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Block 6 - week 5 > Retroviruses and the Biology of HIV - Aucoin > Flashcards

Retroviruses and the Biology of HIV - Aucoin Flashcards

1
Q

How are retroviruses classified?

A

As enveloped + strand RNA viruses with DNA intermediate.

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2
Q

Name 2 clinically important viruses in the Retrovirus family.

A
  1. HIV - Human immunodeficiency virus

2. HTLV - Human T-lymphotropic virus

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3
Q

Describe HTLV.

A
  1. Family, Retroviridae
  2. an oncovirus associated with adult T-cell leukemia
  3. cell associated virus spread by infected CD4 T cells
  4. virus present in semen, blood and breast milk
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4
Q

Describe the clinical course of HTLV.

A
  1. ATL has long incubation period - 20-50 years
  2. causes increased skin lesions, leukemia cells, hepatosplenomegaly and hypercalcemia
  3. diagnosis - ELISA for antibody
  4. no vaccine or specific therapy
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5
Q

How does HTLV cause hypercalcemia?

A

The infected cells secrete parathyroid hormone -like protein that leads to increased serum calcium.

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6
Q

Describe HIV.

A

1 Family Retroviridae

  1. glycoprotein 120 binds to CD4 receptor on T cells, monocytes and dendritic cells
  2. transmitted via sexual contact, blood, IV drug use and transferred from mother to fetus
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7
Q

Describe the clinical course of HIV.

A
  1. Acute phase - flu-like symptoms followed by clinical latency period of weight loss, night sweats, fatigue and lymphadenopathy
  2. about 10 years until progression to AIDS
  3. AIDS classified as a CD4 T cell count of 200 cells/ul (normal is 800-1200 cells/ul), can diminish to undetectable levels
  4. diagnosis - serology and RT PCR to quantitate viral load
  5. HAART - high active anti-retroviral therapy
  6. no vaccine available
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8
Q

What important enzyme do retroviruses encode for?

A

RNA-dependent DNA polymerase - also called reverse transcriptase. This enzyme takes pos. strand RNA and replicates it through a DNA intermediate.

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9
Q

What happens to the DNA intermediate that is produces via reverse transcriptase?

A

The DNA copy of the viral genome is integrated into the host chromosome to become a cellular gene. This DNA copy is called a provirus.

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10
Q

What was the first retrovirus to be isolated?

A

The Rous sarcoma virus. Once isolated it caused solid tumors in chickens.

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11
Q

How are cancer causing retroviruses classified?

A

Oncornaviruses or RNA tumor viruses.

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12
Q

How do the retroviruses cause cancer?

A

Normal cells make a protein called c-sarc that control cellular growth. Retroviruses code for an analog called v-sarc. c-sarc has a phosphorylation site that makes it inactive but v-sarc does not - it is always turned on.

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13
Q

What was the first retrovirus found to be associated with human disease?

A

HTLV-1 - isolated from a patient with T-cell leukemia.

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14
Q

What characteristics are used to classify retroviruses?

A
  1. disease caused
  2. tissue tropism and host range
  3. virion morphology
  4. genetic complexity
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15
Q

What are oncoviruses?

A

Retroviruses that can immortalize or transform target tissue. Example - HTLV

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16
Q

What are lentiviruses?

A

Retroviruses associated with neurologic and immunosuppressive diseases. Example - HIV

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17
Q

What are the 3 subfamilies of retroviruses?

A
  1. Oncovirinae: HTLV-1, HTLV-2, HTLV-5
  2. Lentivirinae: HIV-1, HIV-2
  3. Spumavirinae
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18
Q

How is HIV-2 different from HIV-1?

A

HIV-2 is thought to cause less severe disease - although it also leads to AIDS.

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19
Q

What is unique about Spumavirinae?

A

This family of retroviruses does not cause clinical human disease and is used in lab to study retrovirus function.

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20
Q

Describe the virion structure of retroviruses.

A
  1. spherical, enveloped, RNA genome, 80-120 nm in size.
  2. the envelope contains viral glycoproteins and is acquired from the plasma membrane.
  3. the envelope surrounds a capsid that contains two identical copies of the RNA genome.
  4. the RNA genome is 8 genes - about 9 kB in size.
  5. virion also contains about 10-50 copies of reverse transcriptase and integrase enzymes.
  6. virion also contains two cellular tRNA’s - these are base paired to each copy of genome and are used as primer for reverse transcriptase.
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21
Q

What do all polymerases require to function?

A

They all need a 3 prime OH group to add nucleotides to.

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22
Q

Do the HIV and HTLV virus’ have the same morphology?

