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Human Immunodeficiency Virus

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Human Immunodeficiency Virus

  1. 1. SaddamAnsariTbilisi State Medical UniversityHuman Immunodeficiency Virus (HIV)
  2. 2. IntroductionEtiologic agent of Acquired ImmunodeficiencySyndrome (AIDS).Discovered independently by Luc Montagnier of Franceand Robert Gallo of the US in 1983-84.Former names of the virus include:Human T cell lymphotrophic virus (HTLV-III)Lymphadenopathy associated virus (LAV)AIDS associated retrovirus (ARV)
  3. 3. IntroductionHIV-2 discovered in 1986, antigenically distinct virusendemic in West Africa.One million people infected in US, 30 millionworldwide are infected.Leading cause of death of men aged 25-44 and 4thleading cause of death of women in this age group in theUS.
  4. 4. Characteristics of the virusIcosahedral (20 sided), enveloped virus of the lentivirussubfamily of retroviruses.Retroviruses transcribe RNA to DNA.Two viral strands of RNA found in core surrounded byprotein outer coat.Outer envelope contains a lipid matrix within which specificviral glycoproteins are imbedded.These knob-like structures responsible for binding to targetcell.
  5. 5. Characteristics of the virus
  6. 6. Structural GenesThree main structural genes:Group Specific Antigen (Gag)Envelope (Env)Polymerase (Pol)
  7. 7. Group Specific Antigen (Gag)Located in nucelocapsid of virus.Icosahedryl capsid surrounds the internal nucleicacids made up of p24 andp15.p17 lies between protein core and envelope andis embedded in the internal portion of theenvelope.Two additional p55 products, p7 and p9, arenucleic acid binding proteins closely associatedwith the RNA.
  8. 8. Envelope (Env)Envelope (Env) gene codes for envelope proteins gp160,gp120 and gp41.These polyproteins will eventually be cleaved by proteases tobecome HIV envelope glycoproteins gp120 and gp41.gp160 cleaved to form gp120 and gp41.gp120 forms the 72 knobs which protrude from outerenvelope.gp41 is a transmembrane glycoprotein antigen that spans theinner and outer membranes and attaches to gp120.gp120 and gp41 both involved with fusion and attachment ofHIV to CD4 antigen on host cells.
  9. 9. Polymerase (Pol)Polymerase (Pol) codes for p66 and p51 subunits ofreverse transcriptase and p31 an endonuclease.Located in the core, close to nucleic acids.Responsible for conversion of viral RNA into DNA,integration of DNA into host cell DNA and cleavage ofprotein precursors.
  10. 10. Viral ReplicationFirst step, HIV attaches to susceptible host cell.Site of attachment is the CD4 antigen found on avariety of cellshelper T cellsmacrophagesmonocytesB cellsmicroglial brain cellsintestinal cellsT cells infected later on.
  11. 11. Early Phase HIV InfectionIn early phase HIVinfection, initial viruses areM-tropic.Their envelopeglycoprotein gp120 is ableto bind to CD4 moleculesand chemokine receptorscalled CCR5 found onmacrophages
  12. 12. In late phase HIV infection,most of the viruses areT-tropic, having gp120capable of binding to CD4and CXCR4 found onT4-lymphocytes.
  13. 13. Viral ReplicationThe gp120 protein on virus binds specifically to CD4receptor on host cell with high affinity.Gp41 causes fusion of the virus to the cell membrane.After fusion virus particle enters cell.Viral genome exposed by uncoating particle.
  14. 14. Viral ReplicationReverse transcriptase produces viral DNA from RNA.Becomes a provirus which integrates into host DNA.Period of latency occurs.
  15. 15. Viral ReplicationAfter a period of latency lasting up to 10 years viralreplication is triggered and occurs at high rate.CD4 cell may be destroyed in the process, bodyattempts to replace lost CD4 cells, but over the courseof many years body is unable to keep the count at a safelevel.Destruction of large numbers of CD4 cause symptomsof HIV to appear with increased susceptibility toopportunistic infections, disease and malignancy.
  16. 16. HIV (arrows) Infecting a T-lymphocyte
  17. 17. Viral ReplicationMethods of transmission:Sexual transmission, presence of STD increaseslikelihood of transmission.Exposure to infected blood or blood products.Use of contaminated clotting factors by hemophiliacs.Sharing contaminated needles (IV drug users).Transplantation of infected tissues or organs.Mother to fetus, perinatal transmission variable,dependent on viral load and mother’s CD 4 count.
  18. 18. Transmission
  19. 19. Primary HIV SyndromeMononucleosis-like, cold or flu-like symptoms mayoccur 6 to 12 weeks after infection.lymphadenopathyfeverrashheadacheFatiguediarrheasore throatneurologic manifestations.no symptoms (sometimes)
  20. 20. Primary HIV SyndromeSymptoms are relatively nonspecific.HIV antibody test often negative but becomes positivewithin 3 to 6 months, this process is known asseroconversion.Large amount of HIV in the peripheral blood.Primary HIV can be diagnosed using viral load titer assayor other tests.Primary HIV syndrome resolves itself and HIV infectedperson remains asymptomatic for a prolonged period oftime, often years.
  21. 21. Clinical Latency PeriodHIV continues to reproduce, CD4 count graduallydeclines from its normal value of 500-1200.Once CD4 count drops below 500, HIV infected personat risk for opportunistic infections.The following diseases are predictive of theprogression to AIDS:persistent herpes-zoster infection (shingles)oral candidiasis (thrush)oral hairy leukoplakiaKaposi’s sarcoma (KS)
  22. 22. Oral Candidiasis (thrush)
  23. 23. Oral Hairy LeukoplakiaBeing that HIV reduces immunologic activity, the intraoralenvironment is a prime target for chronic secondary infections andinflammatory processes, including OHL, which is due to the Epstein-Barr virus under immunosuppressed conditions
  24. 24. Kaposi’s sarcoma (KS)Kaposi’s sarcoma (shown) is arare cancer of the blood vesselsthat is associated with HIV. Itmanifests as bluish-red oval-shaped patches that mayeventually become thickened.Lesions may appear singly or inclusters.
