How HIV Causes Disease Prof. Bruce D. Walker

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1 How HIV Causes Disease Howard Hughes Medical Institute Massachusetts General Hospital Harvard Medical School 1 The global AIDS crisis 60 million infections 20 million deaths 2 3 The screen versions of these slides have full details of copyright and acknowledgements 1

2 The level of virus in the blood predicts outcome RNA particles/ml plasma 10 million Rapid progression Slow progression Interquartile ranges 60,000 30,000 12,000 One year 4 Factors influencing HIV disease progression Viral Host Immunologic 5 New virus assembly 1-2 days 6 The screen versions of these slides have full details of copyright and acknowledgements 2

3 HIV-1 life cycle 4. Integration into host cell s nucleus 5. Transcription and translation 1. Attachment 2. Uncoating 3. Rev erse transcription 6. Assembly and release of new viruses 7 HIV genome vpu nef LTR gag pol vpr vif env tat rev LTR 8 9 The screen versions of these slides have full details of copyright and acknowledgements 3

Subtype distribution of collected HIV-1 sequences Variation within a subtype: up to 20% Variation among subtypes: up to 38% in some proteins 10 HIV genome vpu nef LTR gag pol vpr vif env tat rev LTR

4 Subtype distribution of collected HIV-1 sequences Variation within a subtype: up to 20% Variation among subtypes: up to 38% in some proteins 10 HIV genome vpu nef LTR gag pol vpr vif env tat rev LTR 11 HIV-1 life cycle 1. Attachment 4. Integration into host cell s nucleus 5. Transcription and translation 2. Uncoating 3. Rev erse transcription 6. Assembly and release of new viruses 12 The screen versions of these slides have full details of copyright and acknowledgements 4

5 Factors influencing HIV disease progression Viral Host Immunologic 13 Host factors Chemokine receptor polymorphisms 14 HIV-1 life cycle 4. Integration into host cell s nucleus 5. Transcription and translation 1. Attachment 2. Uncoating 3. Rev erse transcription 6. Assembly and release of new viruses 15 The screen versions of these slides have full details of copyright and acknowledgements 5

6 R5 virus X4 virus CCR5delta32 CD4 CCR5 CD4 CXCR4 16 Host factors Chemokine receptor polymorphisms Chemokine ligand gene duplications 17 R5 virus R5 virus CCL3L1 CD4 CCR5 32 CD4 CCR5 18 The screen versions of these slides have full details of copyright and acknowledgements 6

7 CCL3L1 Some gene segment duplications exist in the human genome, particularly related to immune response genes CCL3L1 is a potent anti-hiv chemokine Also known as MIP-1αP Low CCL3L1 copy number is associated with more rapid disease progression 19 Host factors Chemokine receptor polymorphisms Trim5α 20 HIV does not infect monkey cells Human cells Monkey cells 21 The screen versions of these slides have full details of copyright and acknowledgements 7

8 Trim5α HIV enters cells from Old World monkeys but does not establish a productive infection Trim5α is a monkey gene that makes a protein that blocks HIV Trim5α localizes in cytoplasmic bodies but the function is not known Stremlau et al., Science, 247: 848, Trim5α blocks reverse transcription by interacting with the viral capsid 1. Attachment 2. Uncoating 23 Host factors Chemokine receptor polymorphisms Trim5α APOBEC 3G 24 The screen versions of these slides have full details of copyright and acknowledgements 8

9 HIV genome LTR gag pol vpr vif vpu env tat rev nef LTR 25 Expression of the viral Vif protein is necessary for infection of some cell types Vif positive virus APOBEC Vif Vif negative virus APOBEC 26 APOBEC 3G APOBEC 3G is a natural antiviral defense mechanism Interacts with the virus to degrade it intracellularly Vif binds to APOBEC 3G and prevents this natural antiviral defense Can one block the Vif-APOBEC interaction as a therapeutic strategy? 27 The screen versions of these slides have full details of copyright and acknowledgements 9

10 Host factors Chemokine receptor polymorphisms APOBEC 3G Trim5 alpha HLA alleles 28 How is an infected cell recognized? 4. Integration into host cell s Presentation nucleus by HLA class I 5. Transcription and translation 1. Attachment 2. Uncoating 3. Rev erse transcription Assembly and 6. release Assembly and release of new viruses 29 K W I I L G L N R K HLA class I molecule 30 The screen versions of these slides have full details of copyright and acknowledgements 10

11 A2 B57 A3 B14 Cw6 Cw4 31 Relative hazard B*58 Cw*14 B*27 Cw*02 B*57 A*26 B*51 A*11 A*02 A*03 B*07 B*35 B*35px 32 Factors influencing HIV disease progression Viral Host Immunologic 33 The screen versions of these slides have full details of copyright and acknowledgements 11

