ii. HIV I, II & III Flashcards
What is AIDS?
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
AIDS diagnosis:
- AIDS diagnosis: aids defining illness (eg pneumocystis pneumonia; kaposi’s sarcoma; toxoplasmosis; candidiasis; tuberculosis)/ CD4 count <200cell/mm3
- Opportunistic infections = hallmarks of AIDS
AIDS: Acquired Immuno-Deficiency Syndrome
Symptoms:
Symptoms: weight loss; fever; night sweats; fatigue; recurrent infections
What is the Immunologic Disease progression of AIDS?
What are the features of the stage of acute infection? (7)
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
What are the features of the chronic infection stage?
Chronic infection (asymptomatic); CD4 and CD8 levels decrease slowly; Antibodies appear; Immune system exhausted therefore opportunistic infections develop; AIDS w/o treatment survival = 3yrs
What is seroconversion?
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
What is the window period of infection?
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
What are opportunistic infections?
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
What are Fiebig Stages of early HIV infection?
Fiebig Stages of early HIV infection: describes various stages of early HIV infection, based on timing and results of diagnostic tests
What is HIV?
Retrovirus which containers an RNA-based genome and integrates permanently into host cell’s DNA-based genome
Central dogma of gene expression:
DNA-mRNA-protein
Viral reverse transcription:
RNA-DNA
Viral genome - 10000 base pairs; 3 overlapping reading frames - encodes for 3 classes of proteins:
Genetic variation - HIV types, groups, subtypes
Zoonotic transfer from Simian Immunodeficiency Virus
- from chimpanzee =
- from Sooty mangabey =
= 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
Viral Structure:
Cellular targets for HIV-1 infection:
Main receptor:
Cluster of differentiation-4 (CD4)
Cellular targets for HIV-1 infection:
Co receptors: (2)
-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
- CCR5= chemokine receptor
- Found on T cells, macrophages, dendritic cells, micro Gila
- Viruses that use CCR5= R5-tropic
- Main CD4+ CCR5 bearing cells= macrophages
Cellular targets for HIV-1 infection:
Minor coreceptors: (3)
- GPR1 - CD4 T reg
- CX3CR1 - macrophage
- APLNR- glial
Anatomical Targets for HIV-1 Infection: (4)
Viral Replication Cycle
Early phases: (5)
- Binding/ viral attachment
- Fusion and entry
- Reverse transcription
- Uncoupling (partial) and nuclear import
- Integration
Viral Replication Cycle
Late phases: (4)
- Pro viral transcription
- Translation
- Assembly
- Budding and maturation
Targets for antiretroviral treatment:
- Fusion and entry
- Reverse transcription
- Integration
- Budding and maturation
Targets for antiretroviral treatment
What are the drug classes? (6)
- 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)
Drug class 1: Fusion inhibitors
HIV-1 target:
ARV:
Entry
Enfuvirtide (T-20) (no others)
Drug class 2: CCR5 antagonists
HIV-1 target:
ARV:
Entry
Maraviroc (no others)
* Requires tropism assay
Drug class 3: NRTI (nucleoside reverse transcriptase inhibitors; nucleotide analogues)
HIV-1 target:
ARV:
Reverse transcription
Zidovudine (AZT); Lamivudine (3TC) + others
Drug class 4: NNRTI
HIV-1 target:
ARV:
Reverse transcription
Nevirapine (NVP); Efavirenz (EFV) + others
Drug class 5: INSTI (Integrase Strand-transfer inhibitors)
HIV-1 target:
ARV:
Integrase
Raltegravir (RAL) ; Dolutegravir (DTG) + others
Drug class 6: PI (protease inhibitors)
HIV-1 target:
ARV:
Protease
Lopinavir (LPV/r); Darunavir (DRV/r)
Targets for antiretroviral treatment:
Step 5:
Integration = 2 step process in which HIV-1 integrase catalyzes both reactions
Targets for antiretroviral treatment:
Step 1:
3’ processing in cytoplasm — INT cleaves “GT” nucleotides at both 3’ ends