A

No, HIV has a cone-like shape while HTLV forms an icosahedral.

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23
Q

How are nucleocapsid proteins bound to nucleic acid?

A

The positively charged nucleocapsid proteins are bound to negatively charged nucleic acids.

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24
Q

All retroviruses include genes that encode what polyproteins?

A
  1. gag: (group specific antigen) - these are structural proteins. Included are capsid, matrix and nucleic acid binding proteins.
  2. pol: (polymerase) - this polyprotein includes reverse transcriptase, protease and integrate.
  3. env: (envelope) - these are glycoproteins. Included are gp120, gp41 for HIV.
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25
Q

What are located at the end of each of the two retrovirus genomes?

A

Long-terminal repeat sequences. These sequences contain promoters and enhancers to bind to cellular transcription factors.

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26
Q

What else do complex retroviruses code for?

A

Complex retroviruses such as HIV and HTLV encode several virulence-enhancing proteins that require more complex transcriptional processing such as splicing.

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27
Q

How are the retroviral glycoproteins produced?

A

By proteolytic cleavage of the polyprotein encoded by the env gene.

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28
Q

Glycoprotein 160 is cleaved into what?

A

Two different glycoproteins called gp41 and gp120. These are the glycoproteins that form the trimer spikes visible on the HIV virion surface.

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29
Q

What does gp120 do?

A

This HIV glycoprotein binds to cell surface receptors which initially determines tissue tropism of HIV. It is also recognized by neutralizing antibodies.

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30
Q

What is a characteristic of gp120 that makes it hard to use as an antigen for immune response?

A

This glycoprotein is extensively glycosylated and its antigenicity and receptor specificity can drift during the course of a chronic HIV infection due to lots of mutation.

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31
Q

What does gp41 do?

A

It promotes cell fusion with the viral envelope.

32
Q

Describe the process of replication of the HIV virus.

A
  1. gp120 on HIV binds to CD4 on T-helper cells. CCR5, a chemokine receptor on the T-helper also binds to the HIV, pulling them closer together.
  2. gp41 promotes membrane fusion.
  3. envelope of virus fuses with plasma membrane.
  4. the capsid and matrix proteins are degraded, leaving viral RNA genome and nucleocapsid proteins in cytoplasm.
  5. RT produces the cDNA from the RNA genome and integrate and the cDNA enter the host nucleus through a pore.
  6. inside, the integrase integrates the cDNA into host chromosome where it is replicated.
  7. viral proteins are made including envelope proteins.
  8. the immature virions are assembled at the plasma membrane where they bud off.
  9. protease inside the virions splice viral polyproteins leading to a mature vision.
33
Q

How do 2 copies of viral genome get into each virion?

A

ssRNA will fold back on itself forming a stem loop. Two homologous regions of the stem loops bind together so that 2 copies of the viral genome are connected and are put into a virion together.

34
Q

What happens to the original RNA strand after it is used to form a DNA-RNA hybrid?

A

Reverse transcriptase degrades this strand so that it can form a double stranded cDNA that can integrate into a host chromosome.

35
Q

What is an important characteristic of reverse transcriptase?

A

It is very error prone and produces a high mutation rate. This allows for the evolution of new strains which can alter pathogenicity and promotes immune evasion.

36
Q

What is integrated viral DNA called?

A

A provirus.

37
Q

What two things allow for integration of viral DNA into host genome?

A
  1. the enzyme integrate
  2. the LTR sequences at the end of each viral genome - the LTR’s contain enhancer and promoter sequences also that regulate transcription
38
Q

What happens to the integrated provirus?

A

Host RNA- polymerase II transcribes the provirus into full length RNA which can be be assembled into new visions and which can be processed into gag, gag-pol or env polyproteins.

39
Q

How is HIV replication regulated?

A

By host cell recognition of enhancers and promoters encoded in the LTR sequences and also by accessory gene products such as tat and nef proteins.

40
Q

What does tat protein do?

A

It causes transactivation of viral and cellular genes leading to the enhanced efficiency of viral transcription.

41
Q

What does nef protein do?

A

It decreases cell surface CD4, induces T cell activation so that the provirus can be integrated and contributes to the progression to AIDS.

42
Q

Where are viral glycoproteins translated?

A

They are translated on the RER. Translation is followed by glycosylation in the ER and delivery to the Golgi where they go through the secretory pathway and are deposited in the plasma membrane to await virion assembly.

43
Q

Describe viral assembly.

A

The viral glycoproteins are produced and modified in the ER and sent to the plasma membrane. gag and gag-pol polyproteins bind to the part of the plasma membrane containing envelope glycoproteins. Two copies of the viral genome and cellular tRNA molecules come to the site and promote budding of the virion. After budding, viral protease cleaves the gag and gag-pol polyproteins to release reverse transcriptase and to form the mature virion core.

