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Virology > Lecture 10: HIV > Flashcards

Lecture 10: HIV Flashcards

1
Q

If untreated, what courses can the disease take after an acute infection?

A
  1. Rapid progressors: (10-15%) develop late stage symptoms in 2 to 3 years
  2. Slow progressors: (70-80%) develop late stage symptoms in 8 to 10 years
  3. Long-term nonprogressors: (5%) show no decline in CD4+ T cell levels
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2
Q

AIDS

A
  • Acquired Immunodeficiency Syndrome
  • High levels of virus in blood and opportunistic infections
  • high level of viral RNA
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3
Q

Clinical latency

A
  • Cytotoxic T lymphocytes (CTLs) and antibodies respond to infection but virus replication persists in
    lymph nodes resulting in gradual depletion in CD4+ T cells
  • lower level of viral RNA
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4
Q

acute infection

A
  • flu-like symptoms, infection of gut-associated lymphoid tissue (GALT)
  • significant drop in CD4+ cells
  • high level of viral RNA
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5
Q

What are the different stages of HIV infection?

A
  1. Acute infection
  2. Clinical latency
  3. AIDS
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6
Q

What does HIV infection result in?

A
  • depletion of CD4+ T cells, rendering the host immunocompromised
  • Patients suffer from multiple opportunistic infections from other pathogens, often results in death
  • these are pathogens that would normally be harmless to us when our immune system works perfectly fine
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7
Q

HIV structure

A
  • Spherical enveloped particle
  • Conical capsid with icosahedral symmetry
  • Linear single-stranded RNA, positive sense genome (+ssRNA)
  • Two identical genome RNAs in each virion
  • Cellular tRNAlys3 molecules packaged in virions used as primers for reverse transcription
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8
Q

What is HIV?

A
  • Human Immunodefiency Virus
  • type of lentivirus
  • slow progression
  • replicates in and kills lymphocytes and macrophages (immune system cells)
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9
Q

How many capsid proteins does HIV have?

A
  1. MA - matrix
  2. CA - capsid
  3. NC - nucleocapsid
  4. p6 (budding
    protein, BP)
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10
Q

What enzymes are in HIV?

A
  • packaged within the virion
    1. PR - protease
    2. RT - reverse transcriptase
    3. IN - integrase
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11
Q

splicing of HIV-1

A
  • has a complex splicing pattern for additional proteins
  • Splicing of HIV-1 primary
    transcript generates more
    than 25 mRNAs
    2 Types:
    1. Singly spliced (4 kb class): usually encodes structural proteins
    2. Doubly spliced (2 kb class): usually encodes regulatory proteins
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12
Q

how does HIV-1 target immune cells?

A
  • recognizes a CD4 receptor and chemokine receptors
  • CD4 (primary receptor) is found on both T lymphocytes and monocytes/macrophages
  • co-receptor of either CCR5 or CXCR4 is also required
  • Variations in viral SU (gp120) determines co-receptor usage
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13
Q

what viruses use CCR5 co-receptors?

A
  • R5
  • macrophage-tropic
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14
Q

what viruses use CXCR4 co-receptors?

A
  • X4
  • T cell-tropic
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15
Q

what does CD4 binding cause?

A
  • conformational changes in viral gp120 (SU)
  • Exposes regions of gp120 that can recognize the co-receptor(s)
  • Exposes gp41 (fusion domain) to insert in host cell membrane
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16
Q

HIV entry and replication

A
  • Fusion occurs after close proximity of viral and host cell membranes, releases viral core into cytoplasm
  • Once inside, nucleocapsid partially breaks down, permits access to
    cellular nucleotide pool (virion needs to use cellular nucleotides for reverse transcription)
  • RT replicates viral genome but generates small mutations due to
    absence of proof-reading activity
17
Q

how does HIV-1 get into the nucleus?

A
  • actively directs transport of proviral DNA into the cell nucleus
  • MA, Vpr and IN (part of preintegration complex) direct transport into nucleus
  • MA has a nuclear import signal and interacts with importins
  • Vpr and IN interact directly with nuclear pore
18
Q

what complicates the elimination of HIV-1 infection?

A
  • host genome integration
  • immune system cannot identify infected cells if viral proteins are not expressed
19
Q

nascent RNA

A

newly synthesized RNA strand still in the process of being transcribed from DNA

20
Q

HIV transcription

A
  • viral Tat (transactivator of transcription) protein is localized in the nucleus (has + charge to facilitate binding to DNA)
  • Tat binds to TAR (Tat responsive element) at transcription start site, increases HIV-1 transcription by supporting elongation by RNA polymerase II
21
Q

what happens in the absence of Tat?

