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MBBCh 2- HAEM2000A > ii. HIV I, II & III > Flashcards

ii. HIV I, II & III Flashcards

1
Q

What is AIDS?

A

AIDS: Acquired Immuno-Deficiency Syndrome
Symptoms and illnesses that develop at the final stage of HIV infection if left untreated = advanced/ late stage HIV infection

May take 10-15 years to dev dep on age, health and background. Leads to death

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2
Q

AIDS diagnosis:

A
  • AIDS diagnosis: aids defining illness (eg pneumocystis pneumonia; kaposi’s sarcoma; toxoplasmosis; candidiasis; tuberculosis)/ CD4 count <200cell/mm3
  • Opportunistic infections = hallmarks of AIDS
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3
Q

AIDS: Acquired Immuno-Deficiency Syndrome

Symptoms:

A

Symptoms: weight loss; fever; night sweats; fatigue; recurrent infections

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4
Q

What is the Immunologic Disease progression of AIDS?

A
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5
Q

What are the features of the stage of acute infection? (7)

A

Acute infection =
- 2-4 weeks after infection w HIV
- flu like symptoms
- viral load multiplies rapidly
- Decrease CD4 T cells
- levels of HIV in blood v high - CD8 increase (compensate)
- Viral set point= 3-6 months after infection

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6
Q

What are the features of the chronic infection stage?

A

Chronic infection (asymptomatic); CD4 and CD8 levels decrease slowly; Antibodies appear; Immune system exhausted therefore opportunistic infections develop; AIDS w/o treatment survival = 3yrs

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7
Q

What is seroconversion?

A

Seroconversion - time period during which a specific antibody develops and becomes detectable in the blood. After seroconversion has occurred the Abs can be detected in blood tests for the disease

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8
Q

What is the window period of infection?

A

Window period - time btw HIV infection and point when test will give an accurate result. In this period patient can have HV and be very infectious but still test HIV negative

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9
Q

What are opportunistic infections?

A

Opportunistic infections - infection caused by non-pathogenic microorganisms which become pathogenic when immune system is impaired by unrelated disease T helper cells (CD4+ cells) play NB role in adaptive immune system and help activity of other immune cells by releasing T cell cytokines. They help suppress or regulate the immune response

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10
Q

What are Fiebig Stages of early HIV infection?

A

Fiebig Stages of early HIV infection: describes various stages of early HIV infection, based on timing and results of diagnostic tests

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11
Q

What is HIV?

A

Retrovirus which containers an RNA-based genome and integrates permanently into host cell’s DNA-based genome

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12
Q

Central dogma of gene expression:

A

DNA-mRNA-protein

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13
Q

Viral reverse transcription:

A

RNA-DNA

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14
Q

Viral genome - 10000 base pairs; 3 overlapping reading frames - encodes for 3 classes of proteins:

A
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14
Q

Genetic variation - HIV types, groups, subtypes
Zoonotic transfer from Simian Immunodeficiency Virus

  • from chimpanzee =
  • from Sooty mangabey =
A

= HIV type 1 div into Group P, O, N, M. M= most common; has subgroups (A, B, C, D, F, G, H, J, K, CRF)

= HIV type 2 - 55% sequence identity; limited to West African; more difficult to transmit; some ARVs don’t work’ lower viral loads; slower rate to aids HIV-1 genetic variability due to: error-prone HIV-1 RT enzyme; Rapid viral replication; Immune pressure; recombination

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15
Q

Viral Structure:

A
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16
Q

Cellular targets for HIV-1 infection:
Main receptor:

A

Cluster of differentiation-4 (CD4)

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17
Q

Cellular targets for HIV-1 infection:

Co receptors: (2)

A

-1.CXCR4 = chemokine receptor, found on B cells, monocytes and some T cells

  • Viruses that use CXCR4 = X4-tropic
  • Main CXCR4 bearing cell = CD4+ T cells
  1. CCR5= chemokine receptor
  • Found on T cells, macrophages, dendritic cells, micro Gila
  • Viruses that use CCR5= R5-tropic
  • Main CD4+ CCR5 bearing cells= macrophages
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18
Q

Cellular targets for HIV-1 infection:

Minor coreceptors: (3)

A
  • GPR1 - CD4 T reg
  • CX3CR1 - macrophage
  • APLNR- glial
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19
Q

Anatomical Targets for HIV-1 Infection: (4)

A
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20
Q

Viral Replication Cycle
Early phases: (5)

A
  1. Binding/ viral attachment
  2. Fusion and entry
  3. Reverse transcription
  4. Uncoupling (partial) and nuclear import
  5. Integration
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21
Q

Viral Replication Cycle
Late phases: (4)

A
  1. Pro viral transcription
  2. Translation
  3. Assembly
  4. Budding and maturation
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22
Q

Targets for antiretroviral treatment:

A
  1. Fusion and entry
  2. Reverse transcription
  3. Integration
  4. Budding and maturation
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23
Q

Targets for antiretroviral treatment

What are the drug classes? (6)

A
  • Drug class 1: Fusion inhibitors
  • Drug class 2: CCR5 antagonists
  • Drug class 3: NRTI (nucleoside reverse transcriptase inhibitors; nucleotide analogues)
  • Drug class 4: NNRTI
  • Drug class 5: INSTI (Integrase Strand-transfer inhibitors)
  • Drug class 6: PI (protease inhibitors)
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24
Q

Drug class 1: Fusion inhibitors

HIV-1 target:
ARV:

A

Entry

Enfuvirtide (T-20) (no others)

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25
Q

Drug class 2: CCR5 antagonists

HIV-1 target:
ARV:

A

Entry

Maraviroc (no others)
* Requires tropism assay

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26
Q

Drug class 3: NRTI (nucleoside reverse transcriptase inhibitors; nucleotide analogues)

HIV-1 target:
ARV:

A

Reverse transcription

Zidovudine (AZT); Lamivudine (3TC) + others

27
Q

Drug class 4: NNRTI

HIV-1 target:
ARV:

A

Reverse transcription

Nevirapine (NVP); Efavirenz (EFV) + others

28
Q

Drug class 5: INSTI (Integrase Strand-transfer inhibitors)

HIV-1 target:
ARV:

A

Integrase

Raltegravir (RAL) ; Dolutegravir (DTG) + others

29
Q

Drug class 6: PI (protease inhibitors)

HIV-1 target:
ARV:

A

Protease

Lopinavir (LPV/r); Darunavir (DRV/r)

30
Q

Targets for antiretroviral treatment:

Step 5:

A

Integration = 2 step process in which HIV-1 integrase catalyzes both reactions

31
Q

Targets for antiretroviral treatment:

Step 1:

A

3’ processing in cytoplasm — INT cleaves “GT” nucleotides at both 3’ ends

32
Q

Targets for antiretroviral treatment:

Step 2:

A

Strand transfer in nucleus — INT integrates pro viral DNA into genome

33
Q

Antiretroviral Drug Resistance:

A
33
Q

Genetic Barrier to resistance:

Low:

A

Virus develops resistance to the drug easily and quickly. Often single drug resistance mutation is sufficient to cause high level drug resistance eg NVP, FTC, 3TC

34
Q

Genetic Barrier to resistance:

High:

A

Virus develops resistance to drug slower. 2+ drug resistance mutations req to cause high-level drug resistance eg DTG, DRV/r

35
Q

ART drug resistance:

Suppressed:

A

Viral load< 20/ 50 ml of HIV-1 in the blood (dep on sensitivity of assay) ie cART treatment success

36
Q

ART drug resistance:

Viraemic:

A

Viral load> 1000 ml of HIV-1 in blood ie cART treatment failure

37
Q

Antiretroviral treatment regimens:

Combination ART (cART):

A

3 ARVs from at least 2 diff ARV classes

38
Q

Antiretroviral treatment regimens:

Eligibility: (2)

A
  • Pregnant/ breastfeeding women regardless of CD4 count or WHO staging
  • Children> 5 yrs old, adolescents and adults w CD4<500 cell/mm3
39
Q

Antiretroviral treatment regimens:

Viral load monitoring:

A

12 months and then once per year

40
Q

General preventative strategies for HIV: (3)

A
  • HIV spreads through body fluids ie blood, semen and pre-seminal fluids, rectal fluids, vaginal fluids, breast milk
  • Cannot be contractile do through casual contact; anyone can get infected
  • General sets to protect yourself: know your HIV-1 status, Have less risky sex, use condoms, limit no. Sexual partners, get tested and treated for STDs, Don’t inject drugs (or use clean needles), Circumcision (60% reductio
41
Q

TLD (TDF/3TC/ DTG) =

A

preferred regimen for cART initiation

42
Q

NNRT-based regimens only switched to TLD w suppressed ___.

