Presentation is loading. Please wait.

Presentation is loading. Please wait.

HIV INFECTION AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

Similar presentations


Presentation on theme: "HIV INFECTION AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)"— Presentation transcript:

1 HIV INFECTION AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

2 HISTORICAL PERSPECTIVES OF AIDS
1981 1982 1983 1984 1986 Recognition of Pneumocystis carinii pneumonia (PCP) and Kaposi’s sarcoma (KS) in young healthy men in NYC and Los Angeles GRID to AIDS by CDC Isolation of Lymphadenopathy-Associated Virus (LAV) by Pasteur Institute (Luc Montagnier) Isolation of Human T-Lymphotrophic Virus , Type III (HTLV-III) by NCI/NIH (Robert Gallo) Recommendation of the name Human Immunodeficiency Virus (HIV) by an international subcommittee on virus taxonomy

3

4

5

6

7 HUMAN IMMUNODEFICIENCY VIRUSES (HIV)
Classification Retroviridae (family) Lentivirus (genus) Characteristics 100 nm in diameter Genome of 2 single strands of RNA Nine genes Reverse transcriptase RNA-dependent DNA polymerase Transcribes RNA into DNA

8

9

10

11 GENOME OF HIV Contains 6 regulatory genes Contains 3 structural genes
Env (Envelope glycoproteins) gp120 and gp41 Gag (Core and matrix proteins) p55, p40 and p24 Pol (Enzymes) Reverse transcriptase (p66, p51) Protease (p11) Integrase (p32)

12

13 HUMAN RETROVIRIDAE (EXOGENOUS RETROVIRUSES)
Seven genera Alpha, Beta, Gamma, Delta, Epsilon, Lenti and Spuma Deltavirus Human T-lymphotropic virus, type I (HTLV-1) Human T-lymphotropic virus, type II (HTLV-II) Lentivirus Human immunodeficiency virus, type 1 (HIV-1) Human immunodeficiency virus, type 2 (HIV-2)

14 CLASSIFICATION OF THE HUMAN IMMUNODEFICIENCY VIRUSES (HIV)
Types Human immunodeficiency virus, type 1 (HIV-1) Human immunodeficiency virus, type 2 (HIV-2) HIV-1 is divided into groups M (Major) N (New) O (Outlier) Group M is divided into Subtypes (Clades) Circulating recombinant forms (CRF)

15 CLASSIFICATION OF HIV

16 ORIGIN OF HUMAN IMMUNODEFICIENCY VIRUSES
Existed as monkey virus in equatorial Africa HIV-1 Chimpanzee (Pan troglodytes troglodytes) HIV-2 Sooty Mangabey (Cercocebus atys) Transition from monkeys to humans When - Circa 1908 Molecular phylogenetics How – Hunter theory

17

18

19 MECHANISM OF PATHOGENICITY OF HIV
Envelope protein (gp120) of HIV binds with CD-4 receptor on surface of T-lymphocytes Macrophages Dendritic cells Microglial cells Coreceptors for attachment of HIV CCR5 (T-cells, macrophages, dendritic cells, microglial cells) CXCR4 (T-cells)

20 MECHANISM OF PATHOGENICITY OF HIV
Early infection CCR5 coreceptor is used (R5 strains) Growth equal in monocytes and lymphocytes Non syncytium-inducing (NSI) Late infection CXCR4 coreceptor is used (X4 strains) Growth in T cells Syncytium-inducing (SI) Emergence of X4 strains associated with accelerated decline in CD4 T cells Cause or consequence?

21 MECHANISM OF PATHOGENICITY OF HIV
Following attachment, virus enters cells and removes protein coat Viral RNA is transcribed into DNA by Reverse transcriptase Viral DNA then integrated into host cell DNA Integrase Integrated viral DNA Referred to as “provirus” Production of active infection

22

23

24 EPIDEMIOLOGY OF HIV INFECTION AND AIDS
Since 1981, 65 million people worldwide have contracted HIV > 25 million deaths 87% of HIV cases in developing nations 64% in sub-Saharan Africa 23% in southern and Southeast Asia Since 1981, 1.5 million people in the U.S. have contracted HIV Approximately 576,000 deaths In 2009, 56K new cases in the U.S.

