Download AIDS

Lectures for biomedical students
Viruses of Herpesviridae
疱疹病毒
Dr. Jing Qian
Dept. of Medical Microbiology and Parasitology
Medical school, Zhejiang university
Email: [email protected]
2014.6.3
Herpesvirus
Introduction
Herpesvirus
Greek word
herpein
----to creep
Herpesvirus
Sarcoma
Variable
Herpesvirus
Sarcoma
Human Herpesviruses
Latent infection
The Virus persists in an occult, or cryptic, from
most of the time. There will be intermittent
flare-ups of clinical disease, Infectious virus
can be recovered during flare-ups. Latent virus
infections typically persist for the entire life of
the host.
Sarcoma
Variable
Human Herpesviruses (HHV)
H
Sarcoma
Variable
Common features
•
Herpesviruses have large, enveloped icosadeltahedral capsids containing
double-stranded DNA genomes.
•
Herpesviruses encode many proteins that manipulate操纵 the host cell and
immune response.
•
Herpesviruses encode enzymes (DNA polymerase) that promote viral DNA
replication and that are good targets for antiviral drugs.
•
DNA replication and capsid assembly occurs in the nucleus.
•
Virus is released by exocytosis, cell lysis, and through cell-cell bridges.
•
Herpesviruses can cause lytic, persistent, latent, and, for Epstein-Barr virus,
immortalizing infections.
•
Herpesviruses are ubiquitous.
•
Cell-mediated immunity is required for control.
Viral genes essential for viral replication in culture
Subfamily
Herpesvirus
Herpes simplex Virus (HSV)
• HSV-1 (HHV-1)
• HSV-2 (HHV-2)
Subfamily
infectant reservoir
patients and carriers
transmitted ways
•HSV-1:
contact
•HSV-2:
sexually
vertical
transmission
Pathogenesis
• primary and recurrent
infections
– cytolytic infection
• latent infection
– latently infected ganglia in a
non-replicating state
– trigeminal ganglia三叉神经
节(HSV-1); sacral ganglia骶
神经节(HSV-2)
Triggers of HSV
Recurrences
•UV-B radiation (skiing, tanning)
•Fever (hence the name "fever blister")
•Emotional stress (e.g. final
examinations, big date)
Primary herpetic gingivostomatitis
原发性疱疹性龈口炎
•Physical stress (irritation)
•Menstruation
•Foods: Spicy, acidic, allergies
•Immunosuppression
•Transient (stress related)
•Chemotherapy, radiotherapy
•Human immunodeficiency virus
Cold sore of recurrent herpes labialis
复发性唇泡疹引起的感冒疮
Clinical
syndromes
• Oropharyngeal disease/
keratoconjunctivitis
– HSV-1 (usually)
– 6m - 2y
• genital herpes
– HSV-2 (usually)
• herpes encephalitis
– HSV-1 (90%)
• neonatal herpes
– HSV-2 (75%)
A baby girl is shown in Slide 22. I took this
picture postmortem; the baby was 28 weeks
gestation and died of disseminated herpes,
neonatal herpes simplex encephalitis. You
can see crusted lesions all over the baby's
face.
http://www.medscape.org/viewarticle/528947_5
Diagnosis
multinucleate cell with dark
staining inclusions
Diagnosis
Plaque Assay
Diagnosis
Diagnosis
Treatment
• acyclovir
• Patients with genital herpes should avoid intercourse
when they have the prodromal itching symptoms or an
active lesion.
Herpesvirus
Varicella-Zoster Virus (HHV-3)
Subfamily
Mechanism of spread of varicella-zoster virus (VZV) within the body
means of spreading: respiratory tract and close contact
primary target cells
mucoepithelial cells
place of latency
neuron
Pathogenesis and clinical syndromes
chicken-pox (Varicella)
Each spot starts as a 2-4 mm diameter
red papule which develops an irregular
outline (rose petal) as a small vesicle
appears on the surface. This 'dew drop
on a rose petal' appearance is very
characteristic of chickenpox.
