Retroviruses Flashcards
genome type
2 copies of (+)ssRNA with a dsDNA intermediate
capsid structure
HIV = cone shaped
enveloped?
enveloped
What two factors enable recombination of retroviruses?
2 copies of (+)ssRNA
they are retrotransposons = integrates into host genome = can pick up new DNA
Where does RT work?
RT begins in the capsid in the cytoplasm
integrase (IN)
inserts dsDNA into host genome
viral protease (PR)
required for maturation
nucleocapsid vs capsid
NC coats viral genome
CA forms cone shell
What are the 3 host dependency factors that are packaged
ICAM-1 assists in binding to target cells
tRNA-Lys is taken from the host and used as a primer for RT
Cyclophilin (CypA) modulates CA uncoating (timer for dsDNA release after RT)
VAP and does it do fusion?
envelope (Env) and it also does fusion
receptor and main coreceptor
Envelope (Env) binds CD4 and coreceptor CCR5
How do we know that the co-receptor usage of HIV is critical for its infection?
Steve Crohn
CCR5(delta)32 mutation
Hetero = susceptible but slower progression
Homo = highly resistant
Be familiar with the virus life cycle of retroviruses. You will not need to write this out from memory.
a. Env binds CD4 and CCR5
b. Env-mediated fusion at the plasma membrane. Conformation change causes fusion
c. RT begins in the capsid
d. Nuclear import of the entire capsid
e. Capsid uncoating in nucleus via CypA
f. dsDNA release into nuclus
g. dsDNA integrates into host genome via integrase
h. transcription and splicing
i. nuclear export of RNA
j. translation of viral proteins
k. assembly and budding
l. maturation
Understand the four basic steps of reverse transcription
a. Host tRNA primer is packaged with the virus
b. RNA-dependant DNA synthesis (RT)
c. Ribonuclease H (RNAse H) in RT degrades the (+)ssRNA
d. End result is dsDNA
the role of (+)ssRNA in HIV
just a template for RT to make dsDNA
Understand how integration occurs, and its consequences
a. Integrase brings both ends of linear DNA together by binding to both at (Long terminal repeats) LTRs
b. Induces double-stranded breaks at both LTRs and the host genome
c. Ligation between viral and host genome
d. Now an integrated provirus
what is the promoter for transcription
the 5’ LTR
gene product fates
Half the HIV genome is produced as polyproteins that will be processed by protease AFTER RELEASE as part of viral maturation
The other gene products are expressed after splicing.
What are retrotransposons
Retrotransposons = genetic regions that copy and paste themselves into different genomic locations
RNA is transcribed, RTed, then reintegrated
Parts of eukaryotic genomes from extinct viruses
What are endogenous retroviruses
Endogenous retroviruses = retrotransposons that are derived from ancient retroviruses
HIV-1 is from?
chimps and gorillas
HIV-2 is from?
monkeys
Which HIV has lead to the pandemic?
HIV-1
What factors prevent us from getting all 40+ SIVs?
Exposure
1. We aren’t that exposed to non-human primates
Spillover
1. Must eat/handle bushmeat or be bit
2. Can have high viral load in blood
3. We are closely related to Old World primates (chimps)
Spread
1. Integrates into genome
2. Replicate in high amounts without killing host too fast
Be familiar with the origins of the HIV-1 pandemic, from initial zoonotic transmission to its introduction to the United States
a. HIV-1 group M(ajor) came from chimps infected with SIVcpz
b. M spread in Kinshasa because it was a fast growing city due to being along the river and having railroads
c. Belgian public health campaigns fucked things up by sharing needles
d. Rail and river travel allowed mass transit
e. Introduced into NYC in the 70s
RT inhibitor
prevents dsDNA intermediate formation
protease inhibitor
prevents maturation
What is the meaning behind the public health message U=U?
Undetectable = Untransmittable
90-90-90
Inform 90% of HIV infected people of their status
Get 90% of them on ART (antiretroviral therapy)
Goal of 90% of those having suppressed viral loads
Why do modern antiretroviral therapies require the use of a combination of drugs?
HIV evolves resistance quickly if only one drug
Be familiar with how Timothy Ray Brown was cured of HIV. Why is this cure not feasible for those living with HIV?
a. HIV caused acute myeloid leukemia
b. Got bone marrow transplant with someone homo for CCR5(delta)32
c. BMT has 50/50 survival and is expensive and hard
What is the latent reservoir? How is the reservoir a barrier to cure?
HIV goes dormant from ART and hides in cell and isn’t actively replicating
Understand one strategy being developed for HIV cure
Shock and kill
Use latency reversal agents (LRAs) to wake HIV out of latency
Kill actively infected cells with immunotherapy
What is the major hurdle in developing a preventative vaccine against HIV? What kinds of antibodies need to be elicited by a vaccine to effectively prevent HIV infection in all people globally?
RT cannot proofread so its very error prone and so the main antigen (Env) is extremely variable
Need broadly-neutralizing antibodies
