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

Time (years) CD4 per mm 3 Natural History of HIV-1 VZVTB Kaposi Sarcoma PCP 15 CMV MAC Crypto Lymphoma symptoms CD4 HIV RNA HIV RNA copies/ml

The level of HIV in the blood stream predicts subsequent survival RNA particles/ml plasma One year Rapid Progression Slow Progression Viral set point

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

Potential factors influencing the viral set point Attenuated virus Host genetic factors Host immune response

Potential factors influencing the viral set point Attenuated virus Host genetic factors Host immune response HAART

New virus assembly 