Human Immunodeficiency Virus a Student Update

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Human Immunodeficiency Virus a Student Update

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Human Immunodeficiency Virus a Student Update

  1. 1. Human Immunodeficiency Virus Infection Student update Dr.T.V.Rao MD Dr.T.V.Rao MD 1
  2. 2. Beginning of HIV/AIDS • The first published article related to AIDS was in 1981. The principal author’s name was Michael Gottlieb and it appeared in the Morbidity and Mortality Weekly Report for June 5th. This article reported that there was a random increase in pneumocystis carinii pneumonia (PCP), a rare lung infection. Dr.T.V.Rao MD 2
  3. 3. Discovery of HIV infection. • In 1982, the term Acquired Immune Deficiency Syndrome is used for the first time. The name was designated by the CDC. • In 1983, French scientists at the Institute Pasteur found a new virus that they called lymphadenopathy-associated virus or LAV. About a year later, Dr. Robert Gallo, of the National Cancer institute discovered HLTV-III. The first discovery was made in France at the Institute Pasteur, but shared credit is given to Dr. Robert Gallo, the discoverer of AIDS and his French counterparts for discovering HIV on April 23, 1984. Dr.T.V.Rao MD 3
  4. 4. History of HIV • The HIV virus first came to light during the early 1980’s. • A number of healthy gay men in New York began to develop rare opportunistic infections & cancers, that were resistant to treatment. • One such viral opportunistic infection is cytomegalovirus that causes blindness & inflammation of the colonDr.T.V.Rao MD 4
  5. 5. Dr. Luc Montagnier wins the Nobel Prize in Medicine in 2008 Dr.T.V.Rao MD 5
  6. 6. What is Human Immune Deficiency Virus • Genus Retroviridae • Lentivirus, which literally means slow virus - it takes such a long time to develop adverse effects in the body. • This virus attacks the immune system • There are two strains – HIV 1 & HIV 2 Dr.T.V.Rao MD 6
  7. 7. What is Human Immune Deficiency Virus • These contain RNA, the genetic material of HIV • The outer layer of the HIV virus cell is covered in coat proteins, which can bind to certain WBCs. This allows the virus to enter the cell, where it alters the DNA. • The virus infects and destroys the CD4 lymphocytes which are critical to the body’s immune response.Dr.T.V.Rao MD 7
  8. 8. HIV Origins • Research teams in the U.S.A & France made independent research discoveries of the virus. • French researchers discovered a virus linked to AIDS in 1983, they called it Lymphadenopathy- Associated Virus (LAV) • In 1984, American researchers isolated a virus that caused AIDS, calling it Human T-lymph tropic Virus type III (HTLV- III ) • These two viruses were later found to be the same virus - HIV Dr.T.V.Rao MD 8
  9. 9. Origin of AIDS; controversial, similar to SIV
  10. 10. Dr.T.V.Rao MD 10
  11. 11. Family : Retroviridae Subfamily : Lentivirus • RNA virus, 120nm in diameter • Envelope gp160; gp120 & gp41 • Icosahedral symmetry • Nucelocapsid – Outer matrix protein (p17) – Major capsid protein (p24) – Nuclear protein (p7) • Diploid RNA with several copies of reverse transcriptase Dr.T.V.Rao MD 11
  12. 12. Retroviral Genes • gag (group-specific antigen): makes the cone shape viral capsid. • pol (polymerase): codes for viral enzymes reverse transcriptase, integrase, and viral protease. • env (envelope): makes surface protein gp120 and trans membrane gp41, enabling HIV to fuse to CD4 cells. Dr.T.V.Rao MD 12
  13. 13. Genes Coding Structural Proteins gag • 1 The gag gene – core and shell expressed as p55 – ( p18,- p17) cleaved as p15, p18,and p24 make up as viral core and shell • p24 seen during early stages reappearance in the late stages exacerbation of disease Dr.T.V.Rao MD 13
  14. 14. Envelop glycoprotein's env • The env determines the synthesizes of envelop glycoprotein's gp160 cleaved into two envelop components gp120 which forms the surface spike and gp 41 which trans membrane protein. The gp120 antibodies are present till the death of the patient. Dr.T.V.Rao MD 14