25

26

27 TRANSMISSION OF HIV INFECTION AND AIDS
Sexual intercourse with infected person Homosexual (MSM) Heterosexual Bisexual Children born to infected mothers Perinatal IV drug addicts sharing contaminated syringes/needles Transfusion of blood and blood products Transfusion recipients Hemophiliacs Occupational exposure in health-care setting

28 CDC CLASSIFICATION OF HIV INFECTION AND DISEASE IN ADULTS AND ADOLESCENTS
Latest revision in 1993 Clinical Categories A B C CD4 T Cell Categories (Absolute number or %) > 500/uL or > 29% of total lymphocytes 200 – 499/uL or 14-28% of total lymphocytes < 200/uL or < 14% of total lymphocytes

29 CDC CLASSIFICATION SYSTEM
CD4 Cell Categories Clinical Categories A Asymptomatic, Acute HIV, or PGL B Symptomatic Conditions, not A or C C AIDS-Indicator Conditions (1) > 500 cells/µL A1 B1 C1 (2) cells/µL A2 B2 C2 (3) < 200 cells/µL A3 B3 C3

30

31

32 CDC CLASSIFICATION SYSTEM (CLINICAL CATEGORY A)
Following initial infection Asymptomatic Acute Retroviral Syndrome Infectious mononucleosis-like or flu-like illness 2 days to 4 weeks following infection Clinical manifestations Fever, headache, lethargy, pharyngitis, myalgias, photophobia, lymphadenopathy and a faint maculopapular rash Resolution within 30 days Persistent generalized lymphadenopathy (PGL)

33

34

35 CDC CLASSIFICATION SYSTEM (CLINICAL CATEGORY B)
Symptomatic conditions not meeting conditions of clinical categories A or C Herpes zoster (shingles) Oropharyngeal Candidiasis (thrush) Candida albicans Vulvovaginal candidiasis Bacillary angiomatosis Bartonella henselae Peripheral neuropathy Idiopathic thrombocytopenic purpura (ITP) Hairy leukoplakia (oral)

36

37

38

39

40 CDC CLASSIFICATION SYSTEM (CLINICAL CATEGORY C)
Acquired Immunodeficiency Syndrome (AIDS) Defining Conditions Esophageal Candidiasis Cryptosporidiosis Pneumocystis jiroveci (carinii) pneumonia Tuberculosis (pulmonary or extrapulmonary) Disseminated Mycobacterium avium complex (MAC) disease Histoplasmosis (disseminated or extrapulmonary)

41 HIV INFECTION IN ADULTS (CLINICAL CATEGORY C)
Acquired Immunodeficiency Syndrome (AIDS) Defining Conditions HIV wasting syndrome Cryptococcal meningitis Cytomegalovirus retinitis Cerebral Toxoplasmosis Progressive multifocal leukoencephalopathy (PML) JC virus Kaposi’s sarcoma Human herpesvirus type 8 (HHV-8)

42

43

44

45

46

47

48

49

50

51

52 PROGNOSIS AND MONITORING OF HIV TREATMENT AND DISEASE
CD4 T cell count (Immunological response) Absolute number Best indicator for patients with counts < 200 cells/uL Percent Best indicator for patients with counts > 200 cells/uL HIV-1 RNA (Viral load) (Virological response) Discordant immunological and virological responses exist

53 TREATMENT OF HIV INFECTION AND DISEASE
Anti-retroviral drugs do not cure HIV infection or disease Suppression of virus to undetectable levels Suppression of virus Drugs must be taken continuously Patients remain infectious Mutation rate in HIV is high and resistance develops Recommendation for combination therapy Combination of drugs from two or more classes Highly Active Anti-Retroviral Therapy (HAART)

54 TREATMENT OF HIV INECTION AND DISEASE
Classes of anti-retroviral drugs Reverse Transcriptase Inhibitors (RTI’s) Nucleoside Nucleotide Non-nucleoside Protease Inhibitors (PIs) Fusion or Entry Inhibitors Act on gp41 or CCR5 coreceptor Integrase Inhibitors Fixed dose combinations Drugs from two or more classes into a single product