A

RNA pol lacks processivity (ability to travel the entire length of a gene

22
Q

what happens in the presence of Tat?

A

cellular Cdk9 and Cyclin T are recruited, increased phosphorylation
(indicated by PPP) of carboxy terminal domain (CTD) in RNA pol, leads to enhanced processivity/efficiency
- RNA pol needs phosphorylation on the CTD for it to work properly

23
Q

what controls how RNA goes in and out of the nucleus?

A
  • CRS (cis-acting repressive sequences) present in gag, pol, env regions inhibit RNA transport to cytoplasm
  • need to have Rev response element (RRE) for transport
  • Doubly-spliced mRNA does not have CRS and can be transported normally
  • viral Rev (regulator of expression of virion proteins) protein mediates cytoplasmic transport of
    viral mRNAs that code for HIV-1 structural proteins
  • REV binds to RRE only on unspliced/single spliced mRNAs
  • allows for transport out of nucleus
24
Q

what proteins are essential for HIV transcription and transport of mRNAs encoding structural proteins?

A

Tat and Rev

25
Q

how are Tat and Rev synthesized and how do they help transcription and transport?

A
  • After proviral DNA integration, only the doubly-spliced (2 kb) RNA is transported out of the nucleus, allows for synthesis of Tat, Rev and Nef (early proteins)
    -Tat and Rev are imported into the nucleus
  • transcription of provirus DNA (Tat)
  • export of RRE containing mRNA (Rev)
26
Q

HIV Vif (viral infectivity factor) protein

A
  • increases virion infectivity
  • in cytoplasm of infected cells
  • Required for counteracting a host cell antiviral factor APOBEC3G cytidine deaminase (changes C to U)
  • APOBEC3G is incorporated into virions and could mutate viral DNA which affects the proteins and reduces infectivity
  • induces ubiquitination and degradation of APOBEC3G by proteasomes which increases infectivity
27
Q

HIV Vpr (virion protein R)

A
  • enhances HIV-1 replication
  • gets recruited into virions
    (interacts with Gag C-terminal)
  • critical role in entry of PIC into the
    nucleus
  • Facilitates packaging of cellular Uracil DNA glycoslase (UNG) (repair enzyme used by host cells that removes uracil from DNA)
  • arrest infected cells in G2 stage of cell cycle
  • G2/M phase provides an optimal environment for viral replication, It suppresses host cell proliferation, diverting cellular resources toward viral production
  • beneficial for HIV-1: transcription
    most active at G2 stage
28
Q

HIV Vpu (viral protein unique to HIV-1)

A
  • enhances release of progeny virions from infected cells
  • inserted into membranes via its N-terminal domain
  • accumulates in golgi and endosomes
  • can trigger degradation of CD4 through its binding to cellular β-TrCP, once degraded proteins are released and can be processed and incorporated into the virion
  • releases gp160 and increases surface expression of gp41 and gp120
  • counteracts host antiviral factors that tether virus to host cell surface, enhances virus release from plasma membrane
  • Expression of HIV-1 Vpu also enhances release of other unrelated viruses
  • Vpu induces degradation of tetherin (host antiviral protein), tetherin promotes endocytosis and degradation of virions
29
Q

HIV Nef (negative effector) protein

A
  • important mediator of pathogenesis and enhances virus infectivity
  • localized to inner surface of
    plasma membrane through a fatty acid modification at its N-terminal amino acid
  • decreases surface expression of CD4 and and major
    histocompatibility complex protein I (MHC I) which are important mediators of immune response
  • Modifies cell signalling in T cells
    that causes general activation
    of T cells without a presence of an antigen and they cannot mount an effective immune response
30
Q

Genome packaging signal (psi) and assembly

A
  • encoded only on genomic RNA
  • Intramolecular base pairing (forms secondary structures) causes ‘psi’ to be inactive
  • formation of genomic RNA dimer exposes ‘psi’
  • allows interaction with nucleocapsid protein (NC)
  • initiates assembly
31
Q

HIV assembly and budding

A
  • Gag proteins interact with NC-genomic RNA complex
  • transported to plasma membrane
    for final assembly and budding via ESCRT complexes
  • Once released, the protease in virion particle is activated and cleaves Gag and Gag-Pol polyproteins into individual peptides
  • self-assemble in virion to form a conical capsid which activates the virion for infection

Virology (16 decks)

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