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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 1981Immune 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 ofhuman immunodeficiency virus infection. N Engl J Med. 1993;328:327-35.
IMMUNE
COMPETENCE
CD4+ / L
TIME (YEARS)
ASIMPTOMATIC PHASE
AIDS
200 / L
HIV exposure atmucosal 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
Sperm11,000 Vaginal
Fluid7,000
Blood18,000
AmnioticFluid 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 Pregnancyor Birth
Breast Feeding
Needle StickInjury
Risk of HIV Transmission with Single Unprotected Exposure
Total Living with HIV 35.3 million
North America1.3 million
[980 000 – 1.9 million]
Latin America1.5 million
[1.2 million – 1.9 million]
Caribbean250 000
[220 000 – 280 000]
Western & Central Europe
860 000[800 000 – 930 000]
Middle East & North Africa260 000
[200 000 – 380 000]
Sub-Saharan Africa25.0 million
[23.5 million – 26.6 million]
Eastern Europe & Central Asia1.3 million
[1.0 million – 1.7 million]
South & South-East Asia3.9 million
[2.9 million – 5.2 million]
Oceania51 000
[43 000 – 59 000]
East Asia880 000
[650 000 – 1.2 million]
84,2
57,9
5,52,9 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
15,711,3
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
450IDU men who have sex with men
heterosexual promiscuity % AIDS presenting
median CD4+
No subjects (% female)Median age (yrs)Non European
2401 (17.9)25,00.4%
751 (32.6)28,01.4%
326 (38.0)33,05.0%
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
% p
atie
nts
Med
ian C
D4+
cell coun
tThe 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 Drugsduring 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 1981Immune system attacked. Victim dies of
secondary infectionsIncreased 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 activationDyslipidemia
Hypercoagulation
Microbial translocation
HIV-associated fatMetabolic syndrome
HIV productionHIV replication
CMVExcess pathogens
Loss of regulatory cells
Co-morbiditiesAging
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 Study23,441 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