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Microbiology > Lecture 12: Virology -Retroviridae, HIV and AIDS > Flashcards

Lecture 12: Virology -Retroviridae, HIV and AIDS Flashcards

1) Retroviridae and oncogenes 2) HIV structure and genome 3) Mechanism of HIV infection, pathogenesis, and clinical significance 4) AIDS, diagnosis and treatment

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Biology 101 flashcards
1
Q

Retroviridae

A

Large groups of RNA viruses that infect animals and humans

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2
Q

Retroviridae

  • Retro
  • Grow
  • Blow
A

Retro -contain reverse transcriptase enzyme which is an RNA-dependent DNA polymerase, converts viral RNA into DNA
Grow -can cause cancer. Some retroviruses carry oncogenes that can cause malignant transformation of normal cells into cancer cells
Blow -some retroviridae are cytotoxic to certain cells (HIV)

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3
Q

Malignant cells lose ______________, divide _________ as long as there is _________________.

A

contact inhibition; continuously; nutrient supply

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4
Q

Normal cell has _______________ in cell membrane that regulate cell __________.

A

receptor proteins; growth

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5
Q

Growth factors (_________) bind to receptor proteins to regulate _______

A

mitogens; growth

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6
Q

__________ stimulation of protein receptors causes intracellular ______________ of _________.

A

Mitogen; phosphorylation, Tyrosine

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7
Q

Oncogenes like ________________ oncogene (src) encodes a transmembrane protein that also phosphorylates Tyrosine but at ____ times the normal rate.

A

Rous sarcoma virus; 10

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8
Q

Most of the retroviridae cause either ____________ or ____________ and called _______________ viruses

A

leukemia; sarcoma; leukemia sarcoma viruses

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9
Q

Some retroviruses cause cancer directly (_____) by integrating and intact oncogene into the ________. Others cause cancer indirectly by activating a host __________.

A

acute; host DNA, proto-oncogene

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10
Q

__________________ carry intact oncogenes within their viral genome, which when integrated into host DNA causes malignant transformation.

A

Acute transforming viruses

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11
Q

Normal host DNA has sequences that are __________ to viral oncogenes but are still inactive (________________)

A

homologous; proto-oncogenes

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12
Q

Retroviridae and proto-oncogenes

-process

A
  • during normal viral infection and integration, a mistake in splicing occurs and a virus captures a proto-oncogene
  • proto-oncogene ultimately becomes activated in the virus, becoming an oncogene
  • non-acute transforming viruses activate host cell proto-oncogenes by integrating viral DNA into a key regulatory area. They do not carry oncogenes
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13
Q

Human Immunodeficiency Virus (HIV)

-Stats

A
  • one of the most destructive pandemics in recorded history
  • since first recognized on December 1,1981 it has claimed more than 36 million people and an estimated 35.3 million live with AIDS today
  • in 2012, about 2.3 million people became newly infected with HIV worldwide
  • estimated that 0.6% of the world’s population has HIV
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14
Q

Acquired Immune Deficiency Syndrome (AIDS)

A

-Even though the first case of AIDS was identified in 1981, it was not until 1984 that HIV was shown as cause of AIDS
-The opportunistic infections in AIDS patients eventually results in death
-AIDS is caused by HIV -there are 2 types (HIV-1 and HIV-2)
HIV-2 is endemic in West Africa and India; most AIDS worldwide is caused by HIV-1

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15
Q

AIDS

-disease characterized by

A

-Disease characterized by susceptibility to infection with opportunistic pathogens or occurrence of -Kaposi’s sarcoma or B cell lymphoma and a profound decrease in number of CD4 Tcells

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16
Q

Structure of HIV

  • type of virus
  • genome
  • nucleocapsid proteins
  • membrane proteins
  • replication proteins
A
  • HIV is a retrovirus
  • virion contains 2 copies of a ssRNA genome ->diploid
  • nucleocapsid of HIV contains 4 proteins: p24, p17, p9, and p7 which are cleaved from the 53 kD molecule (p53) encoded by the gag gene
  • membrane (acquired by budding from host cell) contains 2 viral glycoprotiens, gp120 and gp 41, cleaved from a common precursor, gp 160
  • virion contains 3 virus specific proteins that are essential for replication: reverse transcriptase, protease, and integrase
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17
Q