55 TREATMENT OF HIV INECTION AND DISEASE
Reverse transcriptase inhibitors Nucleoside analog (NARTI, NRTI) Converted into nucleotide Incorporated into and stops viral DNA synthesis Zidovudine (Retrovir) Nucleotide analog (NtARTI, NtRTI) Tenofir (Viread) Non-nucleoside (NNRTI) Not incorporated into viral DNA Binds to enzyme and inhibits function Nevirapine (Viramune)

56 TREATMENT OF HIV INECTION AND DISEASE
Goals of HAART Suppression of HIV Decrease viral load Reduce potential for resistance to anti-viral agents Immune system reconstitution Restore CD4 T cell population Most successful with high baseline CD4 count at HAART initiation Increase of 50 to 150 cells per year

57 TREATMENT OF HIV INECTION AND DISEASE
HAART negatives High cost, medication fatigue, adherence to complicated drug regimens, adverse events, names for anti-retroviral drugs HAART Interruption Minimize negatives using structured treatment interruption (STI) 6 months of IL-2 without HAART Safety (unclear) and efficacy (inferior) HAART associated with Immune reconstitution syndrome

58 IMMUNE RECONSTITUTION SYNDROME (IRS)
Immune reconstitution inflammatory syndrome (IRIS) Strong response by recovering immune system to latent or active infections Risk factors for IRIS following HAART CD4 percent of < 15% CD4 count of < 100 cell/uL High rate of increase of CD 4 count Most commonly associated with Pneumocystis pneumonia Cytomegalovirus disease Herpes zoster Mycobacterium avium complex (MAC) disease Tuberculosis

59 IMMUNE RECONSTITUTION SYNDROME
Important to distinguish between IRIS and clinical failure Clinical failure Disease progression with development of OI or malignancy when drugs given for sufficient time IRIS Seen within first several weeks of therapy when a latent or active infection is present

60 IMMUNE RECONSTITUTION SYNDROME
Management options Inflammatory reaction treated with Steroids Non-steroidal anti-inflammatory drugs (NSAIDS) Antimicrobial agents directed at the infectious agent Antiretroviral therapy Withhold or continue (?)

61 NAMING ANTI-RETROVIRAL DRUGS
Anti-retroviral drugs have at least 3 names Abbreviation Research or chemical name Generic name Trade name Example Abbreviation (Research/Chemical) AZT Abbreviation (Generic name) ZDV Generic Zidovudine Trade Retrovir

62 MARAVORIC (MVC / SELZENTRY)
First in new class anti-retroviral drug CCR5 co-receptor antagonist (entry inhibitor) Indicated for CCR5 tropic HIV-1 showing resistance to multiple anti-retroviral drugs Black box warning Hepatotoxicity Systemic allergic reaction Pruritic rash, eosinophilia, elevated IgE FDA approval on August 8, 2007 Requires tropism testing

63 HIV CO-RECEPTOR TROPISM ASSAY
Trofile ™ (Monogram Bioscience) FDA approval on August 6, 2007 In vitro diagnostic assay Determines tropism of patient’s HIV CCR5 CXCR4 D/M (dual / mixed) Trofile ™ assay Specimen is EDTA plasma Viral load of 1,000 copies/mL TAT of 14 days Cost $$$$$

64

65

66 LABORATORY DIAGNOSIS OF HIV INFECTION
Standard algorithm consists of using two tests for the detection of antibody to HIV-1/2 Screening Enzyme immunoassay (EIA) or Enzyme-linked Immunosorbent Assay (ELISA) High sensitivity Confirmation Western blot (WB) High specificity Sensitivity is “positivity in disease” Specificity is “negativity in disease”

67 LABORATORY DIAGNOSIS OF HIV INFECTION (STANDARD ALGORITHM)
Specimens “initially reactive” by EIA / ELISA are retested in duplicate One or both repeat tests positive, specimens are considered “repeatedly reactive” for antibody Specimens “repeatedly reactive” by EIA / ELISA then tested by Western Blot (WB) assay Specimens “reactive” for both EIA / ELISA and WB are considered “positive” for HIV infection Seroconversion From infection to antibody

