PPT Angarano "Storia naturale dell'HIV"
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  • There are a number of immunologic and clinical features of ageing that are shared by HIV infected individuals and the elderly.There is good evidence that changes occur in T cells as we age such as the accumulation of senescent T cells and emerging evidence of changes in monocytes. These changes are juxtaposed on evidence of chronic inflammation and clinically associated withincreased risk of infection as well as non communicable diseases of ageing

PPT Angarano "Storia naturale dell'HIV" PPT Angarano "Storia naturale dell'HIV" Presentation Transcript

  • Natural History of HIV/AIDS Gioacchino Angarano Clinica delle Malattie Infettive
  • Natural History of HIV/AIDS Acquired Immune Deficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV)
  • reverse transcriptase viral RNA viral DNA Proviral DNA Integrate in cellular DNA integrasi protease assembling budding Human DNA CD4 & coreceptors
  • Hemelaar J.Trends Mol Med. 2012 Jan 11. Tebit DM, Arts EJ. Lancet Infect Dis. 2011 Jan;11(1):45-56. HIV came from non-human primates
  • Global Distribution of HIV-1 Hemelaar J.Trends Mol Med. 2012 Jan 11. The greatest diversity of HIV sequences is seen in Central Africa
  • Natural History of HIV/AIDS Acquired Immune Deficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV) Disease first described in 1981
  • Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon Dec 10, 1981
  • Natural History of HIV/AIDS Acquired Immune Deficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV) Disease first described in 1981 Immune system attacked. Victim dies of secondary infections
  • How HIV causes AIDS  HIV invades immune system cells especially helper T cells which have a vital role in the immune system  Effector T cells attack the virus and stimulate B cells to produce antibodies to the virus. In addition effector T cells stimulate macrophages to ingest cells infected with the virus and killer T cells to destroy infected cells displaying viral proteins  Virus mutates and the proteins on its outer surface (gp120 and gp41) change. Mutant virus particles bearing new surface proteins survive immune system attack and begin new round of infection  Each round of infection reduces numbers of helper T cells because they are infected by the virus and destroyed.  Furthermore, because each lineage of T cells has a limited capacity for replication, after a finite number of rounds of replication the body’s supply of helper T cells becomes exhausted. The immune system eventually is overwhelmed and collapses
  • Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon Dec 10, 1981 Leu3=CD4
  • Natural history of untreated HIV infection Pantaleo G, Graziosi C, Fauci AS. New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med. 1993;328:327-35.
  • IMMUNE COMPETENCE CD4+ / L TIME (YEARS) ASIMPTOMATIC PHASE AIDS 200 / L
  • HIV exposure at mucosal surface (sex) Virus collected by dendritic cells, carried to lymph node HIV replicates in CD4 cells, released into blood Virus spreads to other organs Day 0 Day 0-2 Day 4-11 Day 11+ The HIV Infection mechanism
  • HIV– Acute HIV+ • There is a marked reduction in mucosal CD4 cells — T cells, DCs, and macrophages Profound Depletion of Mucosal Barrier Brenchley JM, et al. J Exp Med. 2004;200:749-759.
