CD4+ cells
• CD4+ cell production compensates for loss due to lysis of cells
by virus production and destruction of infected cells by CTLs
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HIV and AIDS
3. A latent state
Latency of virus and of symptoms
• Virus persists in extra-vascular tissues
• Lymph node dendritic cells
• Resting CD4+ memory cells (last a very
long time - a very stable population of cells) carry provirus
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HIV and AIDS
4. The beginning of disease
•Massive loss of CD4+ cells
• CD4+ cells are the targets of the virus
• Cells that proliferate to respond to the virus are killed by it
• Dendritic cells present antigen and virus to CD4 cells
• Epitope variation allows more and more HIV to escape from
immune response just as response wanes
• Apoptosis of CD4+ cells
• HIV patients with high T4 cell counts do not develop AIDS
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HIV and AIDS
5. Advanced disease - AIDS
CD8+ cells destroy more CD4+ cells
• CD4 cell loss means virus and infected cells no longer
controlled
• As CD4+ cells fall below 200 per cu mm virus titer rises
rapidly and remaining immune response collapses
• CD8+ cell number collapses
• Opportunistic infections
• Death in ~2 years without intervention
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HIV and AIDS
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10 billion HIV particles per day
Virus half life 5.7 hours
10 -100 million virions per ml blood (set
point)
Small minority of T4 cells are infected
Virus found in lymph nodes
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Opportunistic Infections
DIAGNOSIS
Diversity Within the Individual
Homogeneous new infection
Replicates ~ 24hrs
Produces 1010 new virions a day
Average 1 mutation per replicated
genome
Rapidly develop a
“quasispecies”
HIV-1 Diversity Worldwide
HIV-1 group M:
- 9 subtypes (>30% difference)
several circulating recombinant forms
Subtype
A
B
C
D
F, G, H, J. K
CRF01_AE
CRF02_AG
CRF03_AB
other
Hemelaar et al. 2004. WHO/UNAIDS.
Diagnostic Assay Requirements
MUST DETECT ALL SUBTYPES
Antigen Detection
Antibody Detection
PCR
Quantitation
Seroconversion
Resistance
mutants
Different assays vary in their ability to detect various HIV subtypes
Laboratory Diagnosis
Antigen / antibody detection
 ELISA, serum
 HIV-1 & -2 antibodies, HIV-1 CA (p24) antigen
 Screening of blood donors
 Western Blotting
PCR
 Viral RNA or DNA provirus
 Blood or tissue specimens
 Quantitative PCR (viral load): to determine disease stage
and treatment follow up.
Classification of
Antiretroviral medicines
• NRTI (Nucleoside Reverse Transcriptase
Inhibitors)
• NtRTI (Nucleotide Reverse Transcriptase
Inhibitors)
• NNRTI ( Non-Nucleoside Reverse Transcriptase
Inhibitors)
• PI (Protease Inhibitors)
• Entry Inhibitors
• Integrase Inhibitors
Reverse Transcription
Inhibitors
Protease Blockers
X
Highly Active Anti-Retroviral Therapy
Vaccines
• Preventative
– Subunit Vaccines
– Recombinant Vector Vaccines
– DNA Vaccines
• Therapeutic
VACCINE
Vaccine
Design
DNA
How Does this Vaccine Work?
A few HIV genes are inserted into a backbone of DNA known as plasmid
The vaccine is injected into muscle of the recipient where the HIV genes are
expressed into proteins.
The viral proteins are degraded into small peptide fragments, which are then
presented by molecules on the cell surface. T cells recognizing these
molecules generate an immune response.
Live
Vectors:
(Viral and
Bacterial)
No DNA vaccines have yet been approved
for use in humans by the FDA. FDA
guidance on DNA vaccines can be found on
FDA'sConsiderations for Plasmid DNA
Vaccines for Infectious Disease Indications
The HIV or SIV genes are inserted into the genomes of live, infectious, but non- The development of viral vectors has been
disease-causing forms of viruses (e.g., adenovirus) or bacteria (e.g., Bacille
robust, with a few entering Phase III
Calmette-Guerin (BCG).
trials.
These vectors shuttle “foreign” genes along with their own into cells.
Only a few bacterial vectors are under
development in small and large
HIV proteins generated from these recombinant genes inside the cell are either
animal models, and some Phase I
secreted or displayed on the cell surface and presented to the immune
trials. The complex nature of
system.
bacteria hampers the development
of bacterial vector systems.
Viral Chemically synthesized pieces of HIV peptides or proteins that elicit strong T and
B cell responses.
Proteins or
Viral
Peptides
Virus-like
Particles
(VLPs)
Issues for HIV Vaccine
Empty, non-infectious shells of the HIV envelope protein; they mimic the outer
coat of the virus but lack a genome inside and cannot reproduce.
Because VLPs resemble the virus, they can induce high titers of neutralizing
antibodies to protect against viral challenge.
Peptide-based preparations require the
addition of an adjuvant to enhance
immunogenicity. At present, alum is the
only adjuvant authorized by FDA for
general medical use, however many
products are being tested, and some are in
clinical trials.
VLPs represent an exciting new strategy for
HIV vaccines but it has been difficult to
make them reproducibly.
Long-term control of HIV by CCR5 Δ32/Δ32
stem cell transplantation
 Chemotherapy (x4)
 Total-body irradiation (x2)
CCR5 -
off ART
no viral rebound
scBMT
(X2)
CCR5+
CCR5 -
HIV-1+
AML
HIV-1– ?