A

VL

43
Q
  • Women/adolescent girls - counseled through _____ _____ defects w DTG
  • LPV/r based second line regimen
  • _____ drug resistance test for 3rd line regimen
A

neural tube
Genotypic

44
Q

What is Pre-Exposure Prophylaxis (PrEP)?

A

Antiretroviral drugs used by HIV neg individual to prevent risk of infection

45
Q

Pre-Exposure Prophylaxis (PrEP)

Key populations:

A

MSM, transgender, sex workers, IDUs

46
Q

What does the efficacy of Pre-Exposure Prophylaxis (PrEP) depend on?

A

Efficacy dev on good adherence ie consistent and correct usage

46
Q

What are the types of Pre-Exposure Prophylaxis (PrEP)? (2)

A
  • Topical “microbicide” eg Vaginal gel - NRTI (TDF); Vaginal ring - NNRTI (DPV) contraceptive
  • Oral/ subcutaneous “PrEP”eg Oral - “truvada” (2x NRTI: TDF/FTC); Subcutaneous - NRTI (TAF), NNRTI (RPV), INSTI (CAB)
47
Q

What is Post-Exposure Prophylaxis (PEP) ?

A
  • Taken by HIV-1 neg individual after potential exposure to HIV-1
48
Q

Post-Exposure Prophylaxis (PEP)

Full cART regimen: (3)

A

TDF + 3TC (or FTC) + RAL (or ATV/r)

Initiate cART asap (within 72 hrs)

Continue w cART for 28 days w perfect adherence

49
Q

Treatment as Prevention (TasP):

Prevention Mother-to-child transmission (pMTCT):

A
50
Q

What is the PARTNER study?

A
50
Q

What is the preventative vaccine?

A

Preventative vaccine: viral envelope (gp160) targeted by antibody mediated immune response to make “neutralizing antibodies”

51
Q

HIV-1 evades immune system

How does the preventative vaccine initiate an immune response in this case?

A

Preventative vaccine should elicit a roadway neutralizing antibody (bNAb) response

51
Q

Antibody mediated prevention:

10-25% of HIV-1 infected people can develop bNAbs which: (3)

A
  • target diff conserved regions on gp160
  • Have diff potencies and breadth
  • Infusions could potentially prevent HIV-1 infection
52
Q

How can HIV-2 evade bNAbs?

A

HIV-1 can evade bNAbs by developing resistance mutations in envelope

53
Q

What is the cure for HIV?

A

Cure - currently none; ARTs can treat HIV-1 infection but can’t cure

54
Q

What is the mechanism of the sterlizing cure?

A
54
Q

Sterilizing cure:

A

completely removes HIV-1 from body

55
Q

What is the functional cure for HIV-1?

A

Functional cure: naturally suppress HIV-1 replication

56
Q

Functional cure:

HIV-1 reservoirs -

A
56
Q

Functional cure:

HIV-1 latency -

A

Long lived quiescent, memory CD4+ T cells harbor integrated agent (non-rep) HIV proviruses, viral rep resumes upon cellular activation

57
Q

What are the ‘shock and kill’ methods? (4)

A
  • Sterilizing cure
  • latency reversal agents
  • reactivate latent HIV-1 under cART
  • HIV-1 cleared by cytoplasmic effects, immune clearance, cell death
58
Q

What are the ‘block and lock’ methods? (2)

A
  • permanently silent
  • target transcriptional machinery: HIV-1 tat inhibition; LEDGF/ p75; FACT; RNA-induced epigenetic silencing
59
Q

HIV cure trials:

A
59
Q
A

MBBCh 2- HAEM2000A (30 decks)

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