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MSII Microbiology > Unit 1 - HIV Replication and Pathogenesis > Flashcards

Unit 1 - HIV Replication and Pathogenesis Flashcards

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1
Q

why have new HIV infections and AIDS-related deaths passed their peak?

A

deaths peaked 10 years after infections

-due to education, changing behavior (especially screening blood donations and better treatment)

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2
Q

how many independent introductions of SIV into humans occured?

A

three different ones (O, N, M)

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3
Q

what are routes of HIV spread and what are NOT?

A

most common: unprotected sex with infected partner, sharing needles with infected person
almost eliminated: transmission from infected mother to fetus, infected blood products
impossible: casual contact, exposure to saliva or urine, blood-sucking insects

in short, routes of HIV transmission depend on cultural factors

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4
Q

who is at highest risk for HIV infection?

A

young gay and bisexual male African Americans

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5
Q

time frame/steps of HIV exposure and infection

A
  1. crossing barrier within hours
  2. local propagation (R0<1)
  3. local expansion within days
  4. sufficient production of infected cells, virus, and self-propagating systemic infection within days
  5. dissemination within days
  6. establishment in lymphatic tissue reservoir within weeks
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6
Q

HIV exposure and infection details

A

few virions breach epithelium and establish infection (R0<1)

  • brief window to attempt prevention with drugs or vaccines
  • virions infect tissue macrophages, dendritic cells, etc.
  • infected cells make virions and migrate to LN for further infections
  • virions spread from regional LN and GALT to other sites
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7
Q

are women or men more likely to get infected?

A

women

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8
Q

what lymphoid cells does HIV infect?

A

lymphoid cells embedded in vaginal and rectal epithelium

-spreads to lymph nodes and blood

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9
Q

what are symptoms of HIV, generally

A

such symptoms that look like a systemic infection throughout the body

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10
Q

describe what HIV actually is?

A

RNA virus (retroviridae)

  • lentivirus (slow to cause disease, but fast to replicate)
  • ssRNA, +strand
  • two copies in each virion (diploid)
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11
Q

HIV structure? contents?

A

lipid bilayer with TMD

-includes reverse transcriptase, +ssRNA, integrase, protease, nucleocapsid and capsid

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12
Q

HIV cell tropism (early VS late)

A

early: HIV binds to CCR5 coreceptor on macrophages
- non-synctium inducing
late: HIV binds CXCR4 coreceptor on T cells
- synctium inducing

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13
Q

HIV lifecycle overview

A
  1. attachment and fusion
  2. uncoating
  3. reverse transcription
  4. migration of genome to nucleus
  5. integration into host Xm
  6. mRNA and genome synthesis
  7. mRNA export
  8. viral protein synthesis
  9. genomic RNA export
  10. spliced mRNA synthesis
  11. viral membrane protein synthesis
  12. protein maturation
  13. protein accumulation at PM
  14. virion assembly at PM
  15. budding
  16. virion maturation
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14
Q

explain HIV attachment

A

HIV Env is made of TM (gp41) and SU (gp120) domains

  • SU binsd CD4 and chemokine receptors (CCRs) that causes conformational change in TM
  • fusion peptide on TM inserts in target cell membrane and induces virus entry
  • CCR usage shifts between CCR5 (macrophages) and CXCR4 (T cells)
  • presence of CCR determines susceptibility to HIV infection (human genetic variant d32)
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15
Q

explain HIV uncoating

A
  1. attachment and membrane fusion
  2. uncoating and partial capsid disintegration
  3. reverse transcription of ssRNA genomes to DNA
  4. migration of circular genomes to nucleus
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16
Q

what are key points of reverse transcription?

A

tRNA bound to ssRNA is a primer

-templates switch during replication

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17
Q

how does HIV get into the nucleus?

A

HIV uses dNTPs in cytoplasm (may be limiting in non-dividing cells)

  • RT enzyme is error prone
  • newly made circular DNA genomes are bound to HIV protein integrase, which has a nuclear localization signal that directs it to the nucleus
18
Q

key points on HIV genome integration and latency

A
  1. HIV provirus integrates into the host Xm at sites of active genes
    -this is permanent; the viral genome becomes part of the cell for life, creating a “reservoir” of latent virus throughout the body, which is the primary obstacle to eradicating HIV from a person
    -this marks the end of Phase 1 of HIV replication
  2. viral and cellular transcription factors bind promoter in LTR and recruit RNA Pol II
    -several types of mRNA are transcribed, spliced and exported to cytoplasm
    0this marks the start of Phase 2 of HIV replication
19
Q

HIV mRNA transcription and translation

A
  1. some mRNAs are translated on ribosomes that are free in cytoplasm
  2. ribosomal frameshifting infrequently causes a read-through, which translates Gag-Pol precursor, creating the right balance of Gag&raquo_space; Gag-Pol
  3. genomic mRNAs are full-length transcripts
  4. short mRNAs encode Env
  5. Env mRNA is translated at RER
    - Env is integral membrane protein cleaved by host proteases into SU+TM domains
20
Q

explain HIV protein sorting

A
  1. Env matures in Golgi via glycosylation, cleavage, and trimer formation
  2. secretory vesicles traffic Env to plasma membrane
  3. all other proteins and genomic mRNAs accumulate at plasma membrane and concentrate in lipid rafts
    - some enzymes in virion are RT, IN, and PR
21
Q

explain virion budding and maturation

A
  1. virions are formed when they bud from the plasma membrane
    - these immature virions are not infectious
  2. HIV protease cleaves Gag into its subunits (MA-CA-NC) within virion causing the capsid to assume trapezoidal shape in mature virion
    - these extracellular virions are infectious
22
Q

explain why HIV protease is an essential enzyme?