  15. 15. Polymerase reverse transcriptase pol • The pol gene codes for the polymerase reverse transcriptase and other viral enzymes • Expressed as precursor protein which is cleaved into proteins p31, p51,and p66 Dr.T.V.Rao MD 15
  16. 16.  Genome and Proteins of HIV Dr.T.V.Rao MD 16
  17. 17. Other genes • Tat The Tran activator gene influences the function of genes some distance away. It controls transactivation of all HIV proteins. rev • The differential regulator of expression of virus protein genes. vif • The virus infectivity factor gene is required for infectivity as cell-free virus. nef • The negative regulator factor retards HIV replication. vpr • The virus protein R gene has an undetermined function.. Dr.T.V.Rao MD 17
  18. 18. Genes differ HIV I for HIV II • vpu • The virus protein U gene is required for efficient viral replication and release. It is found only in HIV-1. vpx • The virus protein X gene has an undetermined function. It is found only in HIV-2 and SIV. Dr.T.V.Rao MD 18
  19. 19. Types of HIV Dr.T.V.Rao MD 19
  20. 20. Dr.T.V.Rao MD 20
  21. 21. Subtype C is Major type in India • Subtype C is predominant in Southern and East Africa, India and Nepal. It has caused the world's worst HIV epidemics and is responsible for around half of all infections. Dr.T.V.Rao MD 21
  22. 22. Resistance • The virus are inactivated in 10 minutes at 600c and in seconds at 1000c • At room temperature survive for seven days • HIV are inactivated in 10 minutes by treatment with 50% ethanol • 35% Isopropanol. • 0.5% Lysol and paraformaldehyde • 0.3% hydrogen • 10% house hold bleach • Hypochlorite solution at 0.5% • 2% Glutaraldehyde Dr.T.V.Rao MD 22
  23. 23. HIV Replication – Attachment – Penetration – Uncoating – Reverse Transcription – Integration – Replication – Assembly – Release Dr.T.V.Rao MD 23
  24. 24. Life Cycle of HIV 1. Attachment: Virus binds to surface molecule (CD4) of T helper cells and macrophages. • Coreceptors: Required for HIV infection. • CXCR4 and CCR5 mutants are resistant to infection. 2. Fusion: Viral envelope fuses with cell membrane, releasing contents into the cell. Dr.T.V.Rao MD 24
  25. 25. HIV Life Cycle: Attachment Requires CD4 Receptor plus a Coreceptor Dr.T.V.Rao MD 25
  26. 26. • The HIV receptor • Gp160 is composed of gp41 and gp120 and forms the receptor for binding to the host cell (CD4 positive cells). • The gp41 portion is half embedded in the membrane envelope and interacts with gp120 portion on the exterior side of the membrane. • Each receptor is composed of 3 subunits of gp41 and 3 subunits of gp120. Dr.T.V.Rao MD 26
  27. 27. The HIV Receptor Dr.T.V.Rao MD 27
  28. 28. Lifecycle of HIV  HIV particles enter the body in a fluid as it can not survive without a support medium.  The virus targets any cell expressing CD4, including T helper cells, macrophages, dendritic cells and monocytes. Dr.T.V.Rao MD 28
  29. 29. Life Cycle of HIV 3. Reverse Transcription: Viral RNA is converted into DNA by unique enzyme reverse transcriptase. Reverse transcriptase RNA ---------------------> DNA Reverse transcriptase is the target of several HIV drugs: AZT, ddI, and ddC. Dr.T.V.Rao MD 29
  30. 30. Dr.T.V.Rao MD 30
  31. 31. Infection spread throughout the Body • Within the inflammatory cells of the infection (T cells) • Site of replication shifts to lymphoid tissues: • Lymph nodes • Spleen • Liver • Bone marrow • Macrophages and Langerhans cells become reservoirs and sites of • replication but do not die themselves. Dr.T.V.Rao MD 31
  32. 32. Effects of HIV on the immune system 3 areas: 1. Destruction of CD4+ T cells population 2. Immune effects due to HIV infection 3. Progression of HIV infection to AIDS Dr.T.V.Rao MD 32
  33. 33. 2.Host’s immune responses • Both humoral and cell-mediated immune responses partially control the viral production but in this process they destroy the infected CD4+T cells, leading to a gradual decline of CD4+ T cells • HIV-specific CTLs kill infected CD4+ T cells • Antibodies that recognize a variety of HIV antigens are produced - Antibody dependent cell-mediated cytotoxicity • Apoptosis of infected cells Dr.T.V.Rao MD 33