44
Q

What is the major determinant in the pathogenesis and diseases caused by HIV?

A

The virus tropism for CD4 expressing T cells and myeloid cells.

45
Q

What other cells does HIV bind to as well as CD4 T cells?

A

Myeloid cells such as monocytes, macrophages, dendritic cells and microglial cells of the brain.

46
Q

What is a persistent effect of HIV infection?

A

Low-level productive and latent infection of myeloid lineage cells and memory T cells. Infection reduces CD4 T cell numbers and thus reduces helper T-cell maintenance of CD8 T cell, macrophage and other cell functions.

47
Q

Describe some pathogenic effects of HIV infection on T cells.

A
  1. virus causes syncytia formation where infected T cells coalesce to form large, multinucleate cells with large amounts of CD4 antigen. These cells are unstable and lysis occurs causing damage to lymph node tissue.
  2. CD8 T cell and macrophage function also decrease without T-helper cell function so patient becomes even more vulnerable to pathogens.
48
Q

What are some portals of entry for HIV?

A
  1. Blood
  2. colon-rectum
  3. vagina
49
Q

Describe the general events upon HIV infection.

A
  1. virus gains entry and some virus is carried to lymph nodes via macrophage and in blood (viremia and acute symptoms occur). Macrophages are both a reservoir and a means of transport for HIV.
  2. Virus infects CD4 T cells in lymph node, also causing acute stage symptoms.
  3. virus is controlled enough that viremia is mostly cleared and infected T cells are destroyed. Some virus persists in memory T cells and in macrophages. This is the latent stage.
  4. CD4 T cell levels continue to decrease until there is immunodeficiency and progression to AIDS.This will also lead to increased virus load in blood.
50
Q

How does HIV affect macrophage function?

A

Macrophages, including microglial cells in the brain, dendritic cells in the skin and pulmonary alveolar macrophages can be infected by HIV. This can lead to their dysfunction, including cytokine release and dysregulation of immune function. Dysregulation of microglial cells can lead to dementia type symptoms.

51
Q

What are some consequences of T cell infection and loss of cell-mediated immunity?

A
  1. immunodeficiency
  2. loss of B-cell control
  3. lymphadenopathy
    4.hypergammaglobulinemia
  4. loss of delayed type hypersensitivity function
  5. cutaneous infections
  6. intracellular pathogen infection
    All the above can lead to severe systemic opportunistic infections, Kaposi’s sarcoma and lymphoma.
52
Q

What is the co-receptor that gp120 must bind to on T cells?

A

CCR5. Those who are deficient in this co-receptor are resistant to HIV infection.

53
Q

What role do macrophages, dendritic cells, memory T cells and hematopoietic stem cells play in HIV infection?

A

They serve as major reservoirs for the virus and also serve as a means of transmission.

54
Q

What does the development of symptoms of AIDS correlate with?

A

As there is an increase in viral load in the blood and a decrease in CD4 T cells the development of AIDS will progress. One diagnostic indicator is the CD4/CD8 ratio. Normally there are more CD4 than CD8 cells in blood. This ratio flip-flops as the infection progresses.

55
Q

What viral protein is thought to promote the progression of HIV infection to AIDS?

A

Nef protein. Individuals infected with natural mutants of the HIV nef gene do not develop full blown AIDS.

56
Q

What is the acute phase of HIV infection?

A

The acute phase is the initial infection with HIV virus. During the acute phase there is a large burst of virus - (10’7 particles/ml of plasma). T cell proliferation and response promotes a mono-like syndrome.

57
Q

What is the latent period of HIV infection?

A

The latent phase is characterized by the decrease of viral levels in the blood, persistent infection of memory T cells and other cells. During this time there are no symptoms. Viral replication continues in the lymph nodes.

58
Q

What occurs in the late stages of HIV infection?

A

Viral blood levels continue to increase, CD4 and CD8 cell levels decrease significantly, lymph node structure is destroyed and the patient becomes immunosuppressed. This leaves the patient vulnerable to pathogen and AIDS is manifested.

59
Q

What is a titer and how is it important to the management of HIV infection?

A

Titer is the lowest dilution of blood where virus can still be detected. Measuring titers helps the physician to monitor the progression of the infection and treat accordingly.

60
Q

Why does HIV progress to AIDS?

A

CD4 T cells are initiators of immune response by activating macrophages, other T cells, NK cells and B cells. In AIDS, the T cell number is so low that the patient is immunodeficient and lacks the capacity to have a cell-mediated response and is subject to opportunistic infections.

