3. History of HIV HIV 1930 HIV-1 arises 1959 Earliest sero-positive 1981 AIDS emerges 1983 HIV-1 identified 1986 HIV-2 identified 1997 Advent of HAART 2006

4. Complacency High Risk Behavior Human Rights Abuses Stigma- tization Access To Care Sexism Ignorance Poverty Discrimin- ation Disem- powered Women Prejudice Denial Courtesy of Jim Hoxie

6. HIV Treatment: Anti-virals

7. X X Reverse Transcription Inhibitors Protease Blockers

13. HIV latency • Latently infected resting memory CD4+ T cells are the best characterized latent reservoir for HIV-1. • Less than 1 cell per 1,000,000 resting CD4+ T cells from patients on HAART harbor latent HIV-1 provirus. • Sequence of latent proviruses does not evolve , which suggests no ongoing viral replication. • Discontinuation of HAART allows viral relapse from latent reservoir.

15. many lymphocytes can be visualized that produce small amounts of viral RNA, yet do not display markers of activation

16. Potential transcriptional blocks in HIV latency

17. Potential post-transcriptional blocks in HIV latency

19. Potential therapies to disrupt latent proviral HIV infection

21. Purging persistent proviral infection

24. Vaccines from Bench to Clinic

39. How vaccines are developed? Basic research Preclinical development Clinical trials Phase I/II Phase III Safety, Immunogenicity Discovery Human research in vitro & animal studies Laboratory Exploration Efficacy Vaccine concept Experiments in primates Human trials 1 2 3 4 5 6 Safety, immunogenicity Likelihood of protection in humans 1: Recombinant Protein – 2: Synthetic Peptides – 3: Naked DNA 4. Live-recombinant vectors- 5: Whole inactivated virus – 6: Live attenuated virus

40. Why a HIV vaccine might be feasable? 1. Vaccination has been successful against other viral diseases . 2. Experimental HIV/SIV vaccines have protected chimpanzees/macaques . 3. Candidate HIV vaccines are immunogenic. 4. Some humans can regulate infection and/or HIV replication .

41. Approaches to AIDS vaccine designs

46. But … HIV is particularly challenging because it infects exactly the immune system T cells that are supposed to protect you from infections.

48. The goal of an HIV-1 vaccine would be either to prevent infection or to reduce viral loads and clinical disease progression after infection

53. Current strategies to design vaccines to generate broadly neutralising antibodies

55. there are currently no vaccine candidates that are aimed at eliciting broadly reactive Env specific neutralizing antibodies in clinical trials.

56. Cellular immunity Experimental depletion of CD81 lymphocytes has been shown to abrogate immune control of simian immunodeficiency virus (SIV) replication in rhesus monkeys Polyfunctional T lymphocytes capable of performing multiple functions have been reported in long-term non-progressors

62. SAAVI-DNA-C2 and SAAVI-MVA-C for clinical trial

64. http://chi.ucsf.edu/vaccines Ongoing HVTN Trials: Phase II Protocol Number Status as of July 2008 Prime Boost Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant HVTN 502/Merck 023 (Step) (n=3000) Closed to accrual Nonreplicating adenoviral vectors (clade B Gag-Pol-Nef) Merck MRKAd5 trivalent HVTN 503 (n=801) Closed to accrual Nonreplicating adenoviral vectors (clade B Gag-Pol-Nef) Merck MRKAd5 trivalent

65. http://chi.ucsf.edu/vaccines Ongoing HVTN Trials: Phase I (Slide 1 of 2) Protocol Number Status as of July 2008 Prime Boost Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant HVTN 050/Merck 018 (n=435) Closed to accrual Nonreplicating adenoviral vector (clade B Gag) Merck MRKAd5 HIV-1 Gag HVTN 063 (n=156) Closed to accrual DNA plasmid (clade B Gag) Wyeth GENEVAX gag -2962 DNA plasmid cytokine ( IL-15) + bupivacaine Peptides ( poly- epitopic: clade B Env, Gag, Nef ) Wyeth Wyeth multiepitope CTL peptide vaccine RC529-SE, GM-CSF Or DNA plasmids (clade B Gag) Wyeth GENEVAX gag -2962 DNA plasmid cytokine (IL-12) + bupivacaine HVTN 065 (n=120) Closed to accrual DNA plasmid ( clade B Gag, Pro, RT, Env, Tat, Rev, Vpu ) GeoVax HIVB DNA pGA2/JS7 MVA vector (clade B Gag, Pol, Env) GeoVax MVA-HIV 62