Retrovirus genomes

A

-All retroviruses possess in their RNA genome, 2 ending LTR sequences, as well as gag, pol, and env genes

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18
Q

LTRs (Long Terminal Repeat Sequences)

A

flank the whole viral genome
functions:
a) Sticky ends -sequences recognized by integrase that are involved in insertion into host DNA
b) Promoter/enhancer function -once incorporated into host DNA, proteins bind to the LTRs that can modify viral DNA txn

19
Q

Genes and Proteins of HIV-1

-Env (Envelope)

A
  • gp160: precursor of env glycoprotein
  • gp 120: outer env glycoprotein
  • gp 41: transmembrane glycoprotein
20
Q

Genes and Proteins of HIV-1

-Gag (Group specific antigen or core)

A
  • p53: precursor of gag proteins
  • p24: gag protein (capsid structural protein)
  • p17: gag protein (matrix protein)
  • p15, p9, p7: gag proteins
21
Q

Genes and Proteins of HIV-1

-Pol (Polymerase)

A
  • reverse transcriptase: RNA replication
  • Protease: post translational processing of viral proteins
  • integrase: integration of viral DNA
22
Q

Genes and Proteins of HIV-1

-Rev (Regulator)

A

regulates viral mRNA expression -allows export of unspliced transcripts from nucleus

23
Q

Genes and Proteins of HIV-1

-Tat (Transactivator)

A

upregulates viral RNA expression

24
Q

Genes and Proteins of HIV-1

-Nef (Negative regulation factors)

A

down regulates CD4

25
Q

Genes and Proteins of HIV-1

  • Vif, Vpr, Vpu
  • > HIV-1 or HIV-2?
A

only in HIV-1

26
Q

Genes and Proteins of HIV

  • Vpx
  • > HIV-1 or HIV-2?
A

only in HIV-2

27
Q

Life cycle of HIV-1
-entry into cell

(slides 17-18)

A
  • HIV enters cells by means of the 2 env proteins gp120 and gp41
  • gp120 binds to CD4 molecule on the cell surface (T cells, macrophages, microglia in the brain)
  • gp41 mediates fusion of the viral envelope with the plasma membrane of the cell allowing the viral genome and associated viral proteins to enter the cytoplasm
  • in addtion to CD4 molecule, 2 cofactors CXCR4 (fusin) and CCR5 are req’d for HIV entry into T cells and macrophages
28
Q

Life cycle of HIV-1
-replication of genome

(slides 17-18)

A
  • RNA is transcribed into a ss complementary DNA (cDNA) by the viral reverse transcriptase
  • RNA portion of DNA-RNA hybrid is degraded by RNAse H activity of RT
  • ds cDNA using ss CDNA as the template is made
    • > the synthesis of cDNA by RT can be inhibited by azidothymidine (zidovudine or AZT)
  • the viral cDNA is integrated into the host genome by viral integrase and replicates with the cell as a provirus
  • activation of the cell induces the production of viral RNA by host RNA polymerase
29
Q

Infection with HIV generates an ___________ immune response.

A

Adaptive

30
Q

Immune response to HIV infection

  • seroconversion
  • window period
  • asymptomatic period
A
  • Seroconversion: an infected person first exhibits detectable levels of anti-HIV antibodies in their blood serum
  • “Window period”: the interval between infection and seroconversion
  • initial phase of infection is followed by an asymptomatic period called clinical latency during which the virus is replicated in the lymphoid tissues. During this period CD4 T cell counts gradually decline, although antibodies and HIV specific CTL remain at high levels
31
Q

