Biochemistry - Unit III - HIV and AIDS

  1. HIV: what, target
    • causative agent for AIDS, HTLV Family, Retrovirus class (lentivirus subclass)
    • T4 lymphocytes: helper T-cell; helps both T and B cell functions; destroyed by HIV, resulting in immunodeficiency and ultimate demise due to bacterial or viral infections.
    • CD4 receptor; Ig like structure; binds MHC2 complement on the surface of antigen presenting cell
  2. HIV anatomy
    • lipid bilayer membrane
    • glycoprotein - gp41, gp120, ...
    • inside
    • proteins: p17, p24
    • two copies of RNA and reverse transcriptase
  3. Binding of HIV to T4 via
    gp120 to CD4 and CCR5 (chemokine receptor), which allow the entry
  4. HIV Life Cycle
    • vRNA + tRNA primer + viral reverse transcriptase + human nucleotides -> vDNA
    • RNA-vDNA + RT + viral RNase H -> dsDNA (proviral)
    • dsDNA integrated into host DNA
    • proviral DNA -> mRNA -> Protein + RNA -> new viruses -> leaves the cell and affect other healthy cells
  5. viral RNase H only works with ____
    RNA-DNA hybrid
  6. HIV Genome
    • Diploid genome (2 RNA copies/ virus particle)
    • RNA physically linked as a dimer by hydrogen bonds; Harbors tRNAlys (using its CCA end as the primer) for initiating reverse transcription
    • RNA is single-stranded, positive sense, composed of 9749 nucleotides w/ 5' cap and 3' poly-(A) tail
  7. HIV Genome and major gene products
    • HIV genome encodes nine open reading frames, 15 proteins
    • LTR: long terminal repeat sequences at the 5' and 3' ends; 5' one has transcription promoter sites, or transcription factor binding sites; Attracts transcription machinery
    • GAG: a group antigen including MA, CA, NC proteins; Nucleocapsid, core protein (matrix), P-6
    • POL: for proteins inside the membrane; spliced into three parts: PR (protease; self-splices itself out first
    • ), RT, and IN
    • ENV: Gp160; cleaved to Gp120 and Gp41
  8. Small sequences/proteins
    • make the virus infectious
    • regulatory functions; +/- virus production
    • REV: negative control
    • TAT: transcription stimulator
    • NEF: negative regulator, slows down transcription
    • That’s why sometimes you have viral infection and sometimes it’s quiet
  9. Host receptors
    • CD4 antigen: primary receptors, binds HIV gp120
    • Chemokine receptors: essential co-receptors, seven transmembrane GPCR, tropism
    • -CCR5: employed by macrophage-tropic HIV strains involved in critical early stages of infection, CCR5 receptor gene was mapped to human chromosome 3p21 only 18 kb away from CCR2B receptor gene
    • -CXCR4: ligand is a B cell stimulatory factor called fusin, promotes infection /fusion of CD4+ T cells
    • -CCR2: recently identified co-receptor
  10. Nucleoside Class inhibitors: _______ inhibitors, bind to _____, DNA chain terminators. These drugs are phosphorylated to ______ by host cell enzymes before being incorporated into the growing DNA chain and inhibiting further elongation. Eg. ______ etc.
    • competitive
    • the enzyme's active site
    • the triphosphate form
    • AZT (azidothymidine),
    • DDI (didanosine),
    • 3TC (Lamivudine)
  11. Non-Nucleoside Class: these drugs do not need to be phosphorylated to be active, bind elsewhere other than the enzyme’s active site and function in a _______ fashion. These drugs work _____ with nucleoside analogs, exhibit high therapeutic index and good bio-availablity. Eg. ______ etc.
    • noncompetitive
    • synergistically
    • Nevirapine,
    • delavirdine,
    • efavirenz
  12. Every step of the viral life cycle is a potential target
    • Binding: stop w/ antibody; Risky can affect CD4
    • Fusion: antibody
    • Most popular target is reverse transcription, modify nucleotides/sides, eg AZT
    • Interfere with integration - dsDNA cannot go to nucleus
    • Integrase inhibitor
    • Translation - NO; would be lethal to us, too
    • transcription - NO; same
    • Polyprotein can be produced and its cleavage is dependent on protease, which is virally coded.