Pathogenesis and clinical syndromes
ganglia
Pathogenesis and clinical syndromes
Shingles
Pathogenesis and clinical syndromes
The virus may then be
reactivated under stress or
with immune suppression.
Congenital Varicella syndrome
• caused by infection in utero
during the first trimester
• leads to scarring of the skin of
the limbs, damage to the lens,
retina and brain and
microphthalmia
• or at birth from infected mother
• severe skin infection
Treatment
• acyclovir
Vaccine
• live attenuated
vaccine virus
Herpesvirus
Cytomegalovirus (HHV5)
Subfamily
Sources of Cytomegalovirus Infection
Age Group
Source
Neonate
Transplacental transmission, intrauterine
infections, cervical secretions
Baby or child
Body secretions: breast milk, saliva, tears, urine
Adult
Sexual transmission (semen), blood transfusion,
organ graft
Outcomes of cytomegalovirus (CMV) infections
The outcome depends very heavily on the immune status of the patient
LABORATORY DIAGNOSIS
Histology
H&E stain of lung section showing nuclear
inclusions with the appearance of an "owl's
eye". The inclusion is surrounded by a
clear halo that extends to the nuclear
membrane. CMV infection can occur
without the typical cytomegalic cells.
Immune and DNA Probe Techniques
Culture
Serology
Treatment
Ganciclovir
Foscarnet
Acyclovir is not effective
Herpesvirus
Epstein- Barr Virus (HHV4)
Subfamily
potential outcomes of EBV infection
•replicate in B cells or epithelial cells permissive for EBV replication.
•cause latent infection of B cells in the presence of competent T cells.
•stimulate and immortalize B cells.
Diseases related to EBV infection
•Burkitt's lymphoma (Africa)
large multinucleated cells
Diseases related to EBV infection
•Burkitt's lymphoma (Africa)
•nasopharyngeal carcinoma
(Guangdong, China; areas in southeast Asia)
Diseases related to EBV infection
•Burkitt's lymphoma (Africa)
•nasopharyngeal carcinoma (Guangdong, China; areas in southeast Asia)
• infectious mononucleosis (Europe, North America)
A conjunctival hemorrhage of the right eye
of this patient with infectious mononucleosis.
Atypical T-cell (Downey cell) characteristic of infectious
mononucleosis. The cells have a more basophilic and
vacuolated cytoplasm than normal lymphocytes, and the
nucleus may be oval, kidney shaped, or lobulated. The cell
margin may seem to be indented by neighboring red blood
cells.
Treatment and prevention
• no drugs available to treat Epstein-Barr virus.
• A vaccine is being developed.
FDA-Approved Antiviral Treatments for Herpesvirus
Infections
Herpes Simplex 1 and 2
•Acyclovir
•Penciclovir
•Valacyclovir
•Famciclovir
•Adenosine arabinoside
•Iododeoxyuridine
•Trifluridine
Epstein-Barr Virus
•None
Varicella-Zoster Virus
•Acyclovir
•Famciclovir
•Valacyclovir
•Varicella-zoster immune globulin
•Zoster immune plasma
•Live vaccine
Cytomegalovirus
•Ganciclovir*
•Valganciclovir*
•Foscarnet*
•Cidofovir*
Retroviridae
RETROVIRIDAE
IMPORTANT ASPECTS
1. Contain a helical nucleoprotein
complex inside an icosahedral capsid
which is enveloped
2. Genomic RNA undergoes reverse
transcription
3. Genome (as DNA) integrated into
host cellular DNA
4. Some members carry oncogenes
5. HIV-1, the cause of AIDS
HIV
Human Immunodeficiency Virus 1+2
AIDS Acquired ImmunoDefiency Syndromes
Global situation
2006REPORT ON THE GLOBAL AIDS EPIDEMIC (UNAIDS)
UNAIDS: joint united nations programme on HIV/AIDS
UNAIDS strategy goals by 2015:
•Sexual transmission of HIV reduced by half, including among young people, men
who have sex with men and transmission in the context of sex work
•Vertical transmission of HIV eliminated, and AIDS-related maternal mortality reduced
by half
•All new HIV infections prevented among people who use drugs
•Universal access to antiretroviral therapy for people living with HIV who are eligible
for treatment
•TB deaths among people living with HIV reduced by half
•People living with HIV and households affected by HIV are addressed in all national
social protection strategies and have access to essential care and support
•Countries with punitive laws and practices around HIV transmission, sex work, drug
use or homosexuality that block effective responses reduced by half
•HIV-related restrictions on entry, stay and residence eliminated in half of the
countries that have such restrictions
•HIV-specific needs of women and girls are addressed in at least half of all national
HIV responses
•Zero tolerance for gender-based violence
“Zero new HIV infections. Zero discrimination. Zero AIDS-related deaths.”