66. http://chi.ucsf.edu/vaccines Ongoing HVTN Trials: Phase I (Slide 2 of 2) Protocol Number Status as of July 2008 Prime Boost Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant HVTN 067 (n=108) Closed to accrual DNA plasmid (polyepitopic: Gag, Pol, Vpr, Nef, Rev, Env) Pharmexa-Epimmune EP HIV-1233 MVA vector (poly-epitopic: Gag, Pol, Vpr, Nef, Rev, Env) Bavarian-Nordic MVA-mBN32 HVTN 069 (n=90) Closed to accrual DNA plasmids (clade B Gag-Pol-Nef; clade A,B,C Env) given by IM route NIH VRC VRC-HIVDNA-009 Nonreplicating adenoviral vectors (clade B Gag-Pol; clade A,B,C Env) given by SC or ID vs IM route NIH VRC VRC-ADV-014 HVTN 070 (n=120) Enrolling DNA plasmids (clade B Gag, Pol, Env) Univ. of Pennsyl-vania (D. Weiner) PENNVAX-B DNA plasmid cytokines (IL-12 or IL-15) + bupivacaine HVTN 071 (n=35) Closed to accrual Nonreplicating adenoviral vectors (clade B Gag, Pol, Nef) Merck MRKAd5

67. http://chi.ucsf.edu/vaccines Planned HVTN Trials: Phase I, July 2008 Protocol Number Anticipated Start Date Prime Boost Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant HVTN 073 (n=96) Q3 2008 DNA plasmids (clade C Gag, RT, Tat, Nef; clade C Env) SAAVI SAAVI DNA-C2 MVA vector (clade C Gag, RT, Tat, Nef; clade C gp150CT) SAAVI SAAVI MVA-C HVTN 076 Q3 2008 DNA plasmids (clade B Gag, Pol, Nef; Clade A, B, C Env NIH VRC VRC-HIVDNA-016 Non-replicating adenoviral vectors (clade B Gag-Pol; clade A, B, C Env) NIH VRC VRC-ADV-014 HVTN 077 Q3 2008 DNA plasmids (clade A Env) NIH VRC VRC-HIVDNA044 Non-replicating adenoviral vectors , type 5 (clade A Env) NIH VRC VRC-HIVDNA038 OR OR Non-replicating adenoviral vector, type 35 (clade A Env) NIH VRC VRC-HIVADV027 Non-replicating adenoviral vector, type 35 (clade A Env) NIH VRC VRC-HIVADV027

68. http://chi.ucsf.edu/vaccines Completed HVTN Trials, July 2008 (Slide 1 of 5 ) Protocol Number Year Completed Prime Boost Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant References HVTN 039 (n=110) 2003 Canarypox vector (clade B Env, Gag, Pro, RT, Nef) Sanofi Pasteur ALVAC vCP1452 (high-dose) Goepfert P, et al. J Infect Dis 2005; 192:1249-59 HVTN 041 (n=84) 2003 Protein (clade B Nef-Tat fusion protein + clade B Env subunit) GlaxoSmith Kline NefTat + gp120W61D AS02A Goepfert, P et al. Vaccine 2007 Jan 5;25(3):510-8 HVTN 203 (n=330) 2003 Canarypox vector (clade B Env, Gag, Pro, RT, Nef) Sanofi Pasteur ALVAC vCP1452 Protein subunit (clade B Env) VaxGen AIDSVAX B/B (gp120 MN, gp120 GNE8) Aluminum hydroxide gel Russell N, et al. J Acquir Immune Defic Syndr. 2007 Feb 1;44(2):203-12 HIVNET 026 (n=160) 2004 Canarypox vector (clade B Env, Gag, Pro, RT, Nef) Sanofi Pasteur ALVAC vCP1452 Protein subunit (clade B Env) VaxGen gp120 MN Aluminum hydroxide/ thimerosol Cleghorn F, et al . J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):222-30. HVTN 045 (n=30) 2004 DNA plasmid (clade B Env, Gag, Pro, RT, Tat, Vpu, Rev) Emory Univ. (H. Robinson) pGA2/JS2 DNA Mulligan MJ, et al. AIDS Res Hum Retroviruses 2006;22:678-83