    • blocking the viral protease will not allow the polyproteins to form single proteins
  13. Pol (Rt) :
    • AZT/dideoxy nucleosides/
    • non-nucleoside inhibitors, e.g. Nevirapine
  14. Protease:
    • Peptide mimicking compounds that are transition state analogs. They bind the enzyme much more tightly than the natural substrate and function as competitive enzyme inhibitors.
    • saquinavir, indinavir etc.
  15. Integrase:
    Issentress (Merck)
  16. Entry Site (CCR-5):
  17. Fusion Inhibition:
    Enfuvirtide (EFV)
  18. HAART: Highly Active Anti-Retroviral Therapy
    • Combination therapy of multiple anti-HIV drugs
    • the most effective means of controlling HIV-1 infection.
    • Typically, combines one protease inhibitor with two reverse transcriptase inhibitors
  19. Attempts of anti-HIV vaccines
    • Nothing yet
    • Therapeutic vaccines: boost the immune system of an already-infected person
    • Protective/Prophylactic vaccines: to prevent HIV infection in uninfected population
    • Perinatal vaccines: prevent mother-to-child transmission
  20. Viruses cannot reproduce or express their genes without the help of a living cell – not alive but not quite dead
  21. Three levels of defense
    • Innate immunity: barriers
    • Innate immunity: cells and fluids; rapid; no memory; all you need for dental infections
    • Adaptive immunity: Where the CD4 cells are
  22. For the HIV patient, antibiotics usually ______ as in any other patient (even if CD4 count is low)
    not needed unless already has dental infection
  23. Adaptive immunity
    • Along came viruses, fungi and cancer
    • •We needed a system to fight these attackers
    • •We needed a system with memory and a rapid response to fight these invaders
    • •The body developed B-lymphocytes which make antibodies and…
    • •The body developed T-lymphocytes to coordinate the attack and kill the invaders
  24. CD-4
    • The “coach” that helps the system function but does not kill – the cell that the HIV virus attacks.
    • Secretes chemicals (cytokines) to guide rest of immune resp
  25. CD-8
    The killers that directly attack invaders
  26. Theories on CD4 Cell Death
    • Suicide (apoptosis)?– Holes in membrane from release of new virions? –
    • A newer theory - it is a victim of the chronic inflammatory process: In an area of inflammation (like HIV infection) pro-inflammatory signals released by death of cells attract more cells (CD4) into the infected tissue to die and, in turn, produce more inflammation.
  27. HIV – drug/vaccine resistance
    Multiple mutations interrupt the efforts to interrupt HIV life-cycle!
  28. HIV -> AIDS
    • CD4<200
    • if rises >200, still considered that patient has AIDS
    • The immune system weakens
    • The illnesses become more severe leading to an AIDS diagnosis
  29. What is an opportunistic infection?
    • -An infection caused by a pathogen that usually does not cause disease in a healthy host, i.e. one with a healthy immune system
    • - A compromised immune system, however, presents an "opportunity" for a resident pathogen to cause an infection and/or a cancer to develop. Commonly occurring opportunistic infections in the oral cavity of HIV infected patients are:
    • Candidiasis (fungus)
    • Herpes (virus) – the “cold sore” (HSV-1)
    • Kaposi’s Sarcoma (cancer) from the HHV-8 (herpes virus)
    • Tuberculosis - Quantiferon (IGRA) Test
    • Evaluates for latent TB, measures interferons
  30. Prolonged life-span with use of HAART has increased:
    • the numbers of HIV patients that present for dental treatment
    • the challenges related to restorative considerations that may increase with time
    • medical complexity considerations due to prolonged lifespan with co-morbid conditions (other disease, cognitive decline)
  31. Dental Care for Patients with HIV (PHIV) - Overall Considerations
    • no more complex than for any other patient with a significant medical history
    • Risk of transmission to the dental team is negligible if appropriate infection control procedures are followed
    • Standard medical assessment with additional considerations specific for HIV
    • Hemostasis, infection risk, drug actions/interactions, ability to tolerate treatment, co-morbidities
    • HIPAA considerations as for any other patient
    • Signed consent for medical info. sharing (?)
    • TB – no risk unless patient presents with productive cough
  32. Patients with HIV - Health History – Specific Issues
    • The privacy setting
    • Confidentiality with pediatric patients
    • Risk factors – mode of transmission, if disclosed, may have implications for dental treatment
    • Co-morbidities
    • Patient is compliant with medications (?)
    • Patient is following up with MD?