HIV
AIDS
Virology of HIV
HIV structure
• nucleocapsid
– +ssRNA 2copies
– reverse transcriptase (RTase)
– P24 核心蛋白
• envelope
– P17 内膜蛋白
– lipid bilayer membrame
– gp120
-- gp41
HIV genome
• long terminal repeat, LTR (5’, 3’- end)
• 3 structure genes and 6 regulator genes
– gag → P55 → P24, P17, P15( P7,P9)
– pol → RTase, p32 and protease p10
– env → glycoprotein (gp120 and gp41)
– 6 regulator genes
• tat, rev and nef are most important
HIV genome
HIV: 15 proteins (9 genes) and an RNA
~10 kb
role of accessory proteins, multiple functions to counter intrinsic, innate and acquired immunity
Pox viruses: >100 ORFs
(e.g. Smallpox)
~200 kb
The structure and genetic map of HIV
The HIV replication cycle
Electron micrograph showing HIV budding
from the cell surface before release.
(Courtesy of D Hockley.)
The attachment of HIV :
Receptor and coreceptor
Macrophage lineage
Macrophage
Dendritic cells
Microglial celss
M-tropic
The attachment of HIV :
Receptor and co-receptor
T cells
Naiive T cells
T helper cells
T-tropic
HIV
AIDS
Pathogenesis and immunity
Disease Mechanisms of HIV
• Human immunodeficiency virus primarily infects CD4 T cells and cells of the
macrophage lineage (e.g., monocytes, macrophages, alveolar macrophages of
the lung, dendritic cells of the skin, and microglial cells of the brain).
• Virus causes lytic infection of CD4 T cells and persistent low-level productive
infection of macrophage lineage cells.
• Virus causes syncytia formation, with cells expressing large amounts of CD4
antigen (T cells) with subsequent lysis of the cells.
• Virus alters T-cell and macrophage cell function.
CD4+ T cell↓
Means of HIV Escape from the Immune System
Time course and stages of human immunodeficiency virus (HIV) disease.
HIV
AIDS
Transmission
Routes of HIV transmission
•sexual
male homosexual
heterosexual
•parenteral
iv drug users
blood and blood products
•perinatal
Routes of HIV transmission
ROUTES NOT INVOLVED IN TRANSMISSION:
CLOSE PERSONAL CONTACT
Household members; Health care workers not exposed to blood
Routes of HIV transmission
HIV
AIDS
Clinical syndromes
Time course and stages of human immunodeficiency virus (HIV) disease.
