The role of immune responses in HIV-1 Infection Marylyn M. Addo, MD/PhD Partners AIDS Research Center Massachusetts General Hospital Harvard Medical School Boston, MA USA HIV RNA copies/ml CD4 per mm3 Natural History of HIV-1 symptoms 1000 106 CD4 800 105 HIV RNA 600 VZV 104 TB 400 Kaposi Sarcoma 200 PCP CMV MAC Crypto Lymphoma 1 Time (years) 5 10 15 RNA particles/ml plasma The level of HIV in the blood stream predicts subsequent survival Rapid Progression Viral set point Slow Progression One year What influences viral load in HIV infection? Viruses are not able to reproduce on their own New virus assembly 2-3 Days Viral set point is determined by number of viruses produced by infected cells Attenuated virus Potential factors influencing the viral set point Host immune response Host genetic factors Attenuated virus Potential factors influencing the viral set point Host immune response Host genetic factors HAART Example: Sidney blood bank cohort Attenuated viruses Virus had a “mistake” in the nef gene New virus assembly 2-3 Days Attenuated viruses Host genetic factors Co-receptor polymorphisms can prevent entry of virus into cells 32 base pair deletion in CCR5 CD4 CCR5 Some molecules on the cell of an individual are associated with improved viral control and slow disease progression B27 B57 Migueles, PNAS 97:2709, 2000 Attenuated viruses Host genetic factors Host immune responses Humoral Immune System: Neutralizing Antibodies New virus assembly B cell Cellular immune system: Soluble factors Killer T cells Cytotoxic T cell New virus assembly Th Soluble factors New virus assembly B cell Th Th B cell CTL Th The Generals (T helper cells trained to target HIV) Infantry (CTL) Generals (T Helper cells) Enemy Infected cell Why are the generals absent in most infected persons? Infantry (CTL) Generals (T Helper cells) Enemy Infected cell Relative magnitude Virus-Specific T Helper Cells: Essential for Maintenance of Effective CTL Viremia CTL Viremia CTL Th cells absent Th cells present Is there any way to enhance the immune response against HIV? Infantry (CTL) Generals (T helper cells) Enemy (Infected cells) Infantry (CTL) Generals (T Helper cells) HAART Enemy (Infected cell) Magnitude of Helper Cells Effect of Early Treatment on the Generals (HIV-Specific T Helper Cells) 1000 100 10 1 0 20 40 60 Weeks on Treatment 80 What happens if you stop treatment? viral load (copies RNA/mL) Early treatment of acute HIV infection followed by treatment interruption HAART 160000 120000 80000 40000 0 0 5 10 15 20 25 30 35 Weeks after first treatment interruption 40 Very early treatment with HAART leads to enhanced natural control of HIV Where else do we find evidence for immune control in AIDS virus infection ? In monkey studies, removing killer cells led to dramatic increases in viral load and restoring Killer T cells in those same monkey studies led to suppression of viral load Individuals with high levels of Killer T cells have been shown to have low viral loads Two interesting groups of individuals — HIV-1 long-term nonprogressors (LTNP) — HIV-1 exposed, but uninfected individuals (HEPS) LTNP • Infected 21 years • Normal T cells • Undetectable viral load • Never on anti-HIV meds LTNP have strong and broadly directed killer cell responses and helper cell responses HEPS Most well known: — Nairobi sex worker cohort (Rowland-Jones et al.) — Found killer T cell responses in these HEPS, that may contribute to protection from HIV — Our group: collaboration with Lusaka, Zambia (PI: Susan Allen) studying killer cells in discordant couples and their partners Poster session Thursday 12-2 pm (Addo) Vaccine development Based on these pieces of data, it is felt that an effective HIV-1 vaccine needs to elicit cellular immune responses, in particular Killer T cell responses +/- Helper T cell responses Most recent and compelling data derive from monkey studies demonstrating that Killer T cell have an impact on vaccine efficacy in this setting (Robbinson, Barouch/Letvin, Shiver) Many vaccine approaches/trials currently in study Our current Research Understanding of total the killer T cell and helper cell response against HIV, not only to single proteins like previous studies. Analysis of the virus by sequencing Bruce Walker morning Tuesday plenary Addo A05 Tuesday 14-15:30 More research needed for other virus types and other ethnicities Durban, RSA Immune responses in Clade C-Infection Mother to child transmission and pediatric treatment and treatment interruption studies NIH contract Epitope mapping in Non-Caucasians Lab Nelson Mandela School of Medicine University of Natal Why is HIV not controlled by the immune system like other chronic viral infections? Mono Chicken pox Herpes simplex Problems VIRAL ESCAPE VIRAL DIVERSITY How HIV mutates to escape Killer T-cells Viral escape Examples: Goulder et al, Nature 2001 — Viral escape mutants can be transmitted from mother to child Barouch et al, Nature 2002 — Loss of viral control in a vaccinated animal associated with viral escape in one epitope Viral Diversity Comparing Viruses: How much does HIV evolve compared to Flu? Less Variation More Variation 1997-1998 Canadian Flu 1996 Global Flu Influenza variation compared to HIV variation 1997-1998 Canadian Flu 1996 Global Flu Influenza variation compared to HIV variation 1990-1991 Amsterdam 1997 Dem Rep of Congo The extreme variability of HIV over time is a major impediment to immune control, effective drug therapy and vaccine development Acknowledgements Marcus Altfeld Xu Yu Almas Rathod Cecily Fitzpatrick Paul Lee Philip Goulder Christian Brander Eric Rosenberg Bruce Walker Funding Sources: German Research Council (DFG) amfAR Concerned Parents for AIDS Research (CPFA) HLA-B27 is associated with slow progression to AIDS 106 105 Viral Load 104 103 102 n = 10 HLA-B27+ The dominant CTL response in HLA-B27+ individuals: HIV Gag p24 KK10 epitope K I W R G I L L HLA B27 molecule L K B27-KK10 escape is associated with elevated viral load All Arg/Lys at P2 106 105 Viral Load 104 103 p=0.025 102 Controllers Non-controllers HIV Gag p24 KK10 epitope K K M I W R G I L L HLA B27 molecule L K B27-KK10 is recognized more frequently in adult than in pediatric HIV infection 100% CD8 1.55% pbmc 2.73% CD8s IFN-g 80% 60% 40% 20% 0% n=21 86% p=0.02 n=6 33% Adult Pediatric B27-KK10 is not recognized in children of B27-positive mothers 2000 IFN-g SFC/ million PBMC 1925 1600 1200 800 400 0 0 043-C B27-ve mother 0 0 002-C 048-C 049-C B27+ve mothers B27-KK10 non-recognition associated with P2 anchor mutation No P2 anchor mutation 2000 IFN-g SFC/ million PBMC 1600 1200 800 P2 anchor mutation shared with mother 400 0 043-C B27-ve mother 0 0 0 002-C 048-C 049-C B27+ve mothers