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Hannah's Intersystem > HIV-1 Replication and Pathogenesis > Flashcards

HIV-1 Replication and Pathogenesis Flashcards

1
Q

How does Australia’s pattern of HIV transmission/distribution differ from the worldwide trends?

A

Australia: mostly MSM
Worldwide: mostly heterosexual women

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2
Q

List 6 behavioural and social factors promoting a heterosexually transmitted HIV epidemic

A 
Little or no condom use
Multiple partners
Overlapping sexual partners
Large sexual networks
Age mixing (old men and young girls - due to pervasive myths about treatment of HIV)
Women dependent on marriage/prostitution
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3
Q

List 3 biological factors promoting a heterosexually transmitted HIV epidemic

A

High STI rates (especially HSV-2, which accelerates HIV transmission)
High viral loads (due to lack of access to HAART)
Low rate of male circumcision

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4
Q

What type of virus is HIV?

A

Lentivirus (from the family retrovirus)

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5
Q

Describe the genome of HIV

A

Diploid, linear, 9.2kb

+sense ssRNA

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6
Q

What is the origin of HIV?

A

Zoonosis from chimpanzees

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7
Q

Describe the capsid of HIV

A

Icosahedral

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8
Q

Does HIV have an envelope?

A

Yes

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9
Q

What are the 2 glycoproteins located in the envelope of HIV-1 and what are their roles?

A

SU-surface (gp-120): for cell attachment

TM- transmembrane (gp-41): fusion domain and anchors SU into the membrane

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10
Q

What are the 3 proteins located in the virion interior (Gag proteins)?

A

MA-matrix: connects to and encloses the cone-shaped capsid
CA-capsid: encloses the nucleocapsid and important enzymes involved in viral replication
NC-nucleocapsid: encloses RNA genome

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11
Q

What are the 3 viral enzymes of HIV and what are their roles?

A

RT-reverse transcriptase
IN-integrase
PR-protease

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12
Q

How is the envelope of HIV-1 produced?

A

Lipid bilayer derived from host cell plasma membrane during budding (also contains viral GPs)

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13
Q

What are Gag proteins?

A

Structural proteins of the capsid, matrix, core and nucleocapsid

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14
Q

What are Pol proteins? How are they expressed?

A

Viral enzymes including protease, reverse transcriptase, RNAse H, integrase
Expressed as a Gag-Pol polyprotein before autocleavage

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15
Q

How are envelope glycoproteins expressed?

A

From a spliced mRNA

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16
Q

Describe the HIV-1 replication cycle

A

Viral particle binds to CD4 receptors on T-lymphocytes and macrophages
Fusion event causes release of the matrix, capsid and core into the host cell
Reverse transcription of the viral +sense ssRNA into cDNA occurs within the capsid
The provirus cDNA is incorporated into the host cell DNA
Provirus is transcribed, spliced and translated into protein to produce virions and genomic RNA
Virion is assembled and buds out from the host cell, taking part of the plasma membrane as its envelope
Virion matures (aided by activity of viral protease)

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17
Q

What is 1 important mechanism by which HIV is able to evade immunity and how does it achieve this?

A

High degree of variability for Gag and Env proteins means it is difficult for the host to produce a specific immune response to the virus
Mutations are introduced during reverse transcription of the virus +sense ssRNA into cDNA

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18
Q

Describe the process of membrane fusion which occurs during entry of HIV-1

A

Virion attaches to host cell via non-specific cell receptors including C-type lectin receptors (CLRs)
CD4 binding induces conformational changes in gp120
Conformational change exposes chemokine coreceptor sites (including CCR5, CXCR4) which bind to promote gp41 fusion and peptide insertion
Structural rearrangement of gp41 trimers drives membrane fusion to release the core of the virus into the host cell

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19
Q

Give 2 examples of CLRs

A

DC-SIGN or mannose R on astrocytes

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20
Q

When in the course of an infection is CCR5 used?

A

Early (CXCR4 late)

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21
Q

Are HIV virions which use CCR5 M-tropic or T-tropic? What does this mean?

A

M-tropic

Mainly infect macrophages and do not form syncytium

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22
Q

Are HIV virions which use CXCR4 M-tropic or T-tropic? What does this mean?

A

T-tropic

Mainly infect T cells and can form syncytium

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23
Q

What is syncytium?

A

A multinucleated cell resulting from the fusion of multiple uninuclear cells

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24
Q

What is the difference in pathogenicity between CCR5 and CXCR4 HIV virions?

A

CCR5 have moderate virulence

CXCR4 have high virulence

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25
Q

What ligands block HIV with CCR5?

A

RANTES

MIP-1a/B

26
Q

What ligands block HIV with CXCR4?

A

SDF-1

27
Q

What is the most common functional mutation in CCR5?

A

CCR5 D32

28
Q

What is the most functional mutation in CXCR4?

A

SDF-1 (RNA)

29
Q

Describe the process of HIV spread throughout the body

A

Musocal exposure to HIV-1
Selective infection by R5 strains
Virions bind DCs via DC-SIGN
DCs transport virus to regional LNs
Infection spreads to activated CD4+ T lymphocytes
Widespread dissemination occurs, with spread to organs including the brain, spleen, lymph nodes and GALT

30
Q

What is the 1 of the major barriers to clearing HIV in infected patients?

A

Resting CD4+ T cells are infected and can become activated at any time

31
Q

What is the error rate in reverse transcription of the HIV genome? Why is this important?