12 The course of untreated HIV infection RNA particles/ml plasma 10 million 30,000 Months Years AIDS 34 What is the evolution of immune responses? Innate immunity TLR NK cells Adaptive immunity Cellular Humoral 35 Toll-like receptors on adaptive immunity 36 The screen versions of these slides have full details of copyright and acknowledgements 12

13 What role do TLR play in HIV infection? It has been recently demonstrated that ssrna derived from HIV-1 LTR can serve as a TLR7/8 ligand Heil, Science, 2004 Beignon, JCI, 2005 Does this drive immune activation and further destruction? Adaptive immune responses 39 The screen versions of these slides have full details of copyright and acknowledgements 13

14 New virus assembly Th B cell 40 Why do neutralizing antibodies fail to control infection? The screen versions of these slides have full details of copyright and acknowledgements 14

15 Wei et al., 2003, Nature 422: 307 Richman et al., 2003, PNAS 100: What factors might modulate CTL efficacy? Viral peptides Quality of CTL HLA alleles 45 The screen versions of these slides have full details of copyright and acknowledgements 15

16 K W I I L G L N R K HLA class I molecule 46 What factors might modulate CTL efficacy? Viral peptides HLA alleles 47 K K T W W I I I I M L G G L L L N K R K HLA class I molecule 48 The screen versions of these slides have full details of copyright and acknowledgements 16

17 CTL responses and viral imprinting CTL 49 Genetics of immune control On a population level, there is evidence of viral evolution to escape dominant immune responses Persons with rare HLA alleles appear to have an advantage because mutations have not already been selected Moore et al., 2003, Science 296: 1439 Trachtenberg 2003, Nat. Med. 9: 928 Leslie et al., 2004, Nat. Med. 10: 282 Goulder et al., Nature, 2004 Kiepiela et al., Nature Medicine, HIV genome vpu nef LTR gag pol vpr vif env tat rev LTR 51 The screen versions of these slides have full details of copyright and acknowledgements 17

18 52 What factors might modulate CTL efficacy? Viral peptides Quality of CTL HLA alleles 53 Does lack of control relate to a functional defect in CTL? CTL CTL CTL CTL CTL CTL Proliferation 54 The screen versions of these slides have full details of copyright and acknowledgements 18

, Science, 1997 Rosenberg et al., Nature, 2000 Douek et al.

19 What could account for the loss of CTL proliferation? 55 CTLs Infected cells T helper cells Rosenberg et al., Science, 1997 Rosenberg et al., Nature, 2000 Douek et al., Nature, The screen versions of these slides have full details of copyright and acknowledgements 19

20 Massive depletion of CD4 cells in acute SIV infection Monkeys infected with SIV Gut biopsies over the first few weeks of infection 30-60% of memory CD4 T cells are infected at peak viremia - many are resting! Most of these cells disappear within 4 days Authors suggest early treatment Mattapallil, J. J. et al., Nature, PD-1 is a negative regulator of CTL - engagement turns CTL off PD-1 Off PD-L1 59 Use of HLA class I tetramers to quantitate HIV-specific CD8 T cells CTL Tetramer 60 The screen versions of these slides have full details of copyright and acknowledgements 20

21 61 p< p= % PD HIV Total CD8 + Tetramer + (HIV + ) Total CD8 + (HIV - ) Day et al., Nature, Can one block the PD-1 pathway and restore function? Subjects 28 persons with untreated infection Methods Stimulate with cognate epitope in the presence or absence of anti-pdl1 Measure relative degree of expansion of the HIV-specific cells over 6 days 63 The screen versions of these slides have full details of copyright and acknowledgements 21

22 Blockade of PD-1/PD-L1 pathway increases expansion of HIV-specific CD8 T cells no peptide 1.2% anti-pd-l1 no peptide 1.2% + TL9 peptide 5.7% anti-pd-l1 + TL9 peptide 12.4% CD8 B*4201 TL9 64 Interpretation and implications 65 CTLs Infected cells T helper cells PD-1 PD-L1 66 The screen versions of these slides have full details of copyright and acknowledgements 22

23 CTL CTL CTL Conclusions HIV is an infection of the immune system and causes severe damage during acute infection Neutralizing antibody responses are poor due to genetic variation in the envelope and heavy glycosylation preventing contact CTL kill virus infected cells, but immune escape occurs Immune regulatory networks turn off the immune response to HIV over time The tremendous variability of HIV is a major challenge for vaccine development 69 The screen versions of these slides have full details of copyright and acknowledgements 23

24 70 The screen versions of these slides have full details of copyright and acknowledgements 24

Fayth K. Yoshimura, Ph.D. September 7, of 7 HIV - BASIC PROPERTIES

Fayth K. Yoshimura, Ph.D. September 7, of 7 HIV - BASIC PROPERTIES 1 of 7 I. Viral Origin. A. Retrovirus - animal lentiviruses. HIV - BASIC PROPERTIES 1. HIV is a member of the Retrovirus family and more specifically it is a member of the Lentivirus genus of this family.