68

69 LABORATORY DIAGNOSIS OF HIV INFECTION
Rapid detection of HIV-1/2 antibody OraQuick ® ADVANCE ™ Rapid HIV-1/2 Antibody OraSure Technologies, Inc., PA Immunochromatographic assay (ICA) Analytical time of 25 minutes Sensitivity of 99.5% and specificity of 99.9% Specimens of Choice Whole blood Fingerstick Venipuncture (EDTA) EDTA plasma Oral fluid (Oral mucosal transudate)

70

71

72 CLINICAL USE OF ORAQUICK ® RAPID HIV-1/2 ASSAY
Rapid screening HCW with potential HIV exposure Pregnant females with unknown HIV status at time of delivery New HIV clinic patients Same day screening All other patients Reporting of Results Negative for HIV-1/2 Antibodies Preliminary Positive for HIV-1/2 Antibodies. Confirmation by Western Blot testing to follow.

73

74

75

76

77

78 LABORATORY DIAGNOSIS OF HIV INFECTION
Detection of HIV Core Antigen (p24) Serum or CSF Methods EIA or ELISA (Non-ICD) EIA or ELISA (immune complex dissociation) Positives confirmed by neutralization Clinical Use Early diagnosis before antibody response Monitor effectiveness of therapy Marker of disease progression

79 LABORATORY DIAGNOSIS OF HIV INFECTION
Detection of proviral DNA EDTA whole blood Method Polymerase chain reaction (PCR) Clinical Use Diagnosis of infection in neonates of HIV positive mothers Early diagnosis before antibody response

80 LABORATORY PROGNOSIS OF HIV INFECTION
Quantitation of HIV-1 RNA (Viral load) EDTA plasma Methods Reverse Transcriptase – PCR (RT-PCR) Branched chain DNA (bDNA) Clinical Use Determination of amount of free virus (Viral load) Predicting progression and outcome of infection Assessing efficacy of antiviral therapy

81

82 LABORATORY DIAGNOSIS OF HIV INFECTION BY ORAL FLUID TESTING
OraQuick ® ADVANCE ™ Rapid HIV-1/2 Antibody Test Pad on test device used to swab between upper and lower outer gums and cheek Pad is stored in preservative vial and sent for ICA testing Advantages Reduces occupational exposure Patient appeal

83

84 LABORATORY DIAGNOSIS OF HIV INFECTION BY URINE TESTING
Calypte HIV-1 Urine EIA (Calypte Biomedical, Berkeley, CA) FDA approval for EIA (1996) and Western Blot (1998) Sensitivity and specificity Lower compared to blood and oral fluid Question IgG in urine Calypte ® Aware ™ HIV-1/2 Urine Rapid Test Available outside US Advantages Reduces occupational exposure Patient appeal

85 THE IMMUNOLOGY OF HIV INFECTION
Interactions between HIV and human immune system are extremely complex HIV subverts immune system by Infecting CD4 T cells and inducing quantitative and qualitative dysfunction Hyperactivating B cells with resulting hypergammaglobulinemia Inducing cytokine system to own replicative advantage There are no known correlates of protective immunity

86 MECHANISMS OF CD4 T-CELL DEPLETION
Direct killing of infected T cells Increased rate of apoptosis in infected T cells Molecule associated with apoptosis (PD-1) is over-expressed in chronic viremia Syncytia formation Fusion of infected and non-infected T cells Killing of infected CD4 cells by CD8 cells

87 KILLING OF INFECTED CD4 CELLS BY CD8 CELLS – ALTERNATIVE VIEW
Mechanism that keeps HIV in check in long term non-progressors (LTNPs) Long term non-progressors (LTNPs) Carry the virus but do not get AIDS Have 20 times more CD8 T cells than progressors Function of CD8 T cell surplus Up-regulate production (2X rate of progressors) of 2 killer proteins Perforin Granzyme B

88

89 IMMUNE DYSFUNCTION DURING HIV INFECTION - SUMMARY
HIV infection is multifactorial process capable of disarming immune system by direct and indirect mechanisms Certain chemokine receptors function as necessary coreceptors for entry of HIV into cells Central Paradox Progression of HIV disease in setting of vigorous immune response Lack of correlates of protective immunity are major obstacle to immunotherapy and vaccine development

90


Download ppt "HIV INFECTION AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)"

Similar presentations


Ads by Google