HIV

1. HIV OCT 2010

2. • HIV disease o An infectious disease caused by HIV, a human retrovirus o HIV disease should be viewed as a spectrum ranging from primary infection, with or without the acute syndrome, to an asymptomatic stage, to advanced disease characterized by profound immunodeficiency and susceptibility to opportunistic infections. • AIDS

4. Etiology Human retroviruses HIV-1 and HIV-2 • Family of human retroviruses (Retroviridae) • Subfamily of lentiviruses • RNA viruses whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase • HIV-1 is the most common cause of AIDS worldwide. • HIV-2 has been identified predominantly in western Africa. o Small numbers of cases have also been reported in Europe, South America, Canada, and the U.S. o Has ~40% sequence homology with HIV-1 o More closely related to simian immunodeficiency viruses

5. o Worldwide Heterosexual transmission is the most common mode of infection. o Male-to-female transmission is 8 times more efficient than female to male. o Receptive anal intercourse is a much more efficient mode of transmission than oral o The presence of other sexually transmitted diseases significantly increases the risk of transmission, especially those with genital ulceration. o Lack of circumcision carries an increased risk of HIV infection. o The association of alcohol consumption and illicit drug use with unsafe sexual behavior leads to an increased risk of sexual transmission of HIV. • Transmission by blood and blood products

6. o Although the virus can be identified from virtually any body fluid, there is no evidence that HIV can be transmitted as a result of exposure to saliva, tears, sweat, or urine. o Transmission of HIV by a human bite can occur but is rare.

7. Transmission by HIV- HIV-tainted blood transfusions, blood products, or transplanted o Intravenous drug users Exposed to HIV while sharing injection paraphernalia, such as needles, syringes, the water in which the drugs are mixed, or the cotton through which drugs are filtered

9. Risk Factors • Sexual transmission o Homosexual and heterosexual contact with an infected person 44% of new HIV/AIDS diagnoses in 2001–2004 were attributed to male-tomale sexual contact. 34% of new HIV/AIDS diagnoses in 2001–2004 were attributed to heterosexual contact.

10. Inside the Body HIV Structure • Major structural elements: • Envelope • gp120 • gp41 • HIV Core • Structural proteins • p24 • 2 copies of single stranded RNA • Enzymes • Reverse transcriptase • Integrase • Protease

11. Typical Virus Components • Outer Covering • Inner Core

12. Envelope Proteins (gp120 & gp41) Lipid Bilayer HIV Envelope

13. HIV Core Integrase Core Proteins RNA genome Reverse Transcriptase Protease

14. HIV Replication http://www.youtube.com/watch?v=RO8MP3wMvqg&feature=related http://www.primeboost3.org/vaccine/images/knowledge/micro41[1].swf http://www.sumanasinc.com/webcontent/animations/content/hiv.html

16. Viral Attachment CD4 Receptors gp120

17. Viral Fusion and Penetration Viral RNA Reverse Transcriptase

18. Reverse Transcription Reverse Transcriptase RNA DNA DNA DNA RNA

19. Integration into the Host Cell Provirus

20. Transcription and Translation Viral mRNA gp160 Ribosome RNA Polymerase II p160 Proviral DNA p55 Viral mRNA exits Nucleus Endoplasmic Reticulum

21. Protein Processing by the HIV Protease Viral Protease Smaller Functional Strands Large polyproteins (E.g. p16/ p55)

22. Assembly and Budding Gag-pol (p160) Gag (p55) Gag (p55) Gag-pol (p160)

23. Contact HIV Mucosa

24. Local Infection HIV Mucosa CD4 Co Receptor CD4+ Lymphocyte Dendritic cell

25. Lymph Nodes HIV Mucosa 2 Days CD4 Co Receptor CD4+ Lymphocyte Dendritic cell

26. Widespread Dissemination HIV Mucosa 2 Days CD4 Co Receptor CD4+ Lymphocyte Dendritic cell 3 Days Brain Spleen Lymph Nodes Gut-associated Lymphoidal tissue

27. How are HIV Reservoirs Formed? Peripheral blood Routes of infection in the body: • Tissue Lymph Nodes Brain Spleen Gut-associated Lymphoidal tissue

28. Where are HIV Reservoirs Found? Brain Skin Lymph Nodes Peripheral Blood RES Gastrointestinal Cells Bone Marrow

29. Evading the Treatment Radar Without HIV Therapy With HIV Therapy HIV Reservoirs Non-activated CD4 T cell Gut-associated Lymphoid tissue Lymph Nodes Brain Spleen HIV Infected Cells Activated CD4 T cell Dendritic cells Macrophages