Clinical findings
•HIV-Positive without Symptoms
•Early Stages of HIV: Signs and Symptoms
•Chronic Phase or Latency: Signs and Symptoms
•AIDS: Signs and Symptoms
Early Stages of HIV: Signs and Symptoms
•Fever
•Chills
•Rash
•Night sweats
•Muscle aches
•Sore throat
•Fatigue
•Swollen lymph nodes
•Ulcers in the mouth
Chronic Phase or Latency: Signs and Symptoms
no symptoms
last up to 10 years—sometimes longer
AIDS: Signs and Symptoms
•rapid weight loss
•dry cough
•recurring fever or profuse night sweats
•profound and unexplained fatigue
•swollen lymph glands in the armpits, groin, or neck
•diarrhea lasting more than a week
•white spots or unusual blemishes on the tongue, in the mouth, or in the throat
•pneumonia
•red, brown, pink, or purplish blotches on or under the skin or inside the mouth,
nose, or eyelids
•memory loss, depression, and other neurological disorders
AIDS: Opportunistic Infections
Brain
Eyes
Cryptoccoccal
Menigitis
Cytomegalovirus
(CMV)
HIV-related
Encephalopathy
Lymphatic
System
Progressive
Multifocal
Leukoencephalo
pathy (PML)
Non-Hodgkin's
lymphoma
Toxoplasmosis
Mouth and
Throat
Candidiasis
Skin
Lung
Herpes Simplex
Coccidiomycosis
Kaposi's
Sarcoma
Histoplasmosis
Shingles
GI Tract
Cryptosporidiosis
Cytomegalovirus
Mycobacterium
Avium Complex
Pneumocystis
Carinii
Recurrent
Pneumonia
Tuberculosis
(TB)
The Chronic Phase of HIV-1
1400
Plasma viral titer by PCR or bDNA assay
Plasma viral titer by culture or p24 antigen
Number of CD4 + cells
106
1200
1000
104
800
103
600
102
400
101
200
1
2
9
CD4+ Count
Plasma Viremia
105
10
Time (Years)
PCR=polymerase chain reaction; bDNA=branched DNA.
Adapted with permission from Saag. In: DeVita et al, eds. AIDS: Etiology, Treatment and Prevention.
4th ed. Lippincott-Raven Publishers; 1997:203-213.
The Late Phase of HIV-1
1400
Plasma viral titer by PCR or bDNA assay
Plasma viral titer by culture or p24 antigen
Number of CD4 + cells
106
1200
1000
104
800
103
600
102
400
101
200
1
2
9
CD4+ Count
Plasma Viremia
105
10
Time (Years)
PCR=polymerase chain reaction; bDNA=branched DNA.
Adapted with permission from Saag. In: DeVita et al, eds. AIDS: Etiology, Treatment and Prevention.
4th ed. Lippincott-Raven Publishers; 1997:203-213.
The Variable Course of HIV-1 Infection
Typical Progressor
AIDS
Viral Replication
 months
B
 months
years
Nonprogressor
years
Clinical Latency
CD4 Level
C
Viral Replication
Primary HIV
Infection
AIDS
CD4 Level
CD4 Level
A
Primary HIV
Infection
Viral Replication
Primary HIV
Infection Clinical Latency
Rapid Progressor
?
 months
years
Reprinted with permission from Haynes. In: DeVita et al, eds. AIDS: Etiology, Treatment and Prevention.
4th ed. Lippincott-Raven Publishers; 1997:89-99.
HIV
AIDS
HIV Diagnosis
Reasons for HIV infection test
•To identify those with the infection
•To identify carriers who may transmit infection to others
specifically:
blood or organ donors
pregnant women
sex partners
•To follow the course of disease and confirm the diagnosis of AIDS
HIV-diagnosis goes to two steps
STEP 1
STEP 2
Case definition of a HIV-positive test result
?
Detection of at least one env gene product
plus another non-env gene product
Confirmed HIV infection
Kinetic of viral makers during primary HIV infection
Elsevier 2004, Infectious Disease 2e
Immunoblot reactivity in a HIV seroconverter
equivocal
HIV positive
Elsevier 2004, Infectious Disease 2e
HIV
AIDS
Treatment, prevention and control
Possible sites of intervention in the inhibition of HIV
replication
Therapeutic intervention
Reverse transcriptase inhibitors
(RTI)
Protease inhibitors
Highly active antiretroviral therapy=HAART
• since 1983:
HAART is a combination therapy of at least 3 antiviral drugs
• efficient>80% of those who receive a therapy
• reduction of viral replication < 100 copies/mL
• reduction in the number of AIDS-affected persons and AIDS-affected
persons and AIDS-deaths in USA and Western Europe
Elsevier 2004, Infectious Disease 2e
Highly active antiretroviral therapy=HAART
• since 1983:
HAART is a combination therapy of at least 3 antiviral drugs
• efficient>80% of those who receive a therapy
• reduction of viral replication < 100 copies/mL
• reduction in the number of AIDS-affected persons and AIDS-affected
persons and AIDS-deaths in USA and Western Europe
Remember: AIDS-therapy does not cure!!!