    • Last CD4 count, viral load - If CD4 down and viral load up, you may have soft tissue risk
  33. HIV – Medications and Drug Interactions
    • Current medications – HAART or for other comorbidity
    • Not taking HAART – why? - Physician care? Non-compliance?
    • GI upset may be from the use of multiple Rx, not GI disease – avoid NSAIDs (?)
    • Drug-drug interactions with HAART medications from commonly dentist-prescribed medications are usually not a significant issue
    • HAART medications may affect blood cell counts (may be from the virus)
  34. HIV Patient –Labs. for Dental Care
    • medical in nature, not specifically focused on HIV (CBC/D, complete metabolic panel, coagulation studies)
    • Altered blood cell counts – reduced red cells, white cells, platelets
    • CD4 count / viral load should be known so as to create an awareness of the potential for oral lesions or other systemic problems
  35. Reduce or Eliminate Risks for Acquiring HIV Infection in the Dental Office
    • Infection control practices
    • Blood and body fluid precautions
  36. HIV – Clinician Guidelines for General Dental Care Treatment Planning
    • Patient assessment and management for general dental procedures are based upon patient’s medical status, not the HIV status
    • Thorough oral soft tissue examination – screening for opportunistic disease and/or cancer (Kaposi’s Sarcoma)
    • Other patient medical issues, whether or not HIV related, can influence planning and management
    • Life-style factors may be issues of concern in dental treatment planning
  37. Antibiotics
    • For the HIV patient with no active oral infection, there is no data to support the need for antibiotic coverage based on a patient’s CD4 count
    • Antibiotics should be used if the absolute neutrophil is low (<500 mm3) or segmented neutrophil count is low as with any other non-HIV patient
    • Other medical issues may require antibiotic use
    • Patients may be on other antibiotics for prevention of opportunistic infections. However, standard dental management protocols are still used (infection, cardiac prophylaxis)
  38. HIV – Clinician Guidelines for General Dental Care
    • Overall, HIV patients do not exhibit dental disease characteristics different from the nonafflicted population
    • Xerostomia from medications can be a common complicating factor
    • As with any medical illness, degree of impairment, care setting and personal hygiene characteristics will strongly influence planning, treatment, follow-up maintenance and prognosis
  39. Oral Surgery: Clinician Guidelines
    • Communicate with patient – pre- and post-op instructions
    • Incidence of post-procedural complications is no greater than in other populations
  40. Noted periodontal manifestations:
    • Linear Gingival Erythema
    • Necrotizing Ulcerative Gingivitis (NUG)
    • Necrotizing Ulcerative Periodontitis (NUP)
    • These periodontal manifestations may occur in non-HIV individuals such as immunocompromised patients
    • NUP may be a marker of immune decline from HIV to AIDS
    • These entities may be superimposed on conventional periodontitis
  41. Linear Gingival Erythema (LGE)
    • Erythematous band along the gingival margin, not always associated with bleeding or discomfort
    • Can present on nonattached gingival tissues as petechiae
    • Not necessarily related to plaque accumulation; may be due to subgingival candida colonization
    • Debridement, chlorhexidine gluconate
  42. Endodontic (Root Canal) Considerations
    •  Endodontic treatment appears to offer many benefits and few drawbacks for HIV patients
    •  Reduced infection risk
    •  Reduced need for extraction
    •  Improved ability to chew
    •  Improved self-esteem
    •  Restorative and maintenance prognosis as with any patient
  43. Special concern should be given to Prosthodontic treatment:
    • overall medical status
    • candidiasis
    • xerostomia
    • wasting syndrome
    • maintenance potential
  44. HIV and Dental Implants
    • Surgical risks should be part of assessment (bleeding, infection)
    • Other life-style factors relating to the illness may be a consideration (illicit drugs, hygiene)
  45. Xerostomia
    • Impacts on hard and soft tissue
    • Impacts on quality of life
    • Treatments choices
    •  Over-the-counter products
    •  Prescription medications
  46. Patients may be on other antibiotics for prevention of opportunistic infections. However, standard dental management protocols are still used (infection, cardiac, other)
  47. There is no evidence to support alterations in oral health care solely based on HIV status.
  48. Rapid HIV Antibody Combo. Test
    • Tests for p24 antigen / HIV antibodies
    • One drop of blood
    • Results in 20 minutes
    • FDA Approved
Card Set
Biochemistry - Unit III - HIV and AIDS
Biochemistry - Unit III - HIV and AIDS