  34. 34. Blood and Body fluids contain High concentration of Viral particles • Blood • Semen/Vaginal fluids (as high as blood) • Breast milk • Pus from sores Dr.T.V.Rao MD 34
  35. 35. Low concentrations of HIV It is highly unlikely you will be infected if you come into contact with: • Sweat • Tears • Urine • Saliva (-highly possible if blood from mouth sores is present)Dr.T.V.Rao MD 35
  36. 36. High Risk Populations: 1. Males, homosexuals & bisexuals 2. IV drug users 3. Improperly screened transfusion recipients 4. Sexual partners of persons infected with HIV 5. Infants of HIV –infected mothers Dr.T.V.Rao MD 36
  37. 37. How is HIV Spread? • ANY type of sexual activity (highest risk) • Sharing used drug needles • Pregnancy-from mother to child • Sharing razors- if blood is present • Kissing- if even the smallest amount of blood is present. (-membranes of mouth are thin enough for HIV to enter straight into the body.) • Tattoos/body piercing if equipment is not clean. Dr.T.V.Rao MD 37
  38. 38. HIV in Body Fluids Semen 11,000 Vaginal Fluid 7,000 Blood 18,000 Amniotic Fluid 4,000 Saliva 1 Average number of HIV particles in 1 ml of these body fluidsDr.T.V.Rao MD 38
  39. 39. Transmission • Vaginal Intercourse • Anal Intercourse (10x higher infection rate than vaginal intercourse because of tissue tear is higher • Oral Intercourse • Blood Transfusion (risk greater than 90% if sample is already infected) • Needles (tattoos, injections) • Infected mother to the infant through: • Pregnancy (placenta), Birth, and breastfeeding Dr.T.V.Rao MD 39
  40. 40. Window Period • This is the period of time after becoming infected when an HIV test is negative • 90 percent of cases test positive within three months of exposure • 10 percent of cases test positive within three to six months of exposure Dr.T.V.Rao MD 40
  41. 41. Pathogenesis of HIV / AIDS Infected T-Cell HIV Virus T-Cell HIV Infected T-Cell New HIV Virus Dr.T.V.Rao MD 41
  42. 42. • Immune responses fail to eradicate all viruses. • Viral load is maintained at low level • Continuous decline of CD4+ T cells Dr.T.V.Rao MD 42
  43. 43. Immune defects due to HIV infection B cells – impaired humoral response • B-cell hyper reactivity • Polyclonal hypergammaglobulinemia due to enhanced nonspecific IgG and IgA production. • Impaired Ab-isotype switching and inability to respond to specific antigen. • High incidence of B-cell lymphomas Lymph nodes • HIV kills cells in the lymph nodes • Early HIV infection: destruction of dendritic cells • Late stage: extensive damage, tissue necrosis, a loss of follicular dendritic cells and germinal centres. • An inability to trap Ag or support activation of T+B cellsDr.T.V.Rao MD 43
  44. 44. CDC Classification of HIV • Category 1: > 500 cells/mm3 (or CD4% > 28%) • Category 2: 200-499 cells/mm3 (or CD4% 14% - • 28%) • Category 3: < 200 cells/mm3 (or CD4% < 14%)(CD4+ T-lymphocyte counts per microliter of blood) Dr.T.V.Rao MD 44
  45. 45. normal Severely impaired Abnormal Slightly reduced Time Acute HIV disease Exposure to HIV Clinical latency period -declining CD4+ T cell amount AIDS Immunecompetence Opportunistic infections Progression of HIV infection Progression of HIV infection • After initial infection with HIV, there is usually an acute flu-like illness. • This illness may include • Fever • Headache • Tiredness • Enlarged lymph nodes • But after this most individuals are clinically asymptomatic for years. This is called the clinical latency period. Dr.T.V.Rao MD 45
  46. 46. WHO clinical case definition for AIDS in South-East Asia • WHO clinical case definition for AIDS in South-East Asia Clinical AIDS in an adult is defined as an individual who has been identified as meeting the two criteria A and B below: A. Positive test for HIV infection by two tests based on preferably two different antigens. B. Any one of the following criteria: • - Weight loss of 10% body weight or cachexia, not known to be due to a condition unrelated to HIV infection - Chronic diarrhoea of one month's duration, intermittent or constant Dr.T.V.Rao MD 46
