HIV seminar Flashcards
(23 cards)
From which animals and where does HIV likely origin?
From chimpanzees in central Africa.
Around 19th century.
Are there any host genes that determine susceptibility to HIV?
Ccr5-delta32 mutation protects vs HIV-1 infection. Present in 4-16% of European descent.
Can disrupt ccr5 (chemokine receptor gene) with CRISPR/Cas9
Describe a primary HIV infection briefly
- Interaction (no activation) between virus and
DC- Infection typically with CCR5 binding strains
- DC-SIGN = PRRs
- Delivery of virus to lymph nodes
- Active replication in lymphoid tissue
- High levels of viruses in blood, systemic
spread - Immune response => down-regulation of virus
replication. - ~6 months: viral set point
What are usually the symptoms at the three phases of an HIV infection (acute, chronic, symptomatic)?
Acute:
Swollen lymph nodes, fever, diarrhea
Chronic:
Usually no symptoms.
Sporadically: fatigue, mild weight loss, generalized swollen lymph nodes, rash, shingles (“helvetesild”)
Symptomatic:
200-500 CD4+ T cells/ml:
Oral/skin lesions, genital warts, development of Kaposi’s sarcoma, reactivation of latent
<200 CD4+ T cells/ml:
Oppurtuinstic infections by protozoa/bacteria/ fungi/viruses, weight loss, malignancies, neurological symptoms
What happens at the cellular level at the three phases of an HIV infection (acute, chronic, symptomatic)?
Acute:
CD4+ T cells decline temporarily.
CD8+ T cells increase temporarily (homeostasis) & and anti-HIV-1 CTLs increase temporarily.
B cells: anti-HIV-1 Abs appear
Chronic:
CD4+ T cells gradually decline.
CD8+ T cells: levels largely unaffected and CTL responses evolve.
B cells: co-evolution of antiviral Abs and viral Ags.
Macrophage tropism develops.
Some patients: infection of CNS
Symptomatic:
CD4+ cell depletion, loss of helper function.
HIV-1-specific CD4+/CD8+ T cell exhausion.
B cells: decrease/dysregulation.
NK cells: impairment of function.
What are the effects of HIV-1 on intestinal mucosa?
Leaky gut syndrome: chronic inflammation of intestinal mucosa. Absence of lymphoid cell aggregates (Peyer’s patches) in terminal Ileum. Rupture of the epithelium.
What are “elite HIV controllers”?
Individuals who maintain normal CD4 counts and undetectable viral loads (1-30 copies of HIV RNA/ml plasma) for >10 years in absense of antiretroviral therapy.
1/3000 persons.
2+% associated with favorable HLA (MHC) types and T cell responses to Gag
Describe the infection process of HIV-1 from APC via latency to reactivation
Virus binds TLR on APC -> internalized and presented via MHC to naïve T cell
-> activated CD4+ T cells
-> infected CD4+ T cells (intact provirus), Latency
-> clonal expansion
-> Virus reactivation
Describe the link between HIV and cancer
Infection -> increased incidence: 40%
Indirect effect of dysregulation of immune system.
- No proper immune surveillance
- High cytokine levels -> inappropriate cell
proliferation, replication of oncogenic
viruses, angiogenesis
Kaposi’s sarcoma:
- Infection with human herpesvirus 8 necessary
for development
Why does HIV-1 escape from neutralizing Ab?
Antigenic variation:
Expression of functionally conserved moieties within a clonal population that are antigenically distinct.
Surface receptors on HIV-1 are changing faster than B cells can produce correct neutralizing Ab
May try to distribute broadly neutralizing Ab to avoid antigenic variation
HIV-1 and primate lentivirus genomes encode a number of proteins not found in simple retroviruses. Name these proteins. What is the unifying function of these proteins?
Simple retroviruses: Gag, Pol, and Env proteins (structural proteins).
Lentiviruses:
Non-structural proteins
- Regulatory proteins: Tat, Rev
- Tat: facilitates initiation + elongation of viral
transcription.
- Rev: Regulation of viral mRNA expression.
Facilitates nuclear export of unspliced or
singly spliced RNAs.
- Accessrory proteins: Vif, Vpu, Nef
- Antagonize cellular proteins/functions that
inhibit virus reproduction.
HIV-1 capsid (CA) is a particularly good target for cellular inhibitors because it is involved in many steps during the infectious cycle and does not easily accommodate amino acid substitutions. What processes is HIV-1 CA NOT involved in?
a. Assembly and budding
b. Protecting the viral genome from cellular sensors
c. Nuclear import
d.Packaging of the viral RNA genome
d. Not involved in packaging of viral RNA genome.
Nucleocapsid protein plays major role for the selective packaging of HIV-1 RNA genome
CA interacts with MT complex -> transported to nucleus.
Interacts iwth NPC (CA-associated preintegration complex is transported through nuclear pore that allows HIV to infect non-dividing cells.
Shields viral RNA and preintegration complex from being recognized by cytoplasmic PRRs.
What is one of the defining effects of HIV-1 reproduction on the immune system? What is the ultimate cause of death in the absence of antiviral therapy?
