Upgrade to remove ads
Virology - Unit 2 - HIV
Terms in this set (65)
Cellular proteins whose function is needed by the virus to successfully complete certain steps of the viral life cycle.
What would the absence of HIV-dependency factors do?
Greatly reduce or suppress cellular susceptibility to HIV-1 infection
Which HIV-1 proteins participate in binding to receptors & entry?
gp120 & gp41
True or False:
Development of a humoral immune response & subsequent generation of antibodies targeting HIV-1 envelope glycoproteins causes the virus to generate new variants that can escape the negative selection pressure exerted by the antibodies
FALSE - Virus is always generating new variants through viral replication, regardless of presence of antibodies
How does the presence or absence of antibodies effect viral variation?
Absence of antibodies: No selection pressure, but variants are still made.
Presence of antibodies: Negative selection pressure that can shape viral evolution.
Steps of Fusion & Entry
1) Receptor binding induces conformational changes in gp120
2) Transmission of conformational rearrangements to gp41
3) Insertion of fusion peptide into target cell membrane
4) Formation of 6-helix bundle intermediate
5) Viral & cell membranes brought into close proximity
6) Facilitation of fusion pore formation & completion of entry
True or False:
Macrophage tropism correlates with structural conformation that is close to CD4-bound conformation and with low dependence on CD4.
What is macrophage tropism most frequently associated with?
Macrophage tropism is most frequent among R5-using envelopes. It correlates with a structural conformation similar to the CD4-bound conformation, and with a low dependence on CD4
True or False:
gp120 binds to Cd4 and to the co-receptor BEFORE gp41 mediates fusion and completion of entry.
What is the most common type of HIV-1 transmission?
True or False: Infection of dendritic cells is mediated by binding of the viral envelope glycoprotein to the DC-SIGN molecules present in the plasma membrane (rather than interaction with CD4 and a co-receptor.)
Infection of dendritic cells is mediated by gp120 binding to CD4 and mostly CCR5.
What is the importance of DC-SIGN in dendritic cell infection?
DC-SIGN is important to capture virions that will either remain trapped in the surface, or be transferred to CD4 and CCR5 for infection, or be endocytosed into lysosomal compartments, where they can be degraded or recycled via exocytosis.
True or False: In the context of transmission of HIV-1 via mucosal surfaces in the genital or rectal tract, infection of dendritic cells is necessary for them to be able to efficiently transmit the virus to CD4+ T cells and spread infection.
FALSE - Viral trapping in the surface of DCs and internalization into endosomal compartments and then recycling through exocytosis are thought to be the main contributors to the process of trans-infection of CD4+ T cells, without the need for the DC to be infected.
What are HIV-1 restriction factors?
Germline-encoded, cellular proteins that mammalian cells have acquired through evolution. Result in species-specific restriction of retroviral infections with viruses from other species, but are largely inactive against wild-type viruses in their own natural host.
Which HIV-1 protein is targeted by the restriction protein Trim5a from rhesus monkeys but not human cells, resulting in altered uncoating?
Which HIV-1 protein counteracts the anti-HIV-1 effects of members of the APOBEC3 family of proteins?
Vif (viral infectivity factor)
What is APOBEC3G?
A DNA cytidine deaminase that is incorporated into virions during viral production and subsequently triggers massive deamination of deoxycytidine to deoxyuridine within the retroviral minus (first)-strand cDNA.
True or False: APOBEC3G, after incorporation into HIV-1 virions during viral production, triggers massive deamination of deoxycytidine to deoxyuridine within the retroviral plus (second)-strand cDNA, thus providing a probable trigger for viral destruction.
APOBEC3G triggers deamination within the retroviral minus (first)-strand cDNA, not plus (second)-strand cDNA. The second strand is synthesized using the first strand as template. Only the first strand cDNA exists as a ssDNA after the degradation of the RNA template and before the second strand synthesis, thus being a target for the action of APOBEC proteins.
Vif greatly reduces APOBEC3G levels in human cells, limiting its effects in a subsequent infection, but it doesn't eliminate it. Why?