Targets for antiretroviral treatment:
Step 2:
Strand transfer in nucleus — INT integrates pro viral DNA into genome
Antiretroviral Drug Resistance:
Genetic Barrier to resistance:
Low:
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
Genetic Barrier to resistance:
High:
Virus develops resistance to drug slower. 2+ drug resistance mutations req to cause high-level drug resistance eg DTG, DRV/r
ART drug resistance:
Suppressed:
Viral load< 20/ 50 ml of HIV-1 in the blood (dep on sensitivity of assay) ie cART treatment success
ART drug resistance:
Viraemic:
Viral load> 1000 ml of HIV-1 in blood ie cART treatment failure
Antiretroviral treatment regimens:
Combination ART (cART):
3 ARVs from at least 2 diff ARV classes
Antiretroviral treatment regimens:
Eligibility: (2)
- Pregnant/ breastfeeding women regardless of CD4 count or WHO staging
- Children> 5 yrs old, adolescents and adults w CD4<500 cell/mm3
Antiretroviral treatment regimens:
Viral load monitoring:
12 months and then once per year
General preventative strategies for HIV: (3)
- 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
TLD (TDF/3TC/ DTG) =
preferred regimen for cART initiation
NNRT-based regimens only switched to TLD w suppressed ___.
VL
- Women/adolescent girls - counseled through _____ _____ defects w DTG
- LPV/r based second line regimen
- _____ drug resistance test for 3rd line regimen
neural tube
Genotypic
What is Pre-Exposure Prophylaxis (PrEP)?
Antiretroviral drugs used by HIV neg individual to prevent risk of infection
Pre-Exposure Prophylaxis (PrEP)
Key populations:
MSM, transgender, sex workers, IDUs
What does the efficacy of Pre-Exposure Prophylaxis (PrEP) depend on?
Efficacy dev on good adherence ie consistent and correct usage
What are the types of Pre-Exposure Prophylaxis (PrEP)? (2)
- 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)
What is Post-Exposure Prophylaxis (PEP) ?
- Taken by HIV-1 neg individual after potential exposure to HIV-1
Post-Exposure Prophylaxis (PEP)
Full cART regimen: (3)
TDF + 3TC (or FTC) + RAL (or ATV/r)
Initiate cART asap (within 72 hrs)
Continue w cART for 28 days w perfect adherence
Treatment as Prevention (TasP):
Prevention Mother-to-child transmission (pMTCT):
What is the PARTNER study?
What is the preventative vaccine?
Preventative vaccine: viral envelope (gp160) targeted by antibody mediated immune response to make “neutralizing antibodies”
HIV-1 evades immune system
How does the preventative vaccine initiate an immune response in this case?
Preventative vaccine should elicit a roadway neutralizing antibody (bNAb) response
Antibody mediated prevention:
10-25% of HIV-1 infected people can develop bNAbs which: (3)
- target diff conserved regions on gp160
- Have diff potencies and breadth
- Infusions could potentially prevent HIV-1 infection
How can HIV-2 evade bNAbs?
HIV-1 can evade bNAbs by developing resistance mutations in envelope
What is the cure for HIV?
Cure - currently none; ARTs can treat HIV-1 infection but can’t cure
What is the mechanism of the sterlizing cure?
Sterilizing cure:
completely removes HIV-1 from body
What is the functional cure for HIV-1?
Functional cure: naturally suppress HIV-1 replication
Functional cure:
HIV-1 reservoirs -
Functional cure:
HIV-1 latency -
Long lived quiescent, memory CD4+ T cells harbor integrated agent (non-rep) HIV proviruses, viral rep resumes upon cellular activation
What are the ‘shock and kill’ methods? (4)
- Sterilizing cure
- latency reversal agents
- reactivate latent HIV-1 under cART
- HIV-1 cleared by cytoplasmic effects, immune clearance, cell death
What are the ‘block and lock’ methods? (2)
- permanently silent
- target transcriptional machinery: HIV-1 tat inhibition; LEDGF/ p75; FACT; RNA-induced epigenetic silencing
HIV cure trials:
