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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


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

Orthoretrovirinae

-­‐
-­‐
-­‐
-­‐

Alpharetrovirus
Betaretrovirus
Gammaretrovirus
Deltaretrovirus


-­‐
-­‐

HTLV-­‐1,  HTLV-­‐2,  HTLV-­‐3

Epsilonretrovirus
LenBvirus

HIV-­‐1,  HIV-­‐2
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 not  new  or  unique  to  humans Equine  infecBous  anemia  virus.  isolated  early  1900s 6 .  HIV-­‐2 -­‐ -­‐ LenBviruses.  4 The  immunodeficiency  viruses:  HIV-­‐1.  2.  causes  fatal   immunodeficiency  of  horses.Two  evolu0onarily  dis0nct  groups  of  human   retroviruses • • The  lymphotropic  viruses:  HTLV  1.  3.

HIV  and  AIDS:  Acquired  ImmunoDeficiency   Syndrome • 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 7 .

000  new  infecBons  each  year.  HIV  has  killed  over  600.  70%  men.000.  30%   women 8 .HIV/AIDS  pandemic • In  the  US.  25%  unaware • Half  of  all  new  infecBons  in  US  occur  in  people  25  or   younger 40.  exceeding  all   US  combat-­‐related  deaths  in  all  wars  fought  in  the   20th  century • • >1  million  in  the  US  are  infected.

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5 million [1.Adults and children estimated to be living with HIV | 2010 Western & Central Europe Eastern Europe & Central Asia 840 000 1.1 million] [3.2 million] 10 .6 million – 4.1 million] 470 000 [350 000 – 570 000] South & South-East Asia 4.3 million – 1.9 million] Caribbean 790 000 Middle East & North Africa 200 000 [170 000 – 220 000] Latin America 1.5 million [770 000 – 930 000] [1.0 million [31.5 million] Oceania 54 000 [48 000 – 62 000] Total: 34.3 million East Asia [1.2 million – 1.6 million – 24.9 million [21.0 million – 1.7 million] North America 1.6 million – 35.0 million Sub-Saharan Africa 22.7 million] [580 000 – 1.

4 million – 2.7 million [2.7 million – 2.1 million] [230 000 – 340 000] Oceania 3300 [2400 – 4200] Total: 2.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 [1.9 million] 11 .

2 million [1.1 million – 1.9 million] 12 .4 million] [210 000 – 280 000] Oceania 1600 [1200 – 2000] Total: 1.8 million [1.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 1.6 million – 1.

0 million – 3.8 million – 3.5 million] [110 000 – 210 000] Oceania 4600 [3600 – 5800] Total: 3.8 million] 13 .1 million [2.4 million [3.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.

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] 14 .

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] 15 .

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) 16 .

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Control  of  AIDS • Triple-­‐drug  therapy  has  slowed  the  pandemic  in   countries  with  money 18 .

. • There  is  as  yet  no  cure -­‐ Can’t  clear  virus  from  an  infected  individual • There  is  no  vaccine -­‐ Can’t  block  primary  infecBon • Can’t  stop  taking  anBviral  drugs -­‐ Reservoirs:  latently  infected  hematopoieBc  progenitor  cells   (TWiV  133:  The  HIV  hideout) • • • Drug  resistant  viruses  appear Drugs  are  expensive AIDS  is  becoming  a  Third  World  disease -­‐ Spreading  unabated  in  sub-­‐Saharan  Africa 19 .But..

 transmissible  than  HIV-­‐1 HIV-­‐2  membrane  proteins  share  homology  with  those   of  SIV 20 .HIV-­‐2 • • • Restricted  primarily  to  populaBons  in  West  Africa • Humans  infected  with  HIV-­‐2  have  anBbodies  that   cross-­‐react  with  SIV • SIV  causes  AIDS-­‐like  disease  in  macaques.  but  is  not   pathogenic  in  some  species  like  African  green   monkeys Less  virulent.

Primate  len0viruses  and  the  origin  of  HIV 21 .

 based  on  sequence  analysis.  is  that   HIV-­‐1  and  HIV-­‐2  came  from  separate  colonizaBon   events  of  simian  lenBviruses  in  humans 22 .Origin  of  HIV • Current  thinking.

HIV-­‐1  clades  or  subtypes • Four  groups  (four  separate  colonizaBons  of  humans   with  SIV) • • Group  M:  at  least  9  disBnct  clades Assignment  based  on  sequence  of  ENV  and  GAG   genes 23 .