Vif likely doesn't completely eliminate APOBEC3G levels because its effects inducing G-to-A hypermutation actually contribute to the genetic variability generated during replication and may be beneficial for the virus
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Nucleos(t)ide analogues that operate as competitive substrate inhibitors of RT, acting as chain terminators that prevent other nucleosides from being incorporated into the nascent DNA chain because of the absence of a 3' OH group.
By preventing growth of the viral DNA chain, this drug prevents it from inserting into the host DNA, so viral replication cannot occur.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Non-competitive inhibitors that bind to an allosteric site of the enzyme, near the active site, affecting its handling of substrates (nucleotides).
Cellular HIV-dependency factor. Contributes to 2 steps of the viral life cycle:
- Nuclear Import
Example of an integrase strand transfer inhibitor
Raltegravir. This drug binds to the catalytic site of HIV-1 integrase, affecting its ability perform the joining or strand transfer reaction
True or False: Raltegravir, the integrase strand transfer inhibitor, can result in the inability of HIV-1 Integrase to bind to the cellular protein LEDGF/p75.
FALSE - Integrase does bind to the cellular protein LEDGF/p75, which helps tethering the viral cDNA to the host chromatin. However, inhibitors of this interaction (which will inhibit integration by a different mechanism than Raltegravir) are still in development
Where does HIV-1 cDNA integrate?
HIV-1 cDNA integrates preferentially at or near active genes. Integration events seem to positively correlate with the levels of expression, except for the most highly expressed genes.
Steps of Reverse Transcription of HIV-1
1) Binding of tRNA-Lys to PBS region in viral RNA
2) Synthesis of minus-strand strong-stop cDNA
3) Degradation of viral RNA in RNA:(strong-stop)DNA hybrid
4) First jump or first strand transfer
5) Completion of synthesis of the first strand of cDNA
6) Degradation of remaining viral RNA (except for polypurine tract) in RNA:(first strand)DNA hybrid
7) Synthesis of plus-strand strong-stop cDNA
8) Degradation of tRNA-Lys from partially double stranded cDNA
9) Second jump or second strand transfer
10) Completion of synthesis of both strands of cDNA
What is the major role of the HIV-1 LTR?
HIV-1 LTR is the promoter of the viral genome, and its role is in the regulation of viral RNA synthesis
What regions makes up the LTR?
U3, R, and U5
Where is the transcription start site located?
Within the LTR
Where is the transactivation response element (TAR) located?
Just downstream of the transcription start site within the LTR
What structure does TAR form?
A stable, bulged stem-loop structure
What binds to the TAR structure?
The viral regulatory protein Tat
What viral protein binds to early acting ESCRT factors?
What HIV-1 Gag motifs bind to ESCRT factors?
Gag binds through 2 late-domain motifs, PTAP & YPXnL
In which of the Gag subunits or domains are PTAP & YPXnL located?
What viral protein induces Tetherin ubiquitination?
How does Vpu induce Tetherin ubiquitination?
Through recruitment of beta-TrCP-2
What is the result of Vpu-induced Tetherin ubiquitination?
Stronger retention in the cell's trans-Golgi network (TGN)
What are the potential fates of resting latently-infected memory CD4+ T-cells?
- Die slowly
- Become source of new infection
- Persist as long-lived cells
- Expand via homeostatic mechanisms
True or False: Resting latently-infected memory CD4+ T-cells differentiate further down the memory phenotype pathway.
FALSE - they do NOT differentiate further
True or False: The presence of anti-retroviral drugs (ART) likely contribute to persistent inflammation and immune system dysfunction in most HIV-infected adults
FALSE - ART is not related to persistent inflammation or immune system dysfunction
In untreated HIV-1 infection, what happens to CD4+ T-cells in the blood and GI tract?
CD4+ T-cells are progressively lost in the blood. But in the GI tract, they are rapidly depleted very early upon initial infection and never recover.
What is "shock & kill"
An immunological strategy in which latent HIV-1 reservoirs in resting CD4+ T cells can be activated (shocked), making them more susceptible to be eliminated (killed) by immunologic effector mechanisms.
What is the overall goal of "shock & kill"?
Achieving HIV-1 eradication from infected individuals.
What are some immunomodulating drugs or biological products that have been or could be tested for their potential to lead to depletion of HIV-1 reservoirs?