  47. 47. WHO clinical case definition for AIDS in South-East Asia • Disseminated, miliary or extra pulmonary tuberculosis • Candidiasis of the oesophagus; diagnosable as dysphasia, odynophagia and oral Candidiasis • Neurological impairment restricting daily activities, not known to be due to a condition unrelated to HIV (e.g. trauma) • Kaposi's sarcoma. Dr.T.V.Rao MD 47
  48. 48. Stage 1 - Primary • Short, flu-like illness - occurs one to six weeks after infection • no symptoms at all • Infected person can infect other people Dr.T.V.Rao MD 48
  49. 49. Stage 2 - Asymptomatic • Lasts for an average of ten years • This stage is free from symptoms • There may be swollen glands • The level of HIV in the blood drops to very low levels • HIV antibodies are detectable in the blood Dr.T.V.Rao MD 49
  50. 50. Stage 3 - Symptomatic • The symptoms are mild • The immune system deteriorates • Emergence of opportunistic infections and cancers Dr.T.V.Rao MD 50
  51. 51. Stage 4 - HIV  AIDS • The immune system weakens • The illnesses become more severe leading to an AIDS diagnosis Dr.T.V.Rao MD 51
  52. 52. Progression to AIDS • During the latency period, lymph nodes and the spleen are sites of continuous HIV replication and cell destruction. • The immune system remains competent at handling most infections with opportunistic microbes but the number of CD4+ T cells steadily declines. Symptoms often experienced months to years before the onset of AIDS. • Lack of energy • Weight loss • Frequent fevers and sweats • Persistent or frequent yeast infections • Persistent skin rashes • Dysfunction of CNS Dr.T.V.Rao MD 52
  53. 53. • Final stage of HIV infection - AIDS • Occurs when the destruction of peripheral lymphoid tissue is complete and the blood CD4+ T cell count drops below 200 cells/mm3. (Healthy adults usually have CD4+ T-cell counts of 1,000 or more). • AIDS – acquired immunodeficiency syndrome – is marked by development of various opportunistic infections and malignancies. • The level of virus in the blood and CD4+ T cell count can predict the risk of developing AIDS. Voral titers often accelerate as the patient progresses towards AIDS. • Without treatment, at least 50% of people infected with HIV will develop AIDS within ten years. Progression to AIDS Dr.T.V.Rao MD 53
  54. 54. Opportunistic Infections
  55. 55. Mother-to-Baby • Before Birth • During Birth • Postpartum –After the birth Dr.T.V.Rao MD 55
  56. 56. How is HIV not spread? • Shaking hands • Hugging • Swimming pools • Toilet seats • Insect bites • Donating blood Dr.T.V.Rao MD 56
  57. 57. THE NATIONAL HIV TESTING POLICY • No individual should be made to undergo a mandatory testing for HIV • No mandatory HIV testing should be imposed as a precondition for - Employment - Providing health care services and facilities • Any HIV testing must be accompanied by a pretest and posttest counseling services (through VCTC) • Testing without consent – hindrance to the control of the epidemic Dr.T.V.Rao MD 57
  58. 58. Counseling Dr.T.V.Rao MD 58
  59. 59. Pre-test Counseling explain to individuals • Transmission • Prevention • Risk Factors • Voluntary & Confidential • Report ability of Positive TestDr.T.V.Rao MD 59
  60. 60. Post-test Counseling • Clarifies test results • Need for additional testing • Promotion of safe behavior • Release of results Dr.T.V.Rao MD 60
  61. 61. Three types of tests (i) Screening tests - ELISA and simple/rapid tests. (ii) Confirmatory or supplemental tests- Western Blot assay. (iii) Nucleic acid and antigen screening tests. Polymerase chain reaction (PCR), Ligase chain reaction (LCR), Nucleic acid based Sequence assays (NASBA) and some ELISA tests. Dr.T.V.Rao MD 61
