Download 3- Opportunistic Infections associated with AIDS

Retroviridae
Classification
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The retroviruses were originally classified by the morphology of the virion
core and genome structure.
1. Alpharetroviruses
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Avian leukosis sarcoma virus (ALV)
2. Betaretroviruses
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Mouse mammary tumor virus (MMTV)
3. Gammaretroviruses
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Murine leukemia viruses (MuLV)
Feline leukemia virus (FeLV, cats)
4. Deltaretroviruses
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HTLV-1, -2 (Human T-lymphotropic virus Type I,2, known to cause a type of
cancer, referred to as adult T-cell leukemia )
5. Epsilonretroviruses (fish)
6. Lentiviruses
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HIV-1,2 , SIV, FIV
7. Spumaviruses ( or foamyviruses)
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Human foamy virus (HFV has been isolated from patients with various
neoplastic and degenerative diseases e.g MS )
Electron micrographs of HIV-infected lymphocytes, showing a large accumulation
of freshly produced virus at the cell surface
Virion Structure
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The immature virion morphology is spherical
The viral genome is a dimer of linear, positive sense,
single-stranded RNA, with each monomer 7 to 13 kb in
size (Important in high recombination rate)
The virions are sensitive to heat, detergent, and
formaldehyde.
Retrovirus Overview
Have outer matrix protein and inner core capsid containing viral genome.
Reverse transcriptase to generate DNA
Viral genes are integrated into host genome.
Ag varibility and only RNA viruses
Inducing cancers
5
Virion proteins
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Gag
◦ MA: Matrix (p17 in HIV)
◦ CA: Capsid (p24 in HIV)
◦ NC: Nucleocapsid (p7 in HIV)
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Pro-pol
◦ Protease
◦ Reverse transcriptase (RT & RNase H)
◦ Integrase
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Env
◦ TM (gp41 in HIV)
◦ SU (gp120 in HIV)
Human Immunodeficiency Virus
(HIV)
Origin of AIDS

HIV in humans originated from crossspecies infections by simian viruses in
rural Africa, probably due to direct human
contact with infected primate blood.
Receptors
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The first receptor identified for any retrovirus was the CD4
molecule, established as essential for infection by HIV-1
◦ CD4 is a surface protein on:
 T cells
 Dendritic cells (DC)
 Macrophages
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Various members of the chemokine receptor family, notably CCR5
and CXCR4, was identified as coreceptors.
◦ Coreceptors were needed to mediate the post binding step of membrane fusion
and virus entry.
HIV (arrows) Infecting a T-lymphocyte
1- Primary HIV Syndrome
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Mononucleosis-like, cold or flu-like symptoms
may occur 6 to 12 weeks after infection.
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lymphadenopathy
fever
rash
headache
Fatigue
diarrhea
sore throat
neurologic manifestations.
no symptoms may be present
2- Clinical Latency Period
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HIV continues to reproduce, CD4 count
gradually declines from its normal value of 5001200.
Lasts for an average of ten years
This stage is free from symptoms
There may be swollen glands
HIV antibodies are detectable in the blood
3- Opportunistic Infections associated with AIDS
Once CD4 count drops below 500, HIV infected person at risk
for opportunistic infections.
The following diseases are predictive of the progression to
AIDS:
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Bacterial
◦ Tuberculosis (TB)
◦ Strep pneumonia
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Viral
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Kaposi Sarcoma
persistent herpes-zoster infection (shingles)
Influenza (flu)
EBV (oral hairy leukoplakia, Burkitt’s lymphoma)
3- Opportunistic Infections associated with AIDS
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Parasitic
◦ Pneumocystis carinii
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Fungal
◦ Candida
◦ Cryptococcus
Oral Candidiasis (thrush)
Oral Hairy Leukoplakia
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Being that HIV reduces immunologic activity, the intraoral
environment is a prime target for chronic secondary
infections and inflammatory processes, including OHL, which
is due to the Epstein-Barr virus under immunosuppressed
conditions
Kaposi’s sarcoma (KS)
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Kaposi’s sarcoma (shown) is
a rare cancer of the blood
vessels that is associated
with HIV. It manifests as
bluish-red oval-shaped
patches that may eventually
become thickened. Lesions
may appear singly or in
clusters.