Effects:
- Reduction in number of CD4+ T cells in
infected individuals near end-stage disease
(greatest impact on immune system)
- Chronic inflammation. Low viral load ->
inflammation
- Can accelerate physical changes normally
associated with aging.
- AIDS – Acquired Immunodeficiency Syndrome
Cause of death:
Inability of immune system to fight infections by other pathogens (AIDS).
What are the two main contributors to the genetic diversity of the HIV-1 genome?
How do modern drug regiments combat the diversity?
Rapid replication cycle (~24 hrs).
- About 10^10 virus particles released in blood per day -> ~1 cycle per infected cell per day
High error rate of RT
- No proofreading activity
Modern drug regiments:
- Use multiple drugs that target different viral
enzymes.
Limits possibility of acquiring mutations that
allow viral escape from all drugs
simultaneously.
How are lentiviral genomes maintained in latently infected cells? How is the latent reservoir maintained during antiretroviral therapy?
After integration of retroviral DNA into cellular chromosomes, cell division will maintain integrated viral DNA (provirus) in all daughter cells.
Antiretroviral therapy:
- Targets viral replication factors/viral
replication.
- Maintenance of latent reservoir:
- Integration into transcriptionally inactive
regions -> expression suppressed -> latency
- Occasional low-level, local virus
reproduction in cells in “sanctuary” sites,
e.g., lymph nodes or in the brain, that are
not readily accessible to drugs.
Which cellular receptors enable HIV-1 entry?
Enters T cells and macrophages.
Binding of viral envelope protein gp120 to coreceptor CD4
-> envelope subunit gp41 can bind coreceptor CCR5 or CXR4 on target cell membrane
-> fusion.
Can also bind lectins -> endocytosis entry (into DCs + macrophages)
Describe the role of APOBEC3 related to HIV-1. Is there a viral counter-mechanism?
Cytidine deaminase.
Packed into virions.
Edits HIV-1 genome after infection of target cells during reverse transcription
C->U in (-) ssDNA -> G-A mutation in HIV genome (often premature stop codon)
Inhibits HIV-1 replication
HIV-1 Vif (accessory protein) promotes APOBEC3 ubiquitination by E3 ligase -> degradation
Species-specific interaction.
What is the role of TRIM5α related to a HIV-1 infection?
Major determinant of species tropism of retroviruses.
E3 ubiquitin ligases
Blocks replication during capsid uncoating.
Can act as PRR
What are the functions of tetherin during an HIV-1 infection? What is the role of viral Vpu?
Hold viruses at cell surface by inserting glycosylphosphatidylinositol membrane anchor into virion envelope or by dimerization (one at host, one at virus membrane).
->
Internalization of virus by endocytosis + degradation in endosomes.
Virus targets:
Many enveloped viruses. Retroviruses, filoviruses, herpesvirus…
Evolves under positive selection.
Vpu (accessory protein) promotes degradation of tetherin.
How can SAMHD1 block HIV-1 transcription in myeloid cells? How do viruses overcome this?
Does TREX1 have the same role as SAMHD1?
Regulates dNTP pool
-> block HIV reverse transcription
SAMHD1 = antiviral
Avoids infecting DCs to avoid IFN induction but passes through DCs to facilitate infection of helper T cells. Some viruses express Vpx accessory protein (induces SAMHD1 destruction)
TREX1 = proviral
Binds cytosolic HIV DNA and digests excess non-productive DNA that would otherwise activate IFN expression.
What are virus restriction factors? Examples?
Cellular factors that block virus infection by direct interaction with viral factors or by rendering the cellular environment incompatible with viral replication. Sct at different stages of HIV life cycle. Often induced by IFNs.
Species often differ by one/few aa due to evolution.
Examples:
APOBEC3 - Included in virus particle during assembly. Restricts replication by causing mutation -> premature stop codon
TRIM5α - inhibits uncoating
Tetherin - Inhibits fusion, facilitates endosomal destruction.
SAMHD1 - limits viral reverse transcription by reducing dNTP levels
Provirus factor:
TREX1 - exonuclease, limits immune response against HIV by degrading excessive vDNA
What is the relevance of APOBEC3 (and other restriction factors) in terms of interspecies transmission?
Restriction factors often differ with one/few amino acids due to evolution.
For APOBEC3: seq differences determine if the viral Vif protein can recognize and bind APOBEC3 (from that species) to degrade it.
One hallmark of restriction factors:
Accumulation of aa differences between proteins from different species owing to their rapid evolution in conflict with viral pathogens..
Often work as barriers to the cross-species transmission of retroviruses.
Can you mention some HIV accessory proteins and their functions?
HIV-1: Nef, Vif, Vpu, Vpr
Vif - “Viral infectivity factor”, counteracts APOBEC3G.
Vpr - viral protein R (rapidity); rapidity of virus replication + destroys T cells
Vpu - viral protein u (unique); targets tetherin
Nef - downregulates CD4 and MHCI, but give either increased or decreased viral replication.
Vpx - in HIV-2 and SIV; degrades SAMHD1
