Transcript Human immunodeficiency virus

Retroviruses反錄病毒 (C65, p657)
l Viruses are named because of reverse transcriptase.
l Family members are listed in Table 1 and Fig. 1.
l Human pathogens include HTLV-1, -2 and HIV-1, -2.
Table 65-1. Classification of Retroviruses
Subfamily
Characteristics
Examples
Oncovirinae
Are associated with cancer and neurologic disorders
-
B
Have eccentric nucleocapsid core in mature virion
Mouse mammary tumor virus
C
Have centrally located nucleocapsid core in mature virion
Human T-lymphotropic virus*
(HTLV-1, HTLV-2, HTLV-5),
Rous sarcoma virus (chickens)
D
Have nucleocapsid core with cylindrical form
Mason-Pfizer monkey virus
Lentivirinae
Have slow onset of disease: cause neurologic disorders and immunosuppression; Human immunodeficiency virus*
are viruses with D-type, cylindrical nucleocapsid core
(HIV-1, HIV-2), visna virus
(sheep), caprine
arthritis/encephalitis virus (goats)
Spumavirinae
Cause no clinical disease but characteristic vacuolated "foamy" cytopathology
Human foamy virus*
Endogenous
viruses
Have retrovirus sequences that are integrated into human genome
Human placental virus
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1. Structure: +ssRNA (about 9 kb for HIV) X2, capsid and envelope)
(Fig. 3)
2. viral genome include LTR,
Gag (group specific Ag, capsid, matrix, and nucleic acid proteins),
pol (reverse transcriptase, integrase, polymerase, and protease),
and env (envelope glycoproteins).
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Table 65-2. Retrovirus Genes and Their Function
Gene
Virus
Function
gag
All
Group-specific antigen: core and capsid proteins
int
All
Integrase
pol
All
Polymerase: reverse transcriptase, protease, integrase
pro
All
Protease
env
All
Envelope: glycoproteins
tax
HTLV
Transactivation of viral and cellular genes
tat
HIV-1
Transactivation of viral and cellular genes
rex
HTLV
Regulation of RNA splicing and promotion of export to cytoplasm
rev
HIV-1
Regulation of RNA splicing and promotion of export to cytoplasm
nef
HIV-1
Alteration of cell activation signals; progression to AIDS (essential)
vif
HIV-1
Virus infectivity, promotion of assembly, blocks a cellular antiviral
protein
vpu
HIV-1
Facilitates virion assembly and release, decrease of cell surface CD4
vpr (vpx*)
HIV-1
Transport of complementary DNA to nucleus, arresting of cell growth
LTR
All
Promoter, enhancer elements
﹛
pol
Simple v.s. complex viruses
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2. Replication (Fig. 5)
-- Virus infects mφ, dendritic cells, microglial cells and activated T cells via CD4 and CCR5
( M-tropic) and naïve and helper T cells via CD4 and CXCR4 (T-tropic)(Fig. 6 ).
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1.
Drug target
2.
Provirus
3.
Error rate (about
4.
1/2,000 base)
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(provirus)
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4. Human immunodeficiency virus
(HIV)
-- It is non-oncogenic virus.
-- HIV infects CD4-expressing mφand T cells
(M-tropic  T-tropic).
-- Infection reduces the number (due to cytolysis
by virus or cytotoxic T cells) and function of
CD4 T cells to cause
acquired immunodeficiency syndrome (AIDS).
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Table 65-3. Means of HIV Escape from the Immune System
Characteristic
Function
Infection of lymphocytes
and macrophages
Inactivation of key element of immune defense
Inactivation of CD4 helper
cells
Loss of activator of the immune system and
delayed-type hypersensitivity
Antigenic drift of gp120
Evasion of antibody detection
Heavy glycosylation of
gp120
Evasion of antibody detection
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4-7
l Epidemiology:
a. Based on the estimation in 2003, there are 5 million new cases each year and
3 million death per year.
b. Geographical distribution: HIV-1 is in Africa, Asia, and US. HIV-2 is in Africa.
c. Global distribution (Fig. 12)
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d. Transmission: HIV is transmitted by body fluid such as blood, semen, and
vaginal secretion (Fig. 11 and Table 4).
e. High risk population includes: sexually active people, drug abusers,
people receiving blood, blood product, and organs before 1985, and
health care workers.