 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 24 .  E  predominate  in  areas  with  highest  rates  of  infec9on -­‐Most  clades  are  found  in  central  Africa •Elsewhere.  D.  C.•Clades  A.

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 25 .

Earliest  records  of  HIV-­‐1  infec0on • Serum  sample  ZR59  from  a  DRC  adult  male  (1959)   found  posiBve  for  HIV-­‐1  in  1998 • • • • 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 26 .

 contaminated  needle  theories 1884  -­‐  1924.  early   spread  concurrent  with  development  of  colonial   ciBes 27 .  comparing  1959  and  1960  sequences Suggested  that  Kinshasa  was  epicenter.When  did  SIV  infect  humans? • • • 1931  (+/-­‐  15  yr) • Hunter.  colonialism.

Transmission • HIV  is  not  a  parBcularly  infecBous  virus.  alimentary.  not   contagious  like  measles  virus • Not  spread  by  respiratory.  or  vector   routes 28 .

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Transmission • • • • 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) 31 .

Co-­‐receptors 32 .

InfecBon  is  typically  with  CCR5  (M-­‐tropic)  strains .Primary  HIV  Infec0on • Virus-­‐dendriBc  cell  interacBon .Importance  of  DC-­‐SIGN   (dendriBc  cell-­‐specific.  Icam-­‐3  grabbind  nonintegrin) • • • • Delivery  of  virus  to  lymph  nodes • 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 33 .

 diarrhea .  weight  loss.  rash.  malaise.  elevated  liver  enzymes • Median  duraBon  of  symptoms:  14  days 34 .  arthralgias.  asepBc  meningiBs .  thrombocytopenia.  mucocutaneous   ulceraBons.Leukopenia.  headache.  faBgue.  nausea.Fever.   vomiBng.Primary  HIV  Infec0on:  Clinical  Characteris0cs • • • 50-­‐90%  of  infecBons  are  symptomaBc Symptoms  generally  occur  5-­‐30  days  aker  exposure Symptoms  and  signs .  pharyngiBs.Adenopathy.

GI  associated  lymphoid  0ssue  following  acute   infec0on Absence  of   lymphoid   cell  aggregates  in   terminal  Ileum 35 .

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Established  HIV  Infec0on • • 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 • At  least  10  x  109  virions  produced  and  destroyed   each  day • T1/2  of  HIV  in  plasma  is  <6  h  and  may  be  as  short  as   30  min 37 .

mulBpotent  hematopoieBc  progenitor  cells  -­‐  latent  reservoir 38 .

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 39 .

Immune  cell  dysfunc0on  in  AIDS 40 .

 Treponema • Fungal:  Candida.  Cryptococcus.  anogenital   carcinoma • Neurological  symptoms:  asepBc  meningiBs.  AIDS  demenBa  complex 41 .   neuropathies.  Histoplasma • Viral:  CMV.  Isospora.  HSV • Malignancies:  EBV  lymphoma.  microsporidia • Bacterial:  Mycobacterium.  Kaposi’s  sarcoma.• <200  CD4+  T  cells/ml AIDS • Protozoal:  Pneumocys@s.   Cryptosporidium.  Toxoplasma.  myelopathies.

Neurological  symptoms 42 .

HIV  and  cancer • HIV-­‐1  infecBon  leads  to  increase  incidence  of   malignancy:  40%  of  infected  individuals • An  indirect  effect  of  dysregulaBon  of  the  immune   system -­‐ -­‐ Absence  of  proper  immune  surveillance High  levels  of  cytokines  leads  to  inappropriate  cell   proliferaBon.   angiogenesis 43 .  replicaBon  of  oncogenic  viruses.

Kaposi’s  sarcoma • • • Described  1872  by  Hungarian  physician • 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.  transfusion  recipients 44 .  2%   of  HIV-­‐1  infected  women.

 CNS.  liver Oken  associated  with  infecBon  by  HHV-­‐8  or  Epstein-­‐ Barr  virus 45 .  intesBne.B-­‐cell  lymphomas • 60-­‐100  Bmes  more  common  in  AIDS  paBents  than   general  populaBon • • Tumors  in  lymph  nodes.

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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? 47 .

HIV-­‐1  escape  from  neutralizing  an0body 48 .

Broadly  neutralizing  an0bodies • Have  been  idenBfied  in  some  HIV-­‐1  infected   individuals • • Neutralize  broadly  across  clades Recognize  conserved  epitopes  on  Env  glycoprotein 49 .

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 50 .

twiv.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.tv/2010/05/16/twiv-­‐82-­‐immunology-­‐in-­‐silico/ 51 .