HIV Pathogenesis
Lecture 18
Virology W3310/W4310
Spring 2012
Nature is not human-­‐hearted
LAO TZU
Tao Te Ching
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HIV is a len0virus
•
First isolated in 1983 from the lymph node of a paBent with lymphadenopathy in Paris
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•
Subsequently isolated at NIH and UCSF
Electron microscopy and sequence analysis revealed them to be lenBviruses, a known group of retroviruses
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Retroviridae
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Orthoretrovirinae
-­‐
-­‐
-­‐
-­‐
Alpharetrovirus
Betaretrovirus
Gammaretrovirus
Deltaretrovirus
‣
-­‐
-­‐
HTLV-­‐1, HTLV-­‐2, HTLV-­‐3
Epsilonretrovirus
LenBvirus
‣
HIV-­‐1, HIV-­‐2
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Two evolu0onarily dis0nct groups of human retroviruses
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The lymphotropic viruses: HTLV 1, 2, 3, 4
The immunodeficiency viruses: HIV-­‐1, HIV-­‐2
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-­‐
LenBviruses, not new or unique to humans
Equine infecBous anemia virus, causes fatal immunodeficiency of horses, isolated early 1900s
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HIV and AIDS: Acquired ImmunoDeficiency Syndrome
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Syndrome: the occurrence together of a characterisBc group or paXern of symptoms
•
•
HIV-­‐1 is the eBological agent of epidemic AIDS
AIDS denialists: the hypothesis that HIV causes AIDS has been tested by inadvertent infecBon of people with HIV-­‐contaminated blood
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HIV/AIDS pandemic
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In the US, HIV has killed over 600,000, exceeding all US combat-­‐related deaths in all wars fought in the 20th century
•
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>1 million in the US are infected; 25% unaware
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Half of all new infecBons in US occur in people 25 or younger
40,000 new infecBons each year; 70% men, 30% women
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Adults and children estimated to be living with HIV | 2010
Western &
Central Europe
Eastern Europe
& Central Asia
840 000
1.5 million
[770 000 – 930 000] [1.3 million – 1.7 million]
North America
1.3 million
East Asia
[1.0 million – 1.9 million]
Caribbean
790 000
Middle East & North Africa
200 000
[170 000 – 220 000]
Latin America
1.5 million
[1.2 million – 1.7 million]
[580 000 – 1.1 million]
470 000
[350 000 – 570 000]
South & South-East Asia
4.0 million
Sub-Saharan Africa
22.9 million
[21.6 million – 24.1 million]
[3.6 million – 4.5 million]
Oceania
54 000
[48 000 – 62 000]
Total: 34.0 million [31.6 million – 35.2 million]
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Estimated number of adults and children
newly infected with HIV | 2010
Western &
Central Europe
Eastern Europe
& Central Asia
[22 000 – 39 000]
[110 000 – 200 000]
30 000
North America
58 000
160 000
[24 000 – 130 000]
Caribbean
Middle East & North Africa
12 000
[9400 – 17 000]
Latin America
100 000
[73 000 – 140 000]
East Asia
88 000
[48 000 – 160 000]
59 000
[40 000 – 73 000]
South & South-East Asia
270 000
Sub-Saharan Africa
1.9 million
[1.7 million – 2.1 million]
[230 000 – 340 000]
Oceania
3300
[2400 – 4200]
Total: 2.7 million [2.4 million – 2.9 million]
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Estimated adult and child deaths from AIDS | 2010
North America
20 000
Western &
Central Europe
Eastern Europe
& Central Asia
[8900 – 11 000]
[74 000 – 110 000]
9900
90 000
East Asia
[16 000 – 27 000]
Caribbean
9000
[6900 – 12 000]
Latin America
67 000
[45 000 – 92 000]
56 000
Middle East & North Africa
[40 000 – 76 000]
35 000
[25 000 – 42 000]
South & South-East Asia
250 000
Sub-Saharan Africa
1.2 million
[1.1 million – 1.4 million]
[210 000 – 280 000]
Oceania
1600
[1200 – 2000]
Total: 1.8 million [1.6 million – 1.9 million]
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Children (<15 years) estimated to be living with HIV | 2010
North America
4500
Western &
Central Europe
Eastern Europe
& Central Asia
[<1000 – 1800]
[14 000 – 23 000]
1400
17 000
East Asia
[4000 – 5800]
Caribbean
16 000
[12 000 – 19 000]
Latin America
42 000
[30 000 – 54 000]
16 000
Middle East & North Africa
[11 000 – 21 000]
40 000
[27 000 – 52 000]
South & South-East Asia
160 000
Sub-Saharan Africa
3.1 million
[2.8 million – 3.5 million]
[110 000 – 210 000]
Oceania
4600
[3600 – 5800]
Total: 3.4 million [3.0 million – 3.8 million]