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Table 65-4. Transmission of HIV Infection
Routes
Specific Transmission
Known Routes of Transmission
Inoculation in
blood
Transfusion of blood and blood products
Needle sharing among intravenous drug abusers
Needlestick, open wound, and mucous membrane exposure in health
care workers
Tattoo needles
Sexual
transmission
Anal and vaginal intercourse
Perinatal
transmission
Intrauterine transmission
Peripartum transmission
Breast milk
Routes Not Involved in Transmission
Close personal
contact
Household members
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Health care workers not exposed to blood
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lClinical Symptoms:
--acute infection: flu like symptoms, mononucleosis, and aseptic meningitis
--Stage 1: lymphoadenopathy
--Stage 2: weight loss, malaise, opportunist infections, diarrhea, night sweats, fatigue,
and wasting (slim) disease in African
--Stage 3 (Onset of disease occurs when CD4 T cells are < 200/μl blood)
Full blown AIDS with weight loss,
diarrhea for > 1 month,
and indicator diseases (p. 668, Table 5) .
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Lab. diagnosis: (Table 6)
Table 65-6. Laboratory Analysis for HIV
Test
Purpose
Serology
Enzyme-linked
Initial screening
immunosorbent assay
Latex agglutination
Initial screening
Rapid oral antibody test
Initial screening
Western blot analysis
Confirmation test
Immunofluorescence
Confirmation test
Virion RNA RT-PCR
Detection of virus in blood
Real-time RT-PCR
Quantitation of virus in blood
Branched-chain DNA
Quantitation of virus in blood
p24 antigen
Early marker of infection
Isolation of virus
Test not readily available
CD4 : CD8 T-cell ratio
Correlate of human immunodeficiency virus disease
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l Prevention, treatment, and control
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BOX 65-4. Potential Antiviral Therapies for HIV Infection
a. Four types of drugs
b. AZT is for infected pregnant women.
c. Antiviral drug cocktail (highly active
antiretroviral treatment, HARRT) is used
for infected people.
d. Education: monogamous and safe sex;
use of condoms; promotion of clean
needles for drug abusers (needle exchange)
e. Blood, blood product, and organ screening
f. Infection control in the hospitals
c. There is no effective preventive or therapeutic
vaccine because HIV mutates rapidly,
there is no good vaccine strategy, and
animal model is not available.
Nucleoside Analogue Reverse Transcriptase Inhibitors
•Azidothymidine (AZT) (Zidovudine/retrovir)
•Dideoxycytidine (ddC) (Zalcitabine )
•Dideoxyinosine (ddI) (Didanosine )
•d4T (Stavudine )
•3TC (Lamivudine )
•Tenofovir disoproxil fumarate (adenosine class)
(Viread)
•ABC (Abacavir)
Non-nucleoside Reverse Transcriptase Inhibitors
•Nevirapine (Viramune)
•Delavirdine (Rescriptor)
•Efavirenz (Sustiva)
Protease Inhibitors
•Saquinavir (Invirase/Fortovase)
•Ritonavir (Norvir)
•Indinavir (Crixivan)
•Lopinavir (Kaletra)
•Nelfinavir (Viracept)
•Amprenavir (Agenerase)
•Fosamprevavir (Lexavir)
•Atazanavir (Reyataz)
Fusion Inhibitor
•T-20 (enfuvirtide/Fuzeon)
Highly Active Antiretroviral Therapy (HAART)
(Combination)
•Abacavir/zidovudine/lamivudine (Trizivir)
•Indinavir/AZT/3TC
•Ritonavir/AZT/3TC
•Nelfinavir/AZT/3TC
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•Nevirapine/AZT/ddI
R10
•Nevirapine/indinavir/3T
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2. Oncogenic retroviruses cause leukemia, sarcoma, and lymphoma.
