Human Immunodeficiency Virus ( HIV)

1. Human Immunodeficiency Virus( HIV) DR VIDYA PAI

2. HIV • Human Immunodeficiency Virus • H = Infects only Human beings • I= Immunodeficiency virus weakens the immune system and increases the risk of infection • V = Virus that attacks the body DR. S.K CHATURVEDI

3. AIDS • Acquired Immune Deficiency Syndrome • A= Acquired, not inherited • I= Weakens the Immune system • D = Creates a Deficiency of CD4+ cells in the immune system • S= Syndrome, or a group of illnesses taking place at the same time DR. S.K CHATURVEDI

4. HIV is a lentivirus • genus of the retroviridaefamily • produce multi-organ diseases • characterized by long incubation periods and persistent infection • infect a wide range of prime hosts, as well as some non-primate mammals • Former names of the virus include: • Human T cell lymphotrophic virus (HTLV-III) • Lymphadenopathy associated virus (LAV) • AIDS associated retrovirus (ARV) Courgnaud et al. J. Virol. 75:857, 2001

5. Two Types of HIV

6. HIV-1 More virulent Responsible for worldwide epidemic Severity of infection varies from person to person HIV-2 Primarily found in western Africa Not transmitted as efficiently Genome more closely related to SIVmm than HIV-1 HIV-1 vs. HIV-2

7. HIV-1 likely descended from SIVcpz HIV-2 likely descended from SIVsm Origins of HIV Pan troglodytes troglodytes Sooty Mangabey

8. Origins of HIV • Researchers claim that these chimps are the source of HIV-1 • Chimps are only rarely infected with SIVcpz • Actual Reservoir maybe a third unidentified primate species • Definite source remains elusive

9. HIV A Brief History of the modern epidemic

10. In The Beginning... • 1675 - Speculation that HIV was first transmitted from chimpanzees to humans • 1926-1946 - Scientists believe HIV first spread from monkeys to humans • 1959 - First proven AIDS death • 1978 - Gay men in US and Sweden begin showing signs of what is now known as AIDS ?

11. 1981 - CDC notices increase in cases of Kaposi’s sarcoma and Pneumocystis carinii pneumonia The First Indications

12. Defining The Problem • 1982 - The term AIDS (acquired immune deficiency syndrome) is used for the 1st time • 1983 – Luc Monteneier, Institut Pasteur isolates HIV-1, CDC issues warning to blood banks about potential problem • 1984 - Dr. Robert Gallo claims discovery of HIV

13. The Start of the War • 1985 - FDA approves first HIV antibody diagnostic test - First International Conference on AIDS • 1986 - HIV-2 isolated • 1987 - AZT approved by FDA (1st anti- HIV drug)

14. Reality Sets In • 1987 - President Reagan says “AIDS” in public - AIDS memorial quilt started

15. The War Against HIV/AIDS • 1988 - FDA begins granting pre- approval distribution status to HIV/AIDS related drugs • 1989 - First licensed HIV-1 diagnostic kit to directly detect virus (rather than antibodies)

16. Fighting a Losing Battle? • 1991 - 10 million people worldwide are HIV-positive - Magic Johnson publicly announces he is HIV positive

17. Increasing The Arsenal • 1992 - FDA starts “accelerated approval” process for HIV/AIDS related drugs • 1995 - Saquinavir (Invirase) is first protease inhibitor approved in US - US admits that Institut Pasteur, not Dr. Gallo, discovered HIV • 1996 - Nevirapine (Viramune) first non- nucleoside reverse transcriptase inhibitor approved in US

18. Transmission • Unprotected sex • Vagina, Penis, Anal, Oral • Shared needles • Drugs, Steroids, Tattoo, Piercing • Mother to child • Birth, Breast Feeding • Blood transfusions

19. Transmission

20. HIV vs. AIDS • HIV causes AIDS by attacking the immune system’s CD4 T cells. • Normal CD4 count is between 500 – 1500 CD4 T cells per ul of blood, while AIDS CD4 count is less than 200 CD4 T cells per ul of blood. • AIDS viral load is about 55,000 HIV RNA copies per ml of blood. • On average, it takes approximately 10 years to develop AIDS from initial infection. • As a person’s CD4 count decreases, he/she is more prone to opportunistic infections.