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Estimated number of children (<15 years)
newly infected with HIV | 2010
North America
<100
Western &
Central Europe
Eastern Europe
& Central Asia
[<200]
[1700 – 2900]
<100
2200
East Asia
[<200]
2100
Caribbean
1200
[<1000 – 1700]
Latin America
3500
[2100 – 5000]
Middle East & North Africa
[<1000 – 3800]
6800
[4800 – 8800]
South & South-East Asia
20 000
Sub-Saharan Africa
350 000
[300 000 – 410 000]
[14 000 – 28 000]
Oceania
<1000
[<500 – <1000]
Total: 390 000 [340 000 – 450 000]
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Estimated deaths in children (<15 years) from AIDS | 2010
North America
<100
Western &
Central Europe
Eastern Europe
& Central Asia
[<200]
[<1000 – 1800]
<100
1200
East Asia
[<200]
1100
Caribbean
1000
[<1000 – 1300]
Latin America
2400
[1300 – 3500]
Middle East & North Africa
[<1000 – 1700]
3900
[2700 – 5000]
South & South-East Asia
14 000
Sub-Saharan Africa
230 000
[200 000 – 260 000]
[8300 – 20 000]
Oceania
<500
[<500 – <500]
Total: 250 000 [220 000 – 290 000]
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Over 7000 new HIV infections a day in 2010
§ About 97% are in low and middle income countries
§ About 1000 are in children under 15 years of age
§ About 6000 are in adults aged 15 years and older, of whom:
─ almost 48% are among women
─ about 42% are among young people (15-24)
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Control of AIDS
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Triple-­‐drug therapy has slowed the pandemic in countries with money
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But...
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There is as yet no cure
-­‐ Can’t clear virus from an infected individual
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There is no vaccine
-­‐ Can’t block primary infecBon
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Can’t stop taking anBviral drugs
-­‐ Reservoirs: latently infected hematopoieBc progenitor cells (TWiV 133: The HIV hideout)
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Drug resistant viruses appear
Drugs are expensive
AIDS is becoming a Third World disease
-­‐ Spreading unabated in sub-­‐Saharan Africa
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HIV-­‐2
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•
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Restricted primarily to populaBons in West Africa
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Humans infected with HIV-­‐2 have anBbodies that cross-­‐react with SIV
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SIV causes AIDS-­‐like disease in macaques, but is not pathogenic in some species like African green monkeys
Less virulent, transmissible than HIV-­‐1
HIV-­‐2 membrane proteins share homology with those of SIV
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Primate len0viruses and the origin of HIV
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Origin of HIV
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Current thinking, based on sequence analysis, is that HIV-­‐1 and HIV-­‐2 came from separate colonizaBon events of simian lenBviruses in humans
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HIV-­‐1 clades or subtypes
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Four groups (four separate colonizaBons of humans with SIV)
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Group M: at least 9 disBnct clades
Assignment based on sequence of ENV and GAG genes
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•Clades A, C, D, E predominate in areas with highest rates of infec9on
-­‐Most clades are found in central Africa
•Elsewhere, one or two clades predominate
-­‐Clade B predominates in the US and Western Europe
•HIV spread changing with 9me
-­‐Spread of the C-­‐clade in Africa
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Sequence comparisons provide insight on HIV origins
• Chimpanzee (SIV •
CPZ) and Mandrill (SIV MND) viruses: closely related to HIV-­‐1
Sooty mangabey virus group (SIV SM): closely related to HIV-­‐2
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Earliest records of HIV-­‐1 infec0on
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Serum sample ZR59 from a DRC adult male (1959) found posiBve for HIV-­‐1 in 1998
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Lymph node sample from DRC adult female (1960)
HIV in Bssue from US teenager died 1969
HIV in Bssue from Norwegian sailor died 1976
Viral genome amplified by PCR and DNA sequence determined
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When did SIV infect humans?