  62. 62. Diagnosis of HIV • Initial test for HIV is an indirect ELISA test • Economic, rapid, performed easily, high sensitivity and specificity • Detects anti-HIV antibodies in patient serum • Antibodies are generally detectable within 3 months of infection • Antibodies are typically directed at the envelope glycoproteins (gp120 and gp41) Dr.T.V.Rao MD 62
  63. 63. Absence of Antibodies to do not confirm absence of HIV infection • Absence of antibody, as in ‘window period’ does not exclude the presence of the virus which can be detected by PCR amplification approx. ten days after infection • ‘Window period’ – time between infection and detection of serological viral marker • Direct ELISA for p24 antigen can also be used although the false negative rate is higher Dr.T.V.Rao MD 63
  64. 64. EIA/ELISA Test PositiveNegative Run IFA Confirmation Repeat Positive Positive End Testing Repeat ELISA Every 3 months for 1 year Negative PositiveNegativeIndeterminate Repeat at 2-4 months Repeat at 3 weeks HIV Testing No HIV Exposure Low Risk HIV Exposure High Risk Negative HIV + Repeat every 6 months for continued High risk behavior Dr.T.V.Rao MD 64
  65. 65. Diagnosis of HIV • Positive or indeterminate ELISA tests for anti-HIV antibodies are confirmed by immunoblotting (Western Blotting) which identifies specific HIV virus proteins • PCR can also be used • Detects pro-viral DNA or viral RNA • It is highly sensitive and specific but is more costly than ELISA • Can be used to test infants born to HIV-infected mothersDr.T.V.Rao MD 65
  66. 66. Indirect ELISA test Dr.T.V.Rao MD 66
  67. 67. Western blot Test • Confirms HIV infection • Proteins are separated by electrophoresis and transferred to a nitrocellulose membrane by the passage of an electric current • The proteins are treated with antibodies • Similar to ELISA technique, addition of secondary antibodies with an enzyme attached allows the use of colour to detect a particular protein Dr.T.V.Rao MD 67
  68. 68. Western Blotting • A discrete protein band represents the specific antigen that the antibody recognizes • The bands from a positive Western blot are from antibodies binding to specific proteins and glycoprotein's from the HIV virus • The CDC recommends that the blot should be positive for two of the p24, gp41 and gp120/160 markers (gp160 is the precursor form of gp41 and gp120, the envelope protein) Dr.T.V.Rao MD 68
  69. 69. HIV Western blot Dr.T.V.Rao MD 69
  70. 70. Rapid Tests • ADVANTAGES: • quicker to perform – do not require batching – do not require specialised equipment or trained personnel – results delivered on the same day • Only ‘WHO recommended’ Rapid HIV antibody tests should be used to ensure quality. Dr.T.V.Rao MD 70
  71. 71. The ‘Window period’ Aware of it Follows acute infection with HIV, before HIV antibodies can be detected in the patient’s blood stream. • Patient is highly infectious, despite testing HIV antibody negative, HIV is replicating rapidly in all body compartments. • Typically up to 12 weeks duration but may be shorter in more sensitive HIV antibody assays. Dr.T.V.Rao MD 71
  72. 72. Paediatric HIV Testing Infants born to HIV infected mothers will have antibodies to HIV in their serum as a result of: – maternal-fetal transfer during pregnancy – delivery – breast-feeding they may not necessarily be infected ! Dr.T.V.Rao MD 72
  73. 73. Treatment of HIV • Eradication of HIV infection not possible with currently available drugs • Viral replication can not be completely suppressed • Latently infected CD4+ T cells established at early stage • Goals of antiretroviral therapy are to: - Suppress viral replication - Restore and/or preserve immune function - Improve quality of life - Reduce HIV-associated morbidity and mortality • Combinations of antiretroviral drugs are used • Referred to as HAART (highly active antiretroviral therapy) • Suppress levels of plasma viraemia for long periods • Plasma viraemia is a strong prognostic factor in HIV infection Dr.T.V.Rao MD 73