61
Q

Describe the neurologic component to HIV infection.

A

HIV can infect microglial cells and macrophages in the brain. These cells then release neurotoxic substances or chemotactic factors that promote inflammatory responses and neuronal cell death. Infection also leaves the brain vulnerable to opportunistic infections.

62
Q

What types of disease are caused by opportunistic infection with protozoa?

A
  1. toxoplasmosis of the brain
  2. cryptosporidiosis with diarrhea
  3. isosporiasis with diarrhea
63
Q

What types of disease are caused by opportunistic infection with fungi?

A
  1. candidiasis of the esophagus, trachea and lungs
  2. pneumocystis jirovecci mediated pneumonia
  3. extrapulmonary disease mediated by cryptococcosis
  4. disseminated disease mediated by histoplasmosis and coccidioidomycosis
64
Q

What types of disease are caused by opportunistic infection with virus?

A
  1. cytomegalovirus disease
  2. herpes simplex virus infections
  3. progressive multifocal leukoencephalopathy (JV virus)
  4. hairy leukoplakia caused by epstein-barr virus
65
Q

What types of disease are caused by opportunistic infection with bacteria?

A
  1. mycobacterium avium-intracellular complex - disseminated disease
  2. any atypical mycobacterial disease
  3. extrapulopnary tuberculosis
    recurrent salmonella mediated septicemia
66
Q

What types of opportunistic neoplasias may occur in AIDS?

A
  1. kaposi sarcoma
  2. primary lymphoma of the brain
  3. other non-Hodgkin lymphomas
67
Q

What are some other diseases associated with AIDS?

A
  1. HIV wasting syndrome - weight loss and diarrhea for more than 1 month
  2. HIV encephalopathy
  3. lymphoid interstitial pneumonia
  4. lymphadenopathy
  5. AIDS-related dementia - may result from opportunistic infection or HIV infection of macrophages microglial cells of the brain - similar to early Alzheimer’s
68
Q

At what T cell level does HIV infection progress to AIDS?

A
  1. onset of AIDS - less than 350 cells/ul
  2. full blown AIDS - less than 200 cells/ul
  3. T cell found can eventually become undetectable
  4. Viral load is also increases to greater than 75,000 copes/ml
69
Q

Describe the viral factors that affect the epidemiology of HIV.

A
  1. the virus in enveloped so it is easily inactivated and must be transmitted in body fluids
  2. the disease has a long prodromal period
  3. the virus can be shed before development of identifiable symptoms
  4. more males are infected in US than females
70
Q

Describe the transmission of HIV.

A
  1. virus is present and can be spread thru blood, semen and vaginal secretions. It can also be spread directly from mother to fetus.
  2. certain populations such as IV drug users, prostitutes and those who have had blood or organ tansplants before 1985 are vulnerable to infection.
71
Q

Name some ways to decrease risk of HIV infection and/or control infection.

A
  1. antiviral drugs can limit progression
  2. vaccines are not yet available
  3. safe, monogamous sexual practices
  4. sterile injection needles should be used
  5. large-scale screening programs for blood products and transplants
72
Q

Name 4 reasons why tests for HIV are performed.

A
  1. to identify those infected so that antiviral drug therapy can be initiated
  2. to identify carriers who may transmit infection to others
  3. to follow the course of disease and confirm diagnosis of AIDS
  4. to evaluate the efficacy of treatment
73
Q

How is serological testing used in HIV infection?

A
  1. used for monitoring purposes

2. cannot identify recently infected people

74
Q

How are infections identified as recent or late stage?

A
  1. look for p24 viral antigen presence
  2. look for presence of RT enzyme
  3. determine the viral load in blood - larger quantity indicates later stage
75
Q

What is HAART or ART?

A

Highly active antiretroviral treatment or active antiretroviral treatment. This is a mix of several different antiviral drugs used to help slow progression of infection. A mixture is used because it has less potential to select for resistance. Initiation of HAART therapy is recommended when CD4 count is less than 350 cells/ul and/or if viral loads are high.

76
Q

What are some mechanisms of action of antiretroviral drugs?

A
  1. nucleoside analog - inhibit viral polymerases by incorporating a terminal nucleoside.
  2. reverse transcriptase inhibitor - binds to reverse transcriptase to disrupt enzymes catalytic site.
  3. protease inhibitor - inhibits the viral protease that is required at the late stage of HIV replicative cycle.
  4. fusion inhibitor - blocks viral and cellular membrane fusion step involved in entry of HIV into cells

Block 6 - week 5 (8 decks)

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