- PD-1 Inhibitors
- Type I interferons (IFN-α or IFN-β)
True or False: Cytotoxic lymphocyte production follows the rise of HIV-1 viral load in the blood.
Described how HIV specific CD4+ T cells may be especially susceptible to attack and destruction by HIV due to the action of dendritic cells
Since HIV-1 binds to DC-SIGN, a glycoprotein expressed on dendritic cells, migration of HIV-bearing activated dendritic cells to helper T cell areas of lymph nodes may specifically lead to infection of helper T cells specific for HIV peptides.
What will reductions in HIV-specific helper T-cell numbers do to CD8+ T-cells?
Reductions in HIV-specific helper T-cell numbers may lead to decreased activation and survival of cytotoxic CD8+ T cells
What does rapid loss of memory helper T-cells and inability to replace these cells lead to?
Reduced CD4+ T cells may also result in incomplete activation of CD8+ T cells. What would the effect of this be?
Decreased ability to destroy viral infected cells, because CD8+ T-cells are in charge of removing HIV-infected cells.
How does HIV benefit from high mutation rates?
It allows the virus to escape adaptive immune responses
True or False: HIV-1 will only kill cells that express the two receptors (CD4 & CCR5/CXCR4) and have been actively infected by the virus.
FALSE - Both infected cells and uninfected bystander cells die in the context of infection.
Where is expression of CD4 & CCR5 highest?
In memory T cells that reside in mucosal effector lymphoid tissues.
Where is the major site of mucosal immunity?
What happens to these cells?
Intestinal immune system.
HIV-1 rapidly infects and cause death of these cells, even in patients undergoing ART.
What does the progression of HIV-1 infection to AIDS likely depend on?
Loss of homeostasis, the capacity to replace cells destroyed by the virus
True or False: HIV-1 viral genome undergoes reverse transcription and forms double stranded RNA copies of the viral genome.
FALSE - there is no dsRNA involved
How does HIV-1 cDNA integration within the host genome make development of an HIV-1 vaccine different than other vaccines?
By potentially establishing a reservoir in some long-lived cell types
How does the rapid and error-prone replication of (untreated) virus make development of an HIV-1 vaccine different than other vaccines?
Results in a large degree of viral diversity, making it difficult to target.
Most effective vaccines are either live-attenuated or killed. Why is this not the case for HIV-1?
The killed variant is not immunogenic and use of live HIV virus is not safe with a risk to actually cause the disease
True or False: - Induction of broadly neutralizing antibodies is currently the most pursued outcome on HIV vaccine field, considering the rapid spread of HIV-1 and the quick establishment of reservoirs after immune cells infection, but they appear to be very difficult to generate.
True or False: Helper and cytotoxic CD4+ T lymphocytes are thought to be as relevant as cytotoxic CD8+ T lymphocytes (CTL) for an effective immune response that prevents progression to AIDS, and CD4+ T cells have a defined role in antibody maturation and affinity.
True or False: - Historically successful vaccines achieved disease eradication using whole inactivated or attenuated microorganisms and induced neutralizing antibodies, and this strategy should also work for HIV-1.
FALSE - These strategies don't seem to work or be adequate for development of an HIV-1 vaccine.
What did the RV144 human clinical trial use?
Recombinant poxvirus vector carrying HIV-1 envelope (env), gag and protease genes as priming and recombinant Env proteins as booster
What was the outcome of the RV144 human clinical trial?
Provided modest but unprecedented 31% of protection against HIV acquisition in a low-risk population
What may be the reason for RV144's relative success, compared to other trials?
Further studies suggest that antibodies against the variable (V1 and V2) region of HIV-1 envelope contributed to protection against HIV-1 infection.
THIS SET IS OFTEN IN FOLDERS WITH...
Virology - Unit 2 - HIV Proteins
Virology - Unit 3 - Oncogenic Viruses
Molecular Biology of HIV
YOU MIGHT ALSO LIKE...
Human immunodeficiency virus (HIV)
GENS340 MID-TERM REVIEW
Immuno Exam 1 Chapter 2
OTHER SETS BY THIS CREATOR
committee meeting 2
Virology - Unit 4