21. Characteristics of the virus • Icosahedral (20 sided), enveloped virus of the lentivirus subfamily of retroviruses. • Retroviruses transcribe RNA to DNA. • Two viral strands of RNA found in core surrounded by protein outer coat. • Outer envelope contains a lipid matrix within which specific viral glycoproteins are imbedded. • These knob-like structures responsible for binding to target cell.

22. Characteristics of the virus • An RNA retrovirus – subfamilyLentivirus • Contains: • 2 copies of RNA • Enzymes: • Reverse Transcriptase • Integrase • Protease • Two major envelope proteins: • gp120 • gp41

23. Structural Genes • Three main structural genes: • Group Specific Antigen (Gag) • Envelope (Env) • Polymerase (Pol)

24. Group Specific Antigen (Gag) • Located in nucelocapsid of virus. • Icosahedrylcapsid surrounds the internal nucleic acids made up of p24 andp15. • p17lies between protein core and envelope and is embedded in the internal portion of the envelope. • Two additional p55 products, p7 and p9, are nucleic acid binding proteins closely associated with the RNA.

25. Envelope (Env) • Envelope (Env) gene codes for envelope proteins gp160, gp120 and gp41. • These polyproteins will eventually be cleaved by proteases to become HIV envelope glycoproteins gp120 and gp41. • gp160 cleaved to form gp120 and gp41. • gp120 forms the 72 knobs which protrude from outer envelope. • gp41 is a transmembrane glycoprotein antigen that spans the inner and outer membranes and attaches to gp120. • gp120 and gp41 both involved with fusion and attachment of HIV to CD4 antigen on host cells.

26. Polymerase (Pol) • Polymerase (Pol) codes for p66 and p51 subunits of reverse 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 of protein precursors.

27. Viral Replication • First step, HIV attaches to susceptible host cell. • Site of attachment is the CD4 antigen found on a variety of cells • helper T cells • macrophages • monocytes • B cells • microglial brain cells • intestinal cells • T cells infected later on.

28. Early Phase HIV Infection • In early phase HIV infection, initial viruses are M-tropic. Their envelope glycoprotein gp120 is able to bind to CD4 molecules and chemokine receptors called CCR5 found on macrophages

29. http://www.cat.cc.md.us/courses/bio141/lecguide/unit2/viruses/hivad.htmlhttp://www.cat.cc.md.us/courses/bio141/lecguide/unit2/viruses/hivad.html • In late phase HIV infection, most of the viruses are T-tropic, having gp120 capable of binding to CD4 and CXCR4 found on T4-lymphocytes.

30. Life Cycle

31. Viral Replication • The gp120 protein on virus binds specifically to CD4 receptor 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.

32. Viral Replication • Reverse transcriptase produces viral DNA from RNA. • Becomes a provirus which integrates into host DNA. • Period of latency occurs. • http://www.cat.cc.md.us/courses/bio141/lecguide/unit2/viruses/hivdsdna.html

33. Viral Replication • After a period of latency lasting up to 10 years viral replication is triggered and occurs at high rate. • CD4 cell may be destroyed in the process, body attempts to replace lost CD4 cells, but over the course of many years body is unable to keep the count at a safe level. • Destruction of large numbers of CD4 cause symptoms of HIV to appear with increased susceptibility to opportunistic infections, disease and malignancy.

34. HIV (arrows) Infecting a T-lymphocyte • CD4+ T Cells then chronically die from: • Chronic activation of T cells • Inhibition of thymic output of T cells • Suppression of the bone marrow • Destruction of lymph-node architecture • Low-level ongoing infection of memory CD4+ T cells

35. Primary HIV Syndrome • Mononucleosis-like, cold or flu-like symptoms may occur 6 to 12 weeks after infection. • lymphadenopathy • fever • rash • headache • Fatigue • diarrhea • sore throat • neurologic manifestations. • no symptoms may be present

36. Primary HIV Syndrome • Symptoms are relatively nonspecific. • HIV antibody test often negative but becomes positive within 3 to 6 months, this process is known as seroconversion. • Large amount of HIV in the peripheral blood. • Primary HIV can be diagnosed using viral load titer assay or other tests. • Primary HIV syndrome resolves itself and HIV infected person remains asymptomatic for a prolonged period of time, often years.