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1931 (+/-­‐ 15 yr)
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Hunter, colonialism, contaminated needle theories
1884 -­‐ 1924, comparing 1959 and 1960 sequences
Suggested that Kinshasa was epicenter, early spread concurrent with development of colonial ciBes
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Transmission
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HIV is not a parBcularly infecBous virus, not contagious like measles virus
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Not spread by respiratory, alimentary, or vector routes
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Transmission
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HIV-­‐1 infecBvity reduced by air drying (99%/24 hr)
By heaBng (56°C/30 min)
By 10% bleach or 70% alcohol
By pH extremes (<6 or >10)
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Co-­‐receptors
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Primary HIV Infec0on
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Virus-­‐dendriBc cell interacBon
- InfecBon is typically with CCR5 (M-­‐tropic) strains
- Importance of DC-­‐SIGN (dendriBc cell-­‐specific, Icam-­‐3 grabbind nonintegrin)
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Delivery of virus to lymph nodes
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Viral set point reached aker ~6 months
AcBve replicaBon in lymphoid Bssue
High levels of viremia and disseminaBon
DownregulaBon of virus replicaBon by immune response
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Primary HIV Infec0on: Clinical Characteris0cs
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50-­‐90% of infecBons are symptomaBc
Symptoms generally occur 5-­‐30 days aker exposure
Symptoms and signs
- Fever, faBgue, malaise, arthralgias, headache, nausea, vomiBng, diarrhea
- Adenopathy, pharyngiBs, rash, weight loss, mucocutaneous ulceraBons, asepBc meningiBs
- Leukopenia, thrombocytopenia, elevated liver enzymes
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Median duraBon of symptoms: 14 days
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GI associated lymphoid 0ssue following acute infec0on
Absence of lymphoid cell aggregates in terminal Ileum
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Established HIV Infec0on
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AcBve viral replicaBon throughout course of disease
Major reservoirs of infecBon exist outside of blood
-­‐ LymphoreBcular Bssues (GastrointesBnal tract -­‐ GALT)
-­‐ Central nervous system
-­‐ Genital tract
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At least 10 x 109 virions produced and destroyed each day
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T1/2 of HIV in plasma is <6 h and may be as short as 30 min
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mulBpotent hematopoieBc progenitor cells -­‐ latent reservoir
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The Variable Course of HIV-­‐1 Infec>on
Typical Progressor
AIDS
Viral Replica0on
B
months
years
months
AIDS
CD4 Level
CD4 Level
years
Nonprogressor
Primary HIV
Infec0on
Clinical Latency
CD4 Level
C
Viral Replica0on
A
Clinical Latency
Viral Replica0on
Primary HIV
Infec0on
Rapid Progressor
Primary HIV
Infec0on
?
months
years
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Immune cell dysfunc0on in AIDS
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• <200 CD4+ T cells/ml
AIDS
• Protozoal: Pneumocys@s, Toxoplasma, Isospora, Cryptosporidium, microsporidia
• Bacterial: Mycobacterium, Treponema
• Fungal: Candida, Cryptococcus, Histoplasma
• Viral: CMV, HSV
• Malignancies: EBV lymphoma, Kaposi’s sarcoma, anogenital carcinoma
• Neurological symptoms: asepBc meningiBs, myelopathies, neuropathies, AIDS demenBa complex
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Neurological symptoms
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HIV and cancer
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HIV-­‐1 infecBon leads to increase incidence of malignancy: 40% of infected individuals
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An indirect effect of dysregulaBon of the immune system
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-­‐
Absence of proper immune surveillance
High levels of cytokines leads to inappropriate cell proliferaBon, replicaBon of oncogenic viruses, angiogenesis
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Kaposi’s sarcoma
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Described 1872 by Hungarian physician
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InfecBon with human herpesvirus 8 is necessary for development of KS
Pre-­‐AIDS: mainly in older Mediterranean men
Occurs in 20% of HIV-­‐1 infected homosexual men, 2% of HIV-­‐1 infected women, transfusion recipients
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B-­‐cell lymphomas
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60-­‐100 Bmes more common in AIDS paBents than general populaBon
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Tumors in lymph nodes, intesBne, CNS, liver
Oken associated with infecBon by HHV-­‐8 or Epstein-­‐
Barr virus
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Is an HIV-­‐1 vaccine possible?
Viral Load
AnBviral Immunity
How does HIV-­‐1 persist despite effecBve anB-­‐viral immunity?
How does it eventually outstrip immune control?
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HIV-­‐1 escape from neutralizing an0body
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Broadly neutralizing an0bodies
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Have been idenBfied in some HIV-­‐1 infected individuals
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Neutralize broadly across clades
Recognize conserved epitopes on Env glycoprotein
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CD8+ CTL are important for control of HIV-­‐1
• KineBcs of early CTL response peak as early viremia falls
• Adverse effect of removing CD8+ T cells in SIV-­‐infected macaques
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Elite HIV Controllers
• Individuals who maintain normal CD4 counts and undetectable viral loads (<50 copies HIV RNA/ml of plasma) for >10 years in the absence of anBretroviral therapy
-­‐ EsBmated at 1/300 infected persons
• Associated with favorable HLA types (esp HLA B57 and B27) and T-­‐cell responses (CD4 and CD8) to Gag
• Persistent viremia (1-­‐30 copies of RNA/ml) demonstrable
• Not associated with aXenuated viruses
hXp://www.twiv.tv/2010/05/16/twiv-­‐82-­‐immunology-­‐in-­‐silico/
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