A
  1. Gag polyprotein has 3 domains
    - MA binds to cytoplasmic tail of TM+SU
    - CA is structural
    - NC binds to RNA genome
  2. viral protease is packaged in virion and must cleave Gag into its 3 subunits to form infectious particles
  3. protease processing results in change from indistinct core to typical trapezoidal core of mature HIV-1
  4. anti-retroviral drug therapy targets protease and blocks infectivity
23
Q

explain HIV-1 syncytium formation

A

Env can fuses infected T cells with uninfected T cells

  • syncytia are lethal for T cells (one cause of immunodeficiency)
  • 10 to 100s of cells may be involved
  • syncytium-inducing strains are more virulent than non-syncytium-inducing strains
  • 1 mass of fused cells = syncytium, multiple masses of fused cells = synctia
24
Q

what is the final step in virion maturation?

A

protease cleavage

25
Q

what are the stages of HIV disease? (7)

A
  1. exposure to virus (transmission)
  2. primary HIV infection (acute phase)
  3. seroconversion
  4. clinical latent period
  5. early symptomatic HIV infection
  6. AIDS (CD4<50/mm3)
26
Q

how does AIDS cause immune dysfunction?

A

progressive loss of T helper and memory cells

-but direct killing of T cells by HIV replication does not account for all the losses and immune dysfunction

27
Q

what is possibly the only treatment for AIDS-related diseases?

A 
antiretroviral therapy (ART)
-can restore immunity
28
Q

explain HIV load and CD4 T cells

A

CD4+ and CCR5+ cells are infected by HIV during initial phase of infection

  • mutations in Env enable HIV to infect CD4+ and CXCR4+ cells
  • this changes the course of the disease and is a sign that immunological control (CD8+) cells is waning and risk of AIDS is increasing
  • viral load climbs, and CD4+ cells drop as AIDS progresses
29
Q

overall mechanisms of HIV disease

A

freshly infected T cells are “activated” and secrete abnormal cytokines, which kill bystander T cells

  • accumulation of virulence mutations causes HIV to escape from immune control
  • CXCR4-tropic viruses emerge, and T cell losses accelerate
  • opportunistic infections and tumors cannot be fought, and eventually kill host unless antiretroviral therapy is started
30
Q

what are symptoms that occur at CD4 = 350?

A

TB, oral hairy leukoplakia, oral thrush, Kaposi’s sarcoma (oral), PCP (mild; Pneumocystitis jirovecii), lymphadenopathy, esophageal Candida, Herpes simplex (face), toxoplasmosis (cerebral), progressive multifocal leukoencephalopathy (PML; JC virus), CMV retinitis, mycobacterium avium-intracellulare (MAI, MAC)

31
Q

what are symptoms that occur at CD4 = 500?

A

seborrheic dermatitis, Papulopruritic eruptions (Nodular prurigo)

32
Q

explain seborrheic dermatitis risk factors

A

-stress or fatigue
-weather extremes
-oily skin, or skin problems such as acne
-infrequent shampoos or skin cleaning
-using lotions that contain alcohol
-obesity
-neurologic conditions, including Parkinson’s
disease, head injury or stroke

33
Q

what are the goals of antiretroviral therapy?

A
  1. suppress HIV-1 replication (impedes spread of HIV)
  2. prevent/delay destruction of immune system
  3. achieve normal survival while maintaining a tolerable life
    - some drugs can only maintain for 1 year before resistance

will still have detectable virus in semen and vaginal fluids

34
Q

when should you definitely treat HIV/AIDS?

A
  1. asymptomatic AIDS, yet CD4 < 350, at any value of HIV RNA
  2. symptomatic (AIDS, severe), with any level CD4 and HIV RNA

controversy as to when to begin therapy, but must definitely start if CD4 < 350
-if CD4 > 500, should discuss with patient

35
Q

when would most clinicians defer therapy for HIV/AIDS?

A

asymptomatic, with CD4 > 350, 100,000, some physicians begin treatment
-may also defer if significant barriers to adherence, if comorbidities complicate/prohibit ART, or “elite controllers” with long-term nonprogressors

36
Q

what are potential concerns about early therapy for HIV/AIDS?

A
  1. ARV-related toxicities
  2. non-adherence to ART
  3. drug resistance
  4. cost
37
Q

when should you consider rapid initiation of ART?

A
  1. pregnancy
  2. acute opportunistic infection, or recent infection
  3. CD4 < 200
  4. HIV AN
  5. HBV or HCV coinfection
38
Q

what are the 5 targets of HIV therapy?

A
  1. entry inhibitors (fusion inhibition)
  2. entry inhibitors (CCR5, CXCR5 blockers)
  3. reverse transcriptase inhibitors (NTIs, NNRTIs)
  4. integrase inhibitors
  5. protease inhibitors
39
Q

what are the 6 types of ARV medications?

A
  1. NRTI (nt or ns reverse transcriptase inhibitor)
  2. NNRT (non-nt/ns reverse transcriptase inhibitor)
  3. PI (protease inhibitor)
  4. II (integrase inhibitor)
  5. FI (fusion inhibitor)
  6. CCR5 antagonist
40
Q

what do all preferred ART regiments include?

A

2 NRTIs, then either 1 NNRTI, 1 PI, or 1 II

MSII Microbiology (23 decks)

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