  • HIV in body fluids Sperm 11,000 Vaginal Fluid 7,000 Blood 18,000 Amniotic Fluid 4,000 Saliva 1 Mean number of HIV particles in 1 ml of each body fluid
  • Modes of HIV Transmission Sharing Semen and Vaginal Fluids Sharing Needles & Syringes Through Infected Blood During Pregnancy or Birth Breast Feeding Needle Stick Injury
  • Risk of HIV Transmission with Single Unprotected Exposure
  • Total Living with HIV 35.3 million North America 1.3 million [980 000 – 1.9 million] Latin America 1.5 million [1.2 million – 1.9 million] Caribbean 250 000 [220 000 – 280 000] Western & Central Europe 860 000 [800 000 – 930 000] Middle East & North Africa 260 000 [200 000 – 380 000] Sub-Saharan Africa 25.0 million [23.5 million – 26.6 million] Eastern Europe & Central Asia 1.3 million [1.0 million – 1.7 million] South & South-East Asia 3.9 million [2.9 million – 5.2 million] Oceania 51 000 [43 000 – 59 000] East Asia 880 000 [650 000 – 1.2 million]
  • 84,2 57,9 5,5 2,9 2,73,5 7,3 15 45,7 54,7 8,1 28,7 55,5 62,8 49,5 42,7 23 28,9 15,7 11,3 2824,5 14 13 348 383 239 288 320 392 0 10 20 30 40 50 60 70 80 90 1985-1990 1991-1995 1996-2000 2001-2005 2006-2010 2011-2013 0 50 100 150 200 250 300 350 400 450 IDU men who have sex with men heterosexual promiscuity % AIDS presenting median CD4+ No subjects (% female) Median age (yrs) Non European 2401 (17.9) 25,0 0.4% 751 (32.6) 28,0 1.4% 326 (38.0) 33,0 5.0% 218 (33.0) 36,0 11.3% 204 (23.5) 36,0 14.7% 150 (24.0%) 36,0 21.3% Non B HIV-1 subtypes 0/115 6/77 16/58 33/100 71/204 70/150 %patients MedianCD4+cellcount The UNIBA Infectious Diseases Cohort 4050 new HIV diagnosis since 1985 UNIBAID 2014
  • The impact of HAART on AIDS
  • Anti-Retroviral Therapy
  • Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy: the SAPiT trial Abdool Karim SS, N Engl J Med 2010; 362:697-706
  • TB and IRIS Mean of 15 days after starting HAART Risk factors: • Starting ARV’s within 6 weeks of TB treatment • Disseminated, extra-pulmonary disease • Low base line CD4 count • Rise in CD4 % • Fall in viral load
  • Natural History of HIV/AIDS Acquired Immune Deficiency Syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV) Disease first described in 1981 Immune system attacked. Victim dies of secondary infections Increased inflammation also in patients with controlled infection by the therapy
  • Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon Dec 10, 1981 T10=CD38 Leu3=CD4
  • Inflammation ↑ Monocyte activation ↑ T cell activation Dyslipidemia Hypercoagulation Microbial translocation HIV-associated fat Metabolic syndrome HIV production HIV replication CMV Excess pathogens Loss of regulatory cells Co-morbidities Aging Deeks S et al Lancet 2013
  • Inflammation predicts disease in treated HIV infection, as it does in the general population  Mortality (Kuller, PLoS Med, 2008, Sandler JID 2011, Tien JAIDS 2011)  Cardiovascular Disease (Baker, CROI 2013)  Lymphoma (Breen, Cancer Epi Bio Prev, 2010)  Venous Thromboembolism (Musselwhite, AIDS, 2011)  Type II Diabetes (Brown, Diabetes Care, 2010)  Cognitive Dysfunction (Burdo AIDS 2012)  Frailty (Erlandson, JID 2013)
  • Weber R, et al. Arch Intern Med. 2006;166:1632-41. Cause of Death (Incidence) in the D:A:D Study 23,441 HIV-infected persons prospectively followed for a median of 3.5 years N = 1,246 deaths
  • Fibrinogen and CRP, independent predictors of mortality in the FRAM study Tien, JAIDS 2010  922 HIV-infected participants > 85% on cART (past or present)  70% with history of AIDS   50% HIV-RNA BLD  20% HCV+  5-year mortality risk
  • Immunological and clinical manifestations shared by HIV+ and elderly Immunologic characteristics Naïve T cells T cell diversity Memory cells Differentiated, senescent CD8+ T cells (eg CD28-CD57+) Telomere length CD16+ monocytes monocyte function Functional immune defects Replicative capacity Tumour surveillance Pathogen protection Chronic inflammation Clinical manifestations Vaccine responses Infections Age-associated non communicable diseases (eg CVD, non-AIDS cancers, bone/kidney disease, frailty, neurocognitive decline)
  • HIV Results in Accelerated Age-related Conditions  Development of frailty, muscle wasting  Insulin resistance, diabetes and cardiovascular disease  Chronic kidney disease  Bone disease  Cognitive impairment and dementia  Non AIDS-defining malignancies  Liver disease and HCC Effros RB et al. Clin Infect Dis 2008