30. Relationship Between CD4 Cell Count and Viral Load VL CD4 Health Health

31. Opportunistic Infections and CD4 Cell Count Natural Course of HIV Infection and Common Complications VL CD4+ T cells Relative level of Plasma HIV-RNA TB HZV Asymptomatic Acute HIV infection syndrome OHL OC PCP PPE TB CM CMV, MAC

34. Laboratory Diagnosis of HIV Infection • Anti-HIV-1&2 Testings - เริ่มตรวจพบ สัปดาห์ที่ 3-12 หลังจากติดเชื้อ แทบทั้งหมดตรวจพบเดือนที่ 3….6 หลังจากติดเชื้อ - ปัญหา การตรวจหาในระยะ Window period 1.1 Screening tests: ELISA,GPA,rapid test etc. 1.2 Confirmatory tests: Westem blot* (WB) : Immunofluorescence * In high prevalence area, 2-3 screening assays with different principle in recommended as alternative to WB • Antigen detection: p24 Ag by ELISA • Gene detection: PCR, nested PCR, RT-PCR, Rrt-PCD - Should amplified 3 regions and considered positive if at least 2 regions are amplified 4) HIV culture

35. 5 most common opportunistic infections

36. Costly anti Ols drugs

37. CNS infection in HIV • Cryptococcal meningitis • Toxoplasmic encephalitis • Tuberculous meningitis/myelitis • Bacterial meningitis • Progressive multifocal leucoencephalopathy (PML) • CMV ventriculitis/polyradiculopathy

41. Manifestation of CNS OI in HIV • Headache • Alteration of consciousness • Focal neurodeficit • Dementia

42. GI infection in HIV • Bacteria : Salmonella • Mycobacteria : TB, MAC • Fungus: Histoplasma, P.marneffei • Virus: CMV, HSV • Parasites: Strongyloides, E.histolytica • Isospora, Cryptosporidium, Cyclospora, Microsporidium

43. Manifestation of GI OI in HIV • Abdominal mass/pain • Lymphadenopathy • Peritonitis • Causes • TB, MAC most common

44. HIV-associated FUO • Prolonged fever is common in AIDS patients • The etiology varies with geography • (AIDS 16:909,2002) • Frequency ↑ with ↓ CD4 ;and ↓ with HAART • (Eur J Clin Micro Inf Dis 21:137,2002)

45. Prolonged Fever in HIV-Infected Adult Patients in Northern Thailand • The study was conducted at Chaing Mai University Hospital from January 2002 to March 2003. • history of fever for at least two weeks. • Initial investigations included complete blood analysis, CD4+ lymphocyte counts , blood urea nitrogen, serum creatinine and electrolytes, liver function tests, urinary examination and/or culture, blood cultures for bacteria, and chest roentgenogram. J infect Dis AntimicrobAgents 2005:22:103-10

46. Etiology of prolonged fever • The etiology of prolonged fever could be determined in 71 of 90 patients (78.9%) • Infectious agent was identified as the cause in 70 of these 71 patients • Non-Hodgkins lymphoma was the only diagnosis in the remaining patient. • Among 70 patients with infectious etiology • 56 had a single etiology • 13 had multiple infectious etiologies J infect Dis AntimicrobAgents 2005:22:103-10

47. Etiology of prolonged fever Mycobacterial infection 40 cases M. avium complex 117 M. tubeerculosis 11 M. scrofulaceum 5 Penicilliosis marneffei 16 cases Salmonellosis 13 cases Cryptococcosis 7 cases J infect Dis AntimicrobAgents 2005:22:103-10

48. Selective Pressures of Therapy Treatment begins Drug-susceptible quasispecies Drug-resistant quasispecies Selection of resistant quasispecies Viral load • Incomplete suppression • Inadequate potency • Inadequate drug levels • Inadequate adherence • Pre-existing resistance Time

49. Goal of Therapy Viral load CD4 Relative Levels <50copies/mL at 6 month Limit of Detection Years After HIV Infection Months Acute HIV infection

50. Low-level Viral Rebound and ‘Blips’ Failure HIV RNA (copies/mL) Sustained low-level viremia 50 Resuppression Time Greub G et al. 8th CROI 2001