4- AIDS
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CD4 count drops below 200 person is considered to have
advanced HIV disease
If preventative medications not started the HIV infected
person is now at risk for:
◦ Pneumocystis carinii pneumonia (PCP)
◦ cryptococcal meningitis
◦ toxoplasmosis
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If CD4 count drops below 50:
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Mycobacterium avium
Cytomegalovirus infections
lymphoma
dementia
Most deaths occur with CD4 counts below 50.
Clinical Features
(2)
During the early period after primary infection, there is widespread dissemination of virus and a sharp
decrease in the number of CD4 T cells in peripheral blood. An immune response to HIV ensues, with a
decrease in detectable viremia followed by a prolonged period of clinical latency. Sensitive assays for viral
RNA show that virus is present in the plasma at all times. The CD4 T cell count continues to decrease
during the following years until it reaches a critical level below which there is a substantial risk of
opportunistic diseases
The role of Immune response to Virus
An immune response to HIV occurs 1 week to 3 months after
infection
The immune response is insufficient
HIV-infected cells persist in the lymph nodes
Early stage to Late stage
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monocyte-tropic or macrophage-tropic (M-tropic) strains of HIV-1
Shift
lymphocyte-tropic (T-tropic)
The role of T helper
It is responsible directly or indirectly for induction of
a wide array of lymphoid and nonlymphoid cell
functions
 activation of macrophages
 induction of functions of cytotoxic T cells, natural
killer cells, and B cells
 secretion of a variety of soluble factors that induce
growth and differentiation of lymphoid cells and affect
hematopoietic cells
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RESERVOIRS FOR HIV
 T helper
 Macrophages
 Hematopoietic stem cells
 Brain cells
Risk of transmission
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Sexual Transmission
 Female-to-male transmission
 Male-to-female transmission
 Male-to-male transmission
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Parenteral transmission
 Transfusion of infected blood
 Needle sharing
 Needle stick
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Transmission from mother to infant
Host Immunity
Innate Immune Responses
 Adaptive Humoral Immune Responses
 Adaptive Cellular Immune Responses
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◦ CD8+ T-cell Responses
◦ Virus-specific CD4 T Cells
Treatment
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FDA-approved antiretrovirals
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Nucleoside Reverse Transcriptase Inhibitors (NRTI)
Non-nucleoside RT inhibitors (NNRTI)
Protease Inhibitors (PI)
Fusion inhibitor
Integrase inhibitors (in phase III clinical trials)
Drugs against viral accessory proteins (Nef, Rev, Tat,
Vif, and Vpr)
 Highly active antiretroviral therapy (HAART)
Laboratory Diagnosis of HIV Infection
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Methods utilized to detect:
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Antibody
Antigen
Viral nucleic acid
Virus in culture
Antibodies detected in ELISA include those
directed against: p24, gp120, gp160 and gp41,
detected first in infection and appear in most
individuals
Worldwide Spread of AIDS
It was estimated by the end of 2007, a total of 33 million
people worldwide were living with HIV/AIDS, the majority
having been infected by heterosexual contact . 2.0 million
people died of AIDS and 2.7 million new infections with
HIV occurred, including 370,000 children, many of whom
were babies infected perinatally.
By the year 2005, the World Health Organization estimated
that more than 25 million people worldwide had died of
AIDS and that over 15 million children had been orphaned,
12 million of whom were living in sub-Saharan Africa
Adults and children estimated to be living with HIV/AIDS, by
continent or region, as of December 2007. It is estimated that about
2.0 million people worldwide died of HIV/AIDS in 2007.
Vaccines Against HIV
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all candidate HIV vaccines tested as of 2009 proved ineffective at
preventing infection.
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Vaccine development is difficult because HIV mutates rapidly, is not
expressed in all cells that are infected, and is not completely cleared by
the host immune response after primary infection.
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Most efforts currently are directed at the development of a T-cell based
vaccine and Recombinant viral proteins—especially those of the
envelope glycoproteins , which would be expected to protect from
disease progression rather than to protect from infection.