Human T-leukemia Virus and Other
Oncogenic Retroviruses
Groups of Retroviruses
• Oncovirinae
important
Tumor viruses and similar
• Lentiviruses
important
Long latent period
Progressive chronic disease
HIV
•…
Retroviruses known to cause human cancer
• Human T cell lymphotropic virus -1 (HTLV-1)
Adult T cell leukemia, Sezary T-cell leukemia
Africa, Caribbean, Some Japanese Islands
• Human T cell lymphotropic virus -2 (HTLV-2)
Hairy cell leukemia
From BSE to Prion
Bovine spongiform encephalopathy (BSE)
mad-cow disease
Global mad cow cases map
Dark green areas are countries with confirmed human cases of vCJD. Light
green shows countries which have reported cases of only
CAUSE?
Discovery of PRION
•Stanley B. Prusiner of the University of California, San
Francisco
•Nobel Prize in Physiology or Medicine in 1997
Pathogenesis: from PrPc to PrPsc
PrPc (cellular prion protein)
PrPsc (scrapie prion protein)
in the normal and diseased tissue
only in diseased tissue
with alfa-helix
with beta- pleated sheet and alfa-helix
sensitive to protease K
resistant to protease K
Heterodimer model of prion propagation
Prion replication cycle
The following diseases are associated with prion
• Man
– Kuru disease
– Creutzfeldt-Jacob disease (CJD)
– Gerstmann-Straussler syndrome (GSS)
• Animals
– scrapie of sheep and goats
– transmissible mink encephalopathy(TMM)
– bovine spongiform encephalopathy (BSE, crazy cow)
The characters of Prion diseases
normal
rabies virus
the virus
• member of the Lyassavirus of the Rhabdoviridae
• -ssRNA enveloped virus, helical symmetry
Pathogenesis: rabies
• the commonest mode
of transmission in man
– by the bite of a rabid
animal
– the contamination of
scratch wounds by
virus- infected saliva.
1. Raccoon is bitten by a rabid animal
2. Virus enters wound via saliva
3. Virus spreads through nerves to spinal cord and brain
4. Incubation period of 3-12 weeks with no symptoms
5. In brain the virus replicates and spreads to other tissues including th
6. The animal dies within a week
Pathogenesis: rabies
• the commonest mode
of transmission in man
– by the bite of a rabid
animal
– the contamination of
scratch wounds by
virus- infected saliva.
Pathogenesis: rabies
•
incubation/prodromal period (usually of up
to two weeks),
pain or itching at the site of the wound, fever,
headache and gastrointestinal problems.
•
CNS infection
•
hydrophobia. This fear of water is the result
of the pain associated with drinking.
•
seizures and hallucinations.
•
paralysis may lead to respiratory failure.
•
comatose.
•
Because of the neurological problems
including respiratory paralysis, death ensues
Pathogenesis: rabies
1. Raccoon is bitten by a rabid animal
2. Virus enters wound via saliva
3. Virus spreads through nerves to spinal cord and brain
4. Incubation period of 3-12 weeks with no symptoms
5. In brain the virus replicates and spreads to other tissues
including the salivary glands. Signs of disease occur
6. The animal dies within a week
• laboratory diagnosis
– dogs and cats in a rabies endemic area should beheld for 10 days for
observation
– Histopathology : Negri bodies
– Rapid virus antigen detection
Negri body in infected neuron
Human papillomavirus
•circular dsDNA, naked
•disease
 skin: warts
 Genital warts: HPV 6, 11
 cervix carcinoma: HPV 16, 18
The Nobel Prize in Physiology or Medicine 2008
Harald zur Hausen
Discovery of human papilloma virus causing cervical cancer