Immune response to HIV infection

  • what kills infected T cells?
  • what is a good prognostic indicator of AIDS?
  • opportunistic infections frequent at CD4 count below ____/ul
  • what happens to lymphoid architecture?
  • infected macrophages can do what?
A
  • infected T cells are killed by CTL rather than by the virus itself. Enumeration of CD4 T cells in the blood is a good prognostic indicator for AIDS. Opportunistic infections become frequent when the CD4 count falls below 500/ul
  • the lymphoid architecture is gradually disrupted leading to the destruction of lymphoid follicles
  • infected macrophages also spread the virus to other tissues such as the brain
32
Q

Immune response to HIV infection

  • natural killer cells
  • at what point does an infected individual get AIDS?
A
  • Natrual killer (NK) cells have been shown to kill HIV infected cells. However, infection of NK cells by herpes simplex virus (usually associated with AIDS) allow NK cells to express CD4 and make them susceptible to HIV infection
  • eventually the virus overcomes the immune response and the infected individual get AIDS
33
Q

Clinical Significance

-T-cell death

A
  • healthy person has 1000 CD4+ T helper cells/ul of blood

- HIV induced T-cell death results in a decline of about 60 CD4+ T cells/ul a year

34
Q

Clinical Significance

-Multinucleated giant cells

A

T cell to T cell fusion allows virus to pass from an infected to an uninfected cell bypassing the blood

35
Q

Clinical Significance

-B-lymphocytes

A

B-cell dysfunction with HIV infection.

-Polyclonal activation of B cells results in outpouring of Ig causing hypergammmaglobulinemia

36
Q

Clinical Significance

-Monocytes & macrophages

A

resevoirs of HIV, migrate across BBB to brain

37
Q

Detecting HIV Infection

  • commonly used tests
  • what does each test detect?
A

-most commonly used tests: Western Blotting, Enzyme-linked immunosorbent assay (Elisa), and Polymerase Chain Rxn
-Western Blotting & ELISA: presence of antibodies against HIV are detected in the patient’s blood
PCR: detects the presence of viral particles in the patient’s blood or immune cells. RT-PCR is used to detect the viral particles in the blood whereas PCR detects the proviral DNA
-Viral cultivation can also be used to detect viral particles, viral antigens, or RT

38
Q

Resistance to HIV Infection

-Long Term Non-Progressors

A

individuals that are infected with HIV but show no signs of disease progression for 12+ years
->their disease progression halts for an extended period of time, but eventually progression to AIDS will occur

39
Q

Resistance to HIV Infection

-Highly Exposed Persistently Seronegatives

A

individuals that have been repeatedly exposed to HIV, but never become infected with HIV
**A small population of persistent seronegatives have a deletion of the CCR5 gene that inhibits the virus from entering their CD4+ T cells, thus inhibiting viral replication

40
Q

HIV Vaccine

-Issues

A
  • sequence diversity (high mutation rate and recombination
  • infection of critical immune cells
  • immune avoidance:
    • > masking of neutralization epitopes
    • > immune escape through viral mutation
    • > counter-immunoregulatory mechanism
  • latency
  • lack of ideal animal model to study immune system response
41
Q

HAART (Highly Active Anti-retroviral therapy)

-aimed at inhibiting what?

A
  • AZT (zidovudine or azidothymidine) is aimed at blocking the reverse transcriptase from making the cDNA
  • other nucleoside analogs aimed at inhibiting RT are ddI (2’3’dideoxyinosine; didanosine), ddC (2’3’-deoxycytidine; zalcitabine) and d4T (2’3’-didehydro-3’-deoxythymidine; stavudine)
  • non-nucleoside RT inhibitors (NNRTIs) viramune (nevirapine) and rescriptor stop HIV production by binding directly to RT and preventing cDNA synthesis
42
Q

HAART con’t

A
  • protease inhibitors inhibit the viral protease that cleaves the Gag and Gag-Pol polypeptides and thus prevent viral maturation
  • **combination therapy is more effective than monotherapy
  • anti-HIV gene therapy and genetic immunization are also under trial
43
Q

Mode of action of HAART drugs

see slide30

A

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