RetroViruses, AIDS, & Tumor VIruses Flashcards
who discovered Retroviruses
1911 by Peton Rous
first retrovirus
Rous Sarcoma Virus
who discovered reverse transcriptase
David Baltimore and Howard Temin in 1970
Involvement in finding reverse transcriptase
Temin had the theory; baltimore/temin found the enzyme
Isolation of the first retrovirus for human disease
1981 by Bob Gallo and associates who isolated HTLV-1
The 4H club risk group for Retroviruses
Homosexual men
Heroin addicts
Haitians
hemophiliacs
what did the 4H club die of
of normally benign opportunistics infections in the U.S.- AIDS (acquired immune deficiency syndrome
Disocovery of HIV-1
1980: MOntagnier and assocaites in paris and Gallo and colleagues at NIH isoluate HIV_1 from patients with lymphadenopathy and AIDS
where was HIV-2 discovered
In west africa in 1986
similarity of HIV-1 and HIV-2
HIV-2 RNA sequence is similar to HIV-1 (40%). HIV-2 is mostly heterosexual.
Origin of HIV
Evolved from simian virus in Africa (SIV) and spread through the rest of the world due to an increasingly mobile pop and aberrant sex
SIV>HIV-2>HIV-1 and human infection in 1930
how mnay retroviruses are there
large and diverse group of viruses
replication cycle similarity of retroviruses
Unique, with a DNA intermediate despite using RNA
Retroviruses in vertebrates
ubiquitous
do most retroviruses cause damage
no, most are benign
but other have significant pathogenicity and cause diseas and cancer
2 subfamilies of Retroviruses
Orthoretroviridae
Spumaviridae
Genome of Retroviruses
(+)ssRNA
diploid, identical copies
Virion of Retrovirues
Enveloped
proteins of Retroviruses
Reverse transcriptase (RNA-> DNA, DNA-> DNA
Integrase
Protease
How are Retroviruses characterized historically
nucleocapsid strucutre and location in the particle
how are retroviruses classified now
genome contents used to classify as simple or complex
Simple retroviruses encode what genes
Gag
Pro
Pol
Env
Complex retroviruses encode
all what simple retroviruses encode plus more
replication cycle of a Retrovirus
Attachment Entry Reverse transcription Integration Transcription from provirus Translation Assembly release Maturation - protease activity
what occures in retrovirus reverse transcription
ssRNA genome to dsDNA
what occures in retrovirus integration
Virus dsDNA into host making a provirus
how does a retrovirus enter the cell
due to membrane fusion at the cellular membrane due to receptor mediated endocytosis
The defining feature of retroviruses
Reverese transcription
when does reverse transcription begin
initiates once nucleocapside is in cytoplasm (neeed higher level of NTPs)
what prevents reverse transcription
Low NTP levels
where does Reverse transcription occur
within a large complex similar to nucleocapside
what happens if reverse transcription does not occur for a retrovirus
infection cannot progress
why is Reverse Transcriptase promiscuous
can fall off one genome copy and then continue on another
Why would promiscuous Reverese transcription be silent
When copies are identical
what happens when different genomes are in the virion of a retrovirus
many different recombinations
why are Retrocviruses difficult to vacinate
since Reverse transcriptase can move from one genome to anther, it changes antigens of the retrovirus
what must a retrovirus have access to, in order to inegrate
must access the nucleus
when does a retrovirus access the nucleus during integration
access during mitosis - requires dividng cell
also can do importation to infect non-deviding cells
how does a retrovius integrate
3 prime end of dsDNA from the virus genome is processed/opened up
Attacks target DNA creating a Nick in it
Host then repares DNA and acidentally adds the Virus genome
How can virus DNA be removed
INtegration of Virus DNA is permanent and cannot be removed
what happens if Virus DNA is integrated into the germ-line
provius becomes inherited and is called endogenous
what negative effect can integration of retrovirus cause
may disrupt host genes causing diseases such as cancer
Oncogenes for integration
Transcription factors
Secreted growth factors
GRowth factor receptors
Cell signal transduction pathways
effecienct of retrovirus replication
many defective viruses are made during replication (v. sloppy)
missing at least one of gag, pol, or env
what is required for retrovirus infection to make progeny
Require complementary infection
what can happen when Retroviruses carry oncogenes
oncogenes
do all retroviruses cause problems?