  74. 74. Antiretroviral Drugs • Significant declines in AIDS related morbidity and mortality are seen as a result of HAART • Several strategies for development of effective antiviral drugs • Potential therapies based on knowledge of the way in which HIV gains access into the cells and its method of replication • Targets for therapeutic anti-retroviral drugs: - Inhibiting reverse transcription - Inhibiting proteases - Inhibiting integrate – interferes with integration of viral DNA into host genome - Inhibiting fusion – prevents virus from fusing with host cell Dr.T.V.Rao MD 74
  75. 75. Therapeutic Options • Combination of RT inhibitors protease inhibitors results in potent anti-viral activity • In most cases, two nucleoside analogues and one protease inhibitor are taken together • HAART lowers plasma viral loads in many cases to levels not detectable by current methods • Has improved the health of AIDS patients to the point that they can function at a normal level Dr.T.V.Rao MD 75
  76. 76. AIDS (Pregnancy & AIDS) • Zidovudine(AZT) – recommended for px of maternal fetal HIV transmission & administered after 14 months AOG (PO meds); IVIT during labor;/ neonate post birth for 6 wks. Restrict breastfeeding –infant/neonate is seen by physician at birth, 1 wk. or 2 wks., a mos., 2 mos., & 4 mos. of life * Neonate- asymptomatic for 1st several yrs. Of life & monitored for early sign of immunodeficiency Dr.T.V.Rao MD 76
  77. 77. Antiretroviral Drugs • Nucleoside Reverse Transcriptase inhibitors – AZT (Zidovudine) • Non-Nucleoside Transcriptase inhibitors – Viramune (Nevirapine) • Protease inhibitors – Norvir (Ritonavir) Dr.T.V.Rao MD 77
  78. 78. Prevention and control of HIV • Education • Prevention of blood born HIV transmission • Anti Retro Viral treatment • Combination therapy • Post exposure prophylaxis • Specific prophylaxis • Primary health care Dr.T.V.Rao MD 78
  79. 79. HIV Occupational Exposure • Review facility policy and report the incident • Medical follow-up is necessary to determine the exposure risk and course of treatment • Baseline and follow-up HIV testing • Four week course of medication initiated one to two hours after exposure • AZT (200mg)-TID +lamivudine(3TC)(150mg)BID x 4days • Nelfinavir (750 mg) TID ,AZT/3TC • Exposure precautions practicedDr.T.V.Rao MD 79
  80. 80. HIV Non-Occupational Exposure • No data exists on the efficacy of antiretroviral medication after non-occupational exposures • The health care provider and patient may decide to use antiretroviral therapy after weighing the risks and benefits • Antiretroviral should not be used for those with low-risk transmissions or exposures occurring more than 72 hours after exposure PREVENTION --- FIRST Dr.T.V.Rao MD 80
  81. 81. Play safe • Use the common sense Be faithful to one partner, Use Condom. • Antiretroviral drugs Dr.T.V.Rao MD 81
  82. 82. Abstinence • It is the only 100 % effective method of not acquiring HIV/AIDS. • Refraining from sexual contact: oral, anal, or vaginal. • Refraining from intravenous drug Dr.T.V.Rao MD 82
  83. 83. Monogamous relationship • A mutually monogamous (only one sex partner) relationship with a person who is not infected with HIV • HIV testing before intercourse is necessary to prove your partner is not infected Dr.T.V.Rao MD 83
  84. 84. Sex Education – Best option to Prevent AIDS Move from Past to Future Dr.T.V.Rao MD 84
  85. 85. World AIDS Day, • World AIDS Day, observed December 1 each year, is dedicated to raising awareness of the AIDS pandemic caused by the spread of HIV infection. It is common to hold memorials to honour persons who have died from HIV/AIDS on this day. Government and health officials also observe the event, often with speeches or forums on the AIDS topics. Dr.T.V.Rao MD 85
  86. 86. Do not Discriminate AIDS Patients Dr.T.V.Rao MD 87
  87. 87. • Programme Created by Dr.T.V.Rao MD for Medical and Paramedical Students in the Developing World • Email • doctortvrao@gmail.com Dr.T.V.Rao MD 88

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