They are not cytolytic and belonged to Oncovirinae (also called RNA tumor
viruses).
l Sarcoma, lymphoma, and acute leukemia (non human) viruses have
incorporated cellular genes (protooncogenes) encoding
growth-controlling factors.
.
l Representatives of viral oncogenes are listed in Table 8.
Function
Oncogene
Virus
Tyrosine kinase
Src
Rous sarcoma virus
Abl
Abelson murine leukemia virus
Fes
ST feline sarcoma virus
erb-B (EGF receptor)
Avian erythroblastosis virus
erb-A (thyroid hormone receptor)
Avian erythroblastosis virus
Ha-ras
Harvey murine sarcoma virus
Ki-ras
Kirsten murine sarcoma virus
Myc
Avian myelocytomatosis virus
Myb
Avian myeloblastosis virus
Fos
Murine osteosarcoma virus FBJ
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Avian sarcoma virus
4-11
Growth factor receptors
Guanosine triphosphate-binding proteins
Nuclear proteins
Jun
l Human pathogens include HTLV-1, 2, and 5
a. HTLV-1 causes adult acute T-cell lymphocytic leukemia (ATLL)
and HTLV-1-associated myelopathy (an neurological disorder)
HTLV-2 is isolated from atypical form hairy cell leukemia, and
HTLV-5 is isolated from malignant cutaneous lymphoama.
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b. They can not transform cells so they induce disease by different mechanisms.
Table 65-7. Mechanisms of Retrovirus
Oncogenesis
Disease
Speed
Effect
Acute leukemia
or sarcoma
Fast: Oncogene
Direct effect
Provision of growth-enhancing proteins
Leukemia
Slow:
Indirect effect
Transactivation
Transactivation protein (tax) or long-terminal repeat promoter sequences
that enhance expression of cellular growth genes
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b. Pathogenesis and immunity
l Virus is transmitted by sexual intercourse and body fluid like blood
and breast milk.
l Virus infects CD4 T cells (which reside in skin) and neurons.
l Viral gene, tax, induces IL-2 and its receptor to cause clonal outgrowth
of particular T-cells in adult ATLL in about 30 years.
l Infected hosts elicit Ab against virus glycoprotein gp46.
l Virus infection causes immunosuppression.
c. Epidemiology.
l HTLV-1 is transmitted by the same route as HIV.
l It is endemic in some areas. (35% people are infected in Okinawa).
In those areas, children acquire virus in breast milk and
adults are infected sexually.
Intravenous drug abuse and blood transfusion also transmit virus in US.
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d. Clinical syndromes
l ATLL develops in 5% infected patients over a 30- to 50-year period.
Malignant CD4 helper cells are pleomorphic and have lobulated
nuclei (like flowers).
l Skin lesions develop in ATLL patients.
l ATTL patients die within
a year of diagnosis.
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e. Lab. Diagnosis
ELISA is used to detect viral antigens and specific Ab, and
RT-PCR is used to detect viral genome.
f. Treatment, prevention and control.
l AZT plus interferon alpha are used to treat ATTL.
No treatment and vaccine are available for virus infection.
Control measures are similar to HIV.
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A 28-year-old man had several complaints. He had a bad case of thrush
(oral candidiasis) and low-grade fever, had serious bouts of diarrhea,
had lost 20 pounds in the past year without dieting, and, most
seriously, complained of difficulty breathing. His lungs showed a
bilateral infiltrate on radiographic examination, characteristic of P.
carinii pneumonia. A stool sample was positive for Giardia organisms.
He was a heroin addict and admitted to sharing needles at a
"shooting gallery."
1.
2.
3.
4.
5.
What laboratory tests should have been done to support and confirm a
diagnosis of HIV infection and AIDS?
How did this man acquire the HIV infection? What are other high-risk
behaviors for HIV infection?
What was the immunologic basis for the increased susceptibility of
this patient to opportunistic infections?
What precautions should have been taken in handling samples from
this patient?
Several forms of HIV vaccines are being developed. What are
possible components of an HIV vaccine? Who would be appropriate
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recipients of an HIV vaccine?