37. Clinical Latency Period • HIV continues to reproduce, CD4 count gradually declines from its normal value of 500-1200. • Once CD4 count drops below 500, HIV infected person at risk for opportunistic infections. • The following diseases are predictive of the progression to AIDS: • persistent herpes-zoster infection (shingles) • oral candidiasis (thrush) • oral hairy leukoplakia • Kaposi’s sarcoma (KS)

38. Oral Candidiasis (thrush)

39. Oral Hairy Leukoplakia • Being that HIV reduces immunologic activity, the intraoral environment is a prime target for chronic secondary infections and inflammatory processes, including OHL, which is due to the Epstein-Barr virus under immunosuppressed conditions

40. Kaposi’s sarcoma (KS) • Kaposi’s sarcoma (shown) is a rare cancer of the blood vessels that is associated with HIV. It manifests as bluish-red oval-shaped patches that may eventually become thickened. Lesions may appear singly or in clusters.

41. Kaposi’s Sarcoma

42. Bacillary Angiomatosis • Caused by Bartonella species

43. Herpes Zoster • “Shingles” • Caused by Varicella

44. AIDS • CD4 count drops below 200 person is considered to have advanced HIV disease • If preventative medications not started the HIV infected person is now at risk for: • Pneumocystis carinii pneumonia (PCP) • cryptococcal meningitis • toxoplasmosis • If CD4 count drops below 50: • Mycobacterium avium • Cytomegalovirus infections • lymphoma • dementia • Most deaths occur with CD4 counts below 50.

45. Other Opportunistic Infections • Respiratory system • PneumocystisCarinii Pneumonia (PCP) • Tuberculosis (TB) • Kaposi's Sarcoma (KS) • Gastro-intestinal system • Cryptosporidiosis • Candida • Cytomegolavirus (CMV) • Isosporiasis • Kaposi's Sarcoma • Central/peripheral Nervous system • Cytomegolavirus • Toxoplasmosis • Cryptococcosis • Non Hodgkin's lymphoma • Varicella Zoster • Herpes simplex • Skin • Herpes simple • Kaposi's sarcoma • Varicella Zoster

46. Infants with HIV • Failure to thrive • Persistent oral candidiasis • Hepatosplenomegaly • Lymphadenopathy • Recurrent diarrhea • Recurrent bacterial infections • Abnormal neurologic findings.

47. Immunologic Manifestations • Early stage slight depression of CD4 count, few symptoms, temporary. • Window of up to 6 weeks before antibody is detected, by 6 months 95% positive. • During window p24 antigen present, acute viremia and antigenemia.

48. Immunologic Manifestations • Antibodies produced to all major antigens. • First antibodies detected produced against gag proteins p24 and p55. • Followed by antibody to p51, p120 and gp41 • As disease progresses antibody levels decrease.

49. Immunologic Manifestations • Immune abnormalities associated with increased viral replication. • Decrease in CD4 cells due to virus budding from cells, fusion of uninfected cells with virally infected cells and apoptosis. • B cells have decreased response to antigens possibly due to blockage of T cell/B cell interaction by binding of viral proteins to CD4 site. • CD8 cells initially increase and may remain elevated. • As HIV infection progresses, CD4 T cells drop resulting in immunosuppression and susceptibility of patient to opportunistic infections. • Death comes due to immuno-incompetence.

50. Immunologic Manifestations • Immune abnormalities associated with increased viral replication. • Decrease in CD4 cells due to virus budding from cells, fusion of uninfected cells with virally infected cells and apoptosis. • B cells have decreased response to antigens possibly due to blockage of T cell/B cell interaction by binding of viral proteins to CD4 site. • CD8 cells initially increase and may remain elevated. • As HIV infection progresses, CD4 T cells drop resulting in immunosuppression and susceptibility of patient to opportunistic infections. • Death comes due to immuno-incompetence.