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