69. http://chi.ucsf.edu/vaccines Completed HVTN Trials, July 2008 (Slide 2 of 5) Protocol Number Year Completed Prime Boost Class Producer Product Name Adjuvant Class Pro-ducer Product Name Adjuvant References HIVNET 040 (n=48) 2005 VEE vector (clade C Gag) AlphaVax AVX-101 HVTN 048 (n=42) 2005 DNA plasmid (poly-epitopic: Gag, Pol, Vpr, Nef, Rev, and Env) Epimmune EP HIV-1090 Gorse G, et al. Vaccine. 2008 Jan 10;26(2):215-23. Epub 2007 Nov 20. HVTN 052 (n=180) 2005 DNA plasmids (clade B Gag-Pol-Nef; clade A,B,C Env) NIH VRC VRC-HIVDNA-009 See HVTN 057 HVTN 057 (n=70) (HVTN 052 rollover) 2006 See HVTN 052 Non-replicating adenoviral vectors (clade B Gag-Pol; clade A,B,C Env) NIH VRC VRC-ADV-014 HVTN 044 (n=70) 2006 DNA plasmids (clade B Gag-Pol-Nef; clade A,B,C Env) NIH VRC VRC-HIVDNA-009 DNA plasmid cytokine (IL2-Ig)

70. http://chi.ucsf.edu/vaccines Completed HVTN Trials, July 2008 (Slide 3 of 5) Protocol Number Year Completed Prime Boost Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant HVTN 054 (n=48) 2006 Nonreplicating adenoviral vectors (clade B Gag-Pol; clade A,B,C Env) NIH VRC VRC-ADV-014 HVTN 056 (n=96) 2006 Peptides (polyepitopic: clade B Env, Gag, Nef) Wyeth Wyeth multiepitope CTL peptide vaccine RC-529-SE, GM-CSF HVTN 059 (n=96) 2006 VEE vector ( clade C Gag ) AlphaVax AVX-101 HVTN 042/ANRS VAC19 (n=174) 2007 Canarypox vector (clade B Env, Gag, Pro, RT, Nef) Sanofi Pasteur ALVAC vCP1452 Lipopeptides (poly-epitopic: clade B Gag, Pol, Nef) Sanofi Pasteur/ ANRS LIPO-5 HVTN 068 (n=66) 2007 Nonreplicating adenoviral vectors (clade B Gag-Pol; clade A,B,C Env) NIH VRC VRC-ADV-014 Nonreplicating adenoviral vectors (clade B Gag-Pol; clade A, B, C Env) NIH VRC VRC-HIVADV014 OR DNA plasmids (clade B Gag-Pol-Nef; clade A,B,C Env) NIH VRC VRC-HIVDNA-009

71. http://chi.ucsf.edu/vaccines Completed HVTN Trials, July 2008 (Slide 4 of 5) Protocol Number Year Completed Prime Boost Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant HVTN 055 (n=150) 2007 MVA vectors (clade B Env, Gag; Tat, Rev, Nef, Pol) Therion TBC-M358; TBC-M335 Fowlpox vector (clade B Env, Gag; Tat, Rev, Nef, Pol) Therion TBC-F357;TBC-F349 HVTN 049 (n=96) 2007 DNA plasmids (clade B Gag, Env) Chiron Gag and Env DNA/PLG microparticles PLG Protein subunit (clade B Env) Chiron Oligomeric, V2-deleted HIV gp140 SF-162 HVTN 064 (n=120) 2008 Protein (containing T-helper epitopes from clade B Env, Gag, Pol, Vpu) + DNA plasmid (polyepitopic: Gag, Pol, Vpr, Nef) Pharmexa-Epimmune EP-1043 + EP HIV-1090 Alum (for EP-1043 only) HVTN 204 (n=480) 2008 DNA plasmids (clade B Gag, Pol, Nef; clade A,B,C Env) NIH VRC VRC-HIVDNA-016 Non-replicating adenoviral vectors (clade B Gag-Pol; clade A,B,C Env) NIH VRC VRC-ADV-014

72. http://chi.ucsf.edu/vaccines Completed HVTN Trials, July 2008 (Slide 5 of 5) Protocol Number Year Completed Prime Boost Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant HVTN 060 (n=144) 2008 DNA plasmid (clade B Gag) Wyeth GENEVAX gag -2962 DNA plasmid cytokine (IL-12) + bupivacaine Wyeth peptides (see 056 prime)

73. Nonhuman Primate HIV/SIV Trials Database

75. Savalan-Azerbaycan