  25. 25. AIDSCD4 count drops below 200 person isconsidered to have advanced HIV diseaseIf preventative medications not started the HIVinfected person is now at risk for:Pneumocystis carinii pneumonia (PCP)cryptococcal meningitistoxoplasmosis
  26. 26. Contined…If CD4 count drops below 50:Mycobacterium aviumCytomegalovirus infectionslymphomadementiaMost deaths occur with CD4 counts below 50.
  27. 27. Other Opportunistic InfectionsRespiratory systemPneumocystis Carinii Pneumonia (PCP)Tuberculosis (TB)Kaposis Sarcoma (KS)Gastro-intestinal systemCryptosporidiosisCandidaCytomegolavirus (CMV)IsosporiasisKaposis Sarcoma
  28. 28. Continued…Central/peripheral Nervous systemCytomegolavirusToxoplasmosisCryptococcosisNon Hodgkins lymphomaVaricella ZosterHerpes simplexSkinHerpes simpleKaposis sarcomaVaricella Zoster
  29. 29. Infants with HIVFailure to thrivePersistent oral candidiasisHepatosplenomegalyLymphadenopathyRecurrent diarrheaRecurrent bacterial infectionsAbnormal neurologic findings.
  30. 30. Immunologic ManifestationsEarly stage slight depression of CD4 count, few symptoms,temporary.Window of up to 6 weeks before antibody is detected, by 6months 95% positive.During window p24 antigen present, acute viremia andantigenemia.
  31. 31. Immunologic ManifestationsAntibodies produced to all major antigens.First antibodies detected produced against gagproteins p24 and p55.Followed by antibody to p51, p120 and gp41As disease progresses antibody levels decrease.
  32. 32. Immunologic ManifestationsImmune abnormalities associated with increased viralreplication.Decrease in CD4 cells due to virus budding from cells, fusionof uninfected cells with virally infected cells and apoptosis.B cells have decreased response to antigens possibly due toblockage of T cell/B cell interaction by binding of viral proteinsto CD4 site.CD8 cells initially increase and may remain elevated.As HIV infection progresses, CD4 T cells drop resulting inimmunosuppression and susceptibility of patient toopportunistic infections.Death comes due to immuno-incompetence.
  33. 33. Immunologic ManifestationsImmune abnormalities associated with increased viralreplication.Decrease in CD4 cells due to virus budding from cells, fusionof uninfected cells with virally infected cells and apoptosis.B cells have decreased response to antigens possibly due toblockage of T cell/B cell interaction by binding of viral proteinsto CD4 site.CD8 cells initially increase and may remain elevated.As HIV infection progresses, CD4 T cells drop resulting inimmunosuppression and susceptibility of patient toopportunistic infections.Death comes due to immuno-incompetence.
  34. 34. Laboratory Diagnosis of HIV InfectionMethods utilized to detect:AntibodyAntigenViral nucleic acidVirus in culture
  35. 35. Western BlotMost popular confirmatory test.Utilizes a lysate prepared from HIV virus.The lysate is electrophoresed to separate out the HIV proteins(antigens).The paper is cut into strips and reacted with test sera.After incubation and washing anti-antibody tagged withradioisotope or enzyme is added.Specific bands form where antibody has reacted with differentantigens.Most critical reagent of test is purest quality HIV antigen.The following antigens must be present: p17, p24, p31, gp41,p51, p55, p66, gp120 and gp160.
  36. 36. Western BlotAntibodies to p24 and p55 appear earliest but decrease orbecome undetectable.Antibodies to gp31, gp41, gp 120, and gp160 appear laterbut are present throughout all stages of the disease.
  37. 37. Western BlotInterpretation of results.No bands, negative.In order to be interpreted as positive a minimum of 3 bandsdirected against the following antigens must be present: p24,p31, gp41 or gp120/160.CDC criteria require 2 bands of the following: p24, gp41 orgp120/160.
  38. 38. DNA PCRDNA PCRRNA PCRRNA PCRp24 Agp24 Ag3rd gen ELISA1st gen ELISADetuned ELISA1wk 2wk 3wk 2mo 6mo 1yr 2yr 3yr +8yrgp160gp120p68p55p53gp41-45p40p34p24p18p12gp160gp120p68p55p53gp41-45p40p34p24p18p12gp160gp120p68p55p53gp41-45p40p34p24p18p12early recent / established advancedSpectrumSpectrumof anti-HIVof anti-HIVtestingtesting
  39. 39. Western BlotIndeterminate results are those samples that produce bands butnot enough to be positive, may be due to the following:prior blood transfusions, even with non-HIV-1 infected bloodprior or current infection with syphilisprior or current infection with malariaautoimmune diseases (e.g., diabetes, Grave’s disease, etc)infection with other human retrovirusessecond or subsequent pregnancies in women.run an alternate HIV confirmatory assay.Quality control of Western Blot is critical and requires testingwith strongly positive, weakly positive and negative controls.
  40. 40. Testing of NeonatesDifficult due to presence of maternal IgG antibodies.Use tests to detect IgM or IgA antibodies, IgM lackssensitivity, IgA more promising.Measurement of p24 antigen.PCR testing may be helpful but still not detecting antigensoon enough: 38 days to 6 months to be positive.
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