NO, can be benign
are most retroviruses cytopathic
no
effect of benign retroviruses on the cell
little impact to cell replication and physiology
Chronic infection exert small demand on cell and host resources
How does the host respond to a benign retrovirus
can cause Viremia and elicit an immune response, bt host animals may live normal lives for months and years
never eliminated by the host
Types of Retroviruses that cause disease
Slow Retroviruses
Cytopathic retroviruses
Acute transforming viruses
what is the effect of a slow retrovirus
Like High-level mutagenesis
Eventual result of a slow retrovirus
Results in humorigenesis
how many Retroviruses carry cytopathic genes
Minority
What do Cytopathic retroviruses do
Cause tissue damage directly
what do Acute transforming viruses do
Induce rapid tumor formation
How do Acute transforming viruses lead to rapid tumor formation
carry host genes (mitogenic or antiapoptiotic
Replication defective because host gene replaces an essential gene
Types of Human T-Cell Leukemia Virus (HTLV)
4:1,2,3,4
what type of HTLV is most often associated with humans
HLTV-1
what type of virus is HTLV
Deltaretrovirus
how does HTLV first isolated
in patients with cutaneous T-cell lymphoma in the 1970s
what forms when the Retrovirus first assembles
an immature virus
what happens to turn an immature virus into a mature one
proteases allow the immature to become mature and now it can replicate and infect
how many people are infected with HRLV-1
Millions of people world wide
How is HTLV-1 transmitted person to person
mother to child via breastfeding (endemic areas)
Sharing needles for drugs users
Blood transfusions
Sex transmission (less efficient)
How can HTLV-1 be transmitted within the host
Cell Associated via contact between infected and naive cells
What disease does HTLV-1 cause
Adult T-cell Lymphoma/Leukemia (ATLL)
HYLV-1 Associated Myelopathy / Tropical Spastic Paraparesis (HAM/TSP)
what must HTLV-1 be exposed to to cause Adult T-cell Lymphoma/Leukemia
Following mucosal exposure
how often does HTLV-1 cause ATLL
204% of cases
latent period for ATLL
30-50 years
What does HTLV-1 infect to cause ATLL
Infect memory T-cells
what triggers transcription of provirus HTLV-1
Antigen activation
what triggers cell proliferation with HTLV-1
Virus Tax Proteins and others
what does HTLV-1 do with ATLL
Cell become transformed generating tumors with or without virus protein expression
How often does HAM/TSP occure when infected with HTLV-1
1-2% of cases
how would someone get HAM/TSP
following transfusions
what does HAM/TSP infect
T-cells
once HAM/TSP infects T cells what happens
enter the CNS
Activate AStrocytes, microglial cells
Recruit inflammatory cells- further tissue damage
when does HAM/TSP occure
3 years after infection
progession of HAM/TSP
starts with bladder control issues
Progress to lower back pain, leg weakness or stiffness in hip
men suffer impotence or erectile dysfunction
Preventing HTLV-1
eliminate breastfeeding for HTLV-1 positive moms
INcrease screening for blood products
How to Treat ATLL
treat the lymphoma/leakemia with chemotherapy regardless of HTLV infections
how to treat HAM/TSP
Corticosteriod, interferon yielding temporary relief of symtpoms
types of HIV in humans
type 1 and type 2
type of Virus is HIV
Lentivirus
how was HIV discovered
due to immune deficiency occurring in previously healthy young gay men in 1984
who is most likely to get HIV
Homosexuals
Injection drug users
Hemophiliacs
Transfusion recipients
extent of HIV
World wide pandemic with significant impact
how bad is HIV in sub-saharan africa
it really is decreasing life expectancy
first drug to fight aids
AZT
what does AZT target as an aids med
reverse transcriptase
HIV transmission
Sex transmission (Primary route)
Parenteral
mother to infant
odds of getting HIV in sex
Female to male: 1:600-1:3000
Male to female - 1:200 - 1:2000
Male to Male - 1:10 to 1:1600
odds of getting HIV parenterally
Transfusion - 95%
needle sharing - 1:150
odds of getting HIV from mom to infant
No AZT - 1:4
AZT - less than 1:10
Latent period for AIDS
6 months to 25 years
How does HIV infection begin
Begins in virus containing blood or body fluid to a mucosal surface or blood
what does HIV target
memory T-cells (CD4+)
when does Acute infection with HIV occure
2 weeks aftetr infection
signs of HIV infection
Mucocutaneous ulceration and weight loss
what is seeded as a rusult of an acute infection (reservoir)
GALT
Rounds of infection in GALT
1st Primary infection where it accutely affects the T cell population dormancy T cells eventually begin to drop Constituional symptoms Opportunistic disease Death
Common Opportuistic infections due to HIV
CAndida Coccidioidomycosis Cryptococcus Cytomegalovirus Kaposi sarcoma Tuberculosis Taxoplasmosis Wasting due to HIV infection
Prevention of HIV
sex behavior and protection
Blood screening
Treating HIV
No vaccine
Antiviral treatments
what antivirals are used to treat HIV
Nuceloside reverse transcriptase inhibitors (NRTI)- azidothymidine (AZT)
Protease Inhibitors - Ritonavir
Non-nucleoside RT inhibitors (NNRTI) - Efavirenz
Highly Active Antiretroviral Therapy (HAART) - combines 3 of the treatment options
