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Flashcards in Retroviruses II Deck (33)
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1
Q

HIV and AIDS - Consist of a characteristic decline in _____ _____

A

CD4 T-cells

2
Q

Transmission of HIV infection

A

Inoculation in blood - Transfusion of blood/blood products
- Needle sharing
- Open wound exposure
Sexual Transmission - Vaginal and anal intercourse
Perinatal transmission - Breast milk
- Intrauterine transmission

3
Q

HIV is a _______ retrovirus

A

complex

4
Q

Accessory Proteins (6)

A

Vif, Vpr, Vpu, Nef, Tat, Rev - required for replication or pathogenesis

5
Q

Regulatory Proteins and their functions

A

Tat: Transactivator of transcription - absolutely required for transcription
Rev: Regulator of virion expression - allows structural gene expression by promoting transport of unspliced RNA from nucleus to cytoplasm

6
Q

Restriction Factors

A

Viral proteins that overcome cellular defenses or ‘restriction’

7
Q

Vif

A

Virion infectivity factor - causes a cellular antiviral protein (a deoxycytidine deaminase) to be degraded: it otherwise is incorporated into new virions where block RT in the next cell by inducing massive mutations in viral dsDNA

8
Q

Vpu

A

Promotes virion release from cells by inhibiting a host protein “tetherin” which otherwise blocks release of virus from the cell: works on other enveloped viruses

9
Q

For HIV ___ is the initial receptor present on immune cells

A

CD4

10
Q

Cells that can bind HIV

A

1) CD4 T-helper cells (the main population)
2) Dendritic cells - Not productively infected - assist in virus dissemination
3) Macrophages - reservoir of virus production
4) Microglia - brain infection, contribute to AIDS dementia

11
Q

HIV tropisms for Macrophage and T cells and the co-receptors

M-Tropic:

A

These infect primary T-cells and macrophages, but not T-cell lines - responsible for initial infection and transmission, and predominate in asymptomatic persons

12
Q

HIV tropisms for Macrophage and T cells and the co-receptors

T-Tropic:

A

Infect primary T-cells and T-cell lines, but not macrophages

- Associated with disease progression, arise at AIDS stage of infection

13
Q

CCR5

A

The co-receptor for M-tropic HIV (R5 tropic)

  • The receptor for chemokines RANTES, MIP-1α and MIP-1β
  • These chemokines can specifically inhibit M-tropic HIV by occupying the receptor
14
Q

CXCR4

A

The co-receptor for T-tropic HIV (X4 tropic)

- Natural ligand is the cytokine stromal derived factor 1 (SDF-1) which can specifically block T-tropic HIV infection

15
Q

Basis for strain tropisms:

A

envelope sequence of different HIV types have preference for different co-receptors

16
Q

Which HIV tropism is the source of person to person transmission?

A

M-tropic virus

17
Q

How do some individuals remain sero-negative despite high-risk behavior and presumably repeated viral exposure?

A

Explanation is a 32bp-deletion in CCR5 gene (∆32) that causes non-functional CCR5

  • WT:WT - get infected and progress to disease normally
  • WT:∆32 - get infected but progress to disease more slowly
  • ∆32:∆32 - highly resistant to infection - People are essentially normal despite lack of CCR5 gene expression
18
Q

CCR5 antagonist drug

A

Selzentry (maraviroc)

19
Q

The fusion process

A
  • Envelope initially contacts CD4 and induces a conformation change in envelope to expose the co-receptor binding site
  • Then the gp41 “fusion domains” are exposed and that fusion domain enters the cell membrane
  • Co-receptor engagement triggers a ‘snapback’ of the N and C-terminal helical regions of gp41 (yellow and red cylinders), which brings the membranes together and fuses them
20
Q

T20 “C” peptides

A

Antiviral (Fuzeon) - can bind the N-term helical region and block the snapback

21
Q

HIV pathogenesis and Immunity

A

1) Initial HIV infection - usually at mucosal surfaces
2) Spread to lymph nodes - DC cells can bind and carry HIV to the nodes, where T cells reside and are infected
3) Virus infects T cells, replicates to high levels, and spills into circulation
4) During asymptomatic phase, FDC traps virus, keeps viremia low, but nodes are major site of replication (1 billion/day)

22
Q

Disease mechanisms of HIV

Direct killing of CD4 T cells by HIV (3 methods):

A

1) Massive virus production leads to membrane leakage and death
2) Synctia (fused cells) induced by fusion of infected cell with uninfected cells - cells eventually die (bystander effect)
3) Apoptosis induced by infection, some evidence that cells undergo apoptosis even if infection is unproductive

23
Q

Disease mechanisms of HIV

Indirect effects on infected CD4 cells:

A
  • Immune response kills infected cells, important for clearing initial viremia
  • Soluble gp120 may bind uninfected cells, now susceptible to ADCC (antibody dependent cell-mediated cytotoxicity)
24
Q

Disease mechanisms of HIV

Impairment of immune system function:

A
  • CD4 T-cell function altered and loss of CD4 T cell help leads to severely compromised immune system
  • Infected macrophages are dysfunctional
25
Q

Acute infection and seroconversion (2 steps)

A

1) Initial burst of virus production coincides with decreased CD4 T-cells
2) Early, vigorous CTL, subsequent humoral response, with FDC help, clears viremia - high level virus production persists in lymph nodes

26
Q

Asymptomatic Phase

A
  • Strong immune response, but gradual decline in CD4 counts

- Progression measured by CD4 counts, CD4:CD8 ratio, “viral load” by measuring RNA by PCR

27
Q

Symptomatic AIDS phase:

A
Late in infection
CD4 cells depleted
Immune system begins to fail
Viremia increases
Patients susceptible to many opportunistic infections
28
Q

Laboratory Diagnosis of HIV

A

Serology (cannot detect newly infected until 4-6 wks post infection)
- Ab ELISA
- Ag ELISA
- Western Blott
RNA RT-PCR - detect virus in blood
Real time RT-PCR - quantitate virus in blood (very sensitive)

29
Q

Presently available Drugs (5 types)

A

1) RT inhibitor: Nucleoside/nonnucleoside analogs - Drug resistant strains rapidly appear
2) Protease inhibitors: Extremely effective, reduce viral load by 30-100X alone
3) Fusion inhibitor (T-20) - available but expensive
4) Entry inhibitors - CCR5 co receptor antagonist
5) Integrase inhibitor

30
Q

HAART

A

Highly Active Anti-Retroviral Therapy

  • Triple therapy of different inhibitors: virtually eliminate virus production in some individuals for many years; virus undetectable in plasma, increased CD4 cell counts
  • Long-term patients experience toxicity
31
Q

Infected memory T cells: can detect virus from those on HAART for > ____ years

A

5

32
Q

Enthusiasm for HAART and ‘functional cure’ tempered because:

A

1) not all patients respond to HAART
2) drug regimen is difficult to follow
3) toxic effects seen in long term HAART users
4) Inaccessible pool of virus

33
Q

New attachment inhibitors

A

New CXCR4 and dual receptor inhibitors and anti-CCR5 antibody
RT inhibitors to common drug resistant RT viruses
New integrase inhibitors
Maturation inhibitors that work on gag and gag-pol proteins