A

1:10,000nt
Results in an ~1nt change per infectious cycle, which is the maximum tolerated by nature but which enables the virus to evade the immune system

32
Q

What processes occur in reverse transcription of the viral genome?

A

+sense ssRNA converted to proviral cDNA

Sequences at the end of the virual RNA are duplicated to form a DNA structure called the “long terminal repeat” (LTR)

33
Q

How is the viral cDNA integrated into the host cell DNA?

A

HIV integrase catalyses the random integration of HIV cDNA into cell DNA by binding the LTR (occurs in resting and terminally differentiated cells)

34
Q

What is the role of the 5’LTR?

A

Acts as the HIV gene promoter

35
Q

Give examples of contexts in which 5’LTR increases or decreases HIV expression

A

HIV expression silenced soon after initial replication
Increased expression in response to HIV Tat protein
Responds to cellular proteins made during T-cell immune activation to dramatically increase HIV expression

36
Q

Give an example of a cellular protein made during T-cell activation which dramatically increases HIV expression

A

NF-kB

37
Q

How is HIV basal transcription regulated?

A

By cis- (non-coding DNA, at the integration site) and trans- (coding DNA, expressed during T-cell activation) acting factors

38
Q

Give an example of cis-acting factors

A

Chromatin and associated factors (e.g. HDACs, histone methyltransferases)

39
Q

Give an example of trans-acting factors

A

Transcription factors (e.g. NFkB, NFAT)

40
Q

What is TAR?

A

Trans-activation response RNA element

41
Q

What is Tat?

A

Transactivator of HIV transcription through TAR RNA

42
Q

What is Rev?

A

Regulator of structural gene expression via binding of the Rev-responsive RNA element (RRE)

43
Q

How does Tat promote transcriptional elongation of HIV-1?

A

Bind TAR RNA and recruits Tat-associated kinases (including cyclin T and CDK9) to increase the activity of RNA polymerase, and therefore the number of copies of full length RNA produced

44
Q

How does Rev work? Contrast initial and late cycles of viral replication

A

During late replication, Rev has been accumulated and can bind unspliced (9kb) and partially spliced (4kb) RNA transcripts in a complex with RRE, and export them to the cytoplasm, where they can be translated into structural (Gag-Pol) elements
This is in contrast to initial replication where there is low Rev, and RNA transcript is quickly degraded in the nucleus so that only 1.8kb RNA transcripts can be exported to the cytoplasm and transcribed (these smaller transcripts produce proteins including Tat, Nef, Vpr and more Rev)

45
Q

List 4 HIV-1 regulatory and accessory proteins not essential for replication, and their roles

A

Vif: promotes infectivity of cell free virus by degrading APOBEC3G
Vpr: role in nuclear import of cDNA, cell growth arrest, and weakly in transcription transactivation
Vpu: regulator of particle release and Env processing, promotes MHC I and CD4 degradation, antagonises tetherin, and inhibits surface expression of CD1d
Nef: multifunctional protein important for in vivo pathogenesis, down-modulates cell MHC I and CD4

46
Q

How does Nef down-regulate MHC I expression?

A

By inducing lysosomal degradation of MHC I

47
Q

How does Vpu down-regulate MHC I expression?

A

By inducing lysosomal degradation of MHC I and directing MHC I to the proteosome

48
Q

How does Tat down-regulate MHC I expression?

A

Inhibits MHC I gene transcription

49
Q

What is the role of TRIM5a in the immune response to HIV?

A

Destabilises the viral capsid, causing untimely uncoating leading to proteosomal degradation of the virion

50
Q

What is the role of APOBEC3G in the immune response to HIV?

A

A cytidine deaminase that induces lethal G>A hyper-mutations of the viral genome while it is still ssDNA

51
Q

What is the role of tetherin in the immune response to HIV?

A

Inhibits virus release

52
Q

What events occur during maturation of HIV particles?

A

Icosahedral core matures to form a complex rod shape after budding
Protease activity of Gag-Pol precursor protein causes cleavage of polyproteins into individual proteins

53
Q

What is the half-life of a cell infected with HIV? Of virus particles? Of resting infected T cells?

A

1 day
6 hrs
Months-yrs

54
Q

What cells make up the main latent HIV reservoir?

A

Central and transitional memory T-cells

55
Q

What is the effect of HAART on the latent HIV reservoir?

A

Patients successfully treated with HAART for >10 years have no appreciable decrease in the size of the reservoir; suggests the virus will proliferate immediately following removal of treatment

56
Q

Identify 7 factors which prevent HIV production in latent host cells

A

Cellular factors: limited transcriptional activators
Viral factors: integration in active genes, low acetylation, high methylation, transcriptional interference from host DNA
Impaired RNA export from nucleus
HIV-specific host microRNA

57
Q

How does Tat activate RNA expression?

A

Recruits histone acetyl-transferase (HATs), which displace HDACs leading to acetylation of histones in chromatin
This opens up the structure of the DNA to allow the promoter to be accessed by RNA polymerase and various TFs

58
Q

What determines whether HIV provirus is being actively transcribed, is attenuated or is being completely silenced?

A

Level of Tat activity (critical threshold takes provirus from silenced to attenuated state)

59
Q

What can be measured in a productive infection vs. a latent infection?

A

Productive: can measure RNA in a single copy assay (SCA), viral DNA (integrated or unintegrated)
Latent: can measure integrated DNA

60
Q

What are the units used when measuring integrated HIV DNA?

A

IUPM: infectious units of provirus per million cells

Hannah's Intersystem (16 decks)

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