Donor
Number of people
living with HIV
Total
Adults
Women
Children (<15 years)
35.0 million [33.2 million – 37.2 million]
31.8 million [30.1 million – 33.7 million]
16.0 million [15.2 million – 16.9 million]
3.2 million [2.9 million – 3.5 million]
2014 epidemiology core slides
Global summary of the AIDS
epidemic2013
Total 2.1 million [1.9 million – 2.4 million]
People newly
Adults 1.9 million [1.7 million – 2.1 million]
infected
Children (<15 years) 240 000 [210 000 – 280 000]
with HIV in 2013
AIDS deaths in
Total 1.5 million [1.4 million – 1.7 million]
2013
Adults 1.3 million [1.2 million – 1.5 million]
Children (<15 years) 190 000 [170 000 – 220 000]
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Adults and children estimated to
be living with HIV2013
Eastern Europe &
Central Asia
North America and Western and Central Europe
2.3 million
1.1 million
[980 000– 1.3 million]
[2.0 million – 3.0 million]
Middle East & North Africa
Caribbean
250 000
[230 000 – 280 000]
Latin America
1.6 million
[1.4 million – 2.1 million]
230 000
[160 000 – 330 000]
Asia and the Pacific
4.8 million
Sub-Saharan Africa
[4.1 million – 5.5 million]
24.7 million
[23.5 million – 26.1 million]
Global total: 35.0 million
Sub-Saharan Africa: 24.7 million
Eastern and Southern Africa (ESA) Region: 18.5 million
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Estimated number of adults and children
newly infected with HIV2013
Eastern Europe & Central
Asia
110
000
North America and Western and Central Europe
[86 000 – 130 000]
88 000
[44 000 – 160 000]
Middle East & North Africa
Caribbean
12 000
[9400 – 14 000]
Latin America
94 000
[71 000 – 170 000]
25 000
[14 000 – 41 000]
Asia and the Pacific
350 000
Sub-Saharan Africa
[250 000 – 510 000]
1.5 million
[1.3 million – 1.6 million]
Total: 2.1 million
Sub-Saharan Africa: 1.5 million
Eastern and Southern Africa (ESA) Region: 1.1 million
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Estimated adult and child deaths from AIDS2013
Eastern Europe & Central
Asia
53
000
North America and Western and Central Europe
[43 000 – 69 000]
27 000
[23 000 – 34 000]
Middle East & North Africa
Caribbean
11 000
[8300 – 14 000]
Latin America
47 000
[39 000 – 75 000]
15 000
[10 000 – 21 000]
Asia and the Pacific
250 000
Sub-Saharan Africa
[210 000– 290 000]
1.1 million
[1.0 million – 1.3 million]
Global total: 1.5 million
Sub-Saharan Africa: 1.1 million
Eastern and Southern Africa (ESA) Region: 730,00
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12,9 million people on ART at the end of 2013 globally. 11,7 in low-and
middle income countries - 2 million more than at the end of 2012
Actual and projected numbers of people receiving antiretroviral therapy in low-and
middle-income countries, and by WHO Region, 2003–2015
Source: 2014 Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS).
‫‪2013‬‬
‫المفرق‬
‫المفرق‬
‫المفرق‬
‫المفرق‬
‫المفرق‬
‫المفرق‬
‫‪66‬‬
‫‪66‬‬
‫‪66‬‬
‫اربد‬
‫اربد‬
‫اربد‬
‫اربد‬
‫‪41‬‬
‫‪39‬‬
‫‪41‬‬
‫‪41‬‬
‫عجلون‬
‫عجلون‬
‫عجلون‬
‫عجلون‬
‫عجلون‬
‫عجلون‬
‫‪11‬‬
‫‪2111‬‬
‫جرش‬
‫جرش‬
‫جرش‬
‫جرش‬
‫‪2‬‬
‫‪222‬‬
‫الزرقاء‬
‫الزرقاء‬
‫الزرقاء‬
‫الزرقاء‬
‫‪ 31‬عمان‬
‫‪29‬‬
‫‪29‬‬
‫عمان‬
‫‪29‬‬
‫عمان‬
‫‪29‬‬
‫عمان البلقاء‬
‫البلقاء‬
‫البلقاء‬
‫البلقاء‬
‫‪149‬‬
‫‪149‬‬
‫‪149‬‬
‫‪10 183‬‬
‫‪11‬‬
‫‪10‬‬
‫‪10‬‬
‫مادبا‬
‫مادبا‬
‫مادبا‬
‫مادبا‬
‫‪3333‬‬
‫أردني‬
‫غير اردني‬
‫المجموع‬
‫الكرك‬
‫الكرك‬
‫الكرك‬
‫‪222‬‬
‫‪283‬‬
‫‪739‬‬
‫‪1022‬‬
‫‪ 3‬خارج االردن‬
‫‪ 3‬غير معروف‬
‫معان‬
‫معان‬
‫‪11‬‬
‫الطفيلة‬
‫الطفيلة‬
‫‪22‬‬
‫العقبة‬
‫‪1‬‬
This NAP Webpage
(www.moh.gov.jo)
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Dream
ZERO NEW INFECTION
ZERO DEATH
ZERO DISCRIMINATION
Promise and Accountability
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Important to mobilize all sectors for HIV/AIDS
response: leaving no one behind
Ambition will
be required to
get ahead of
the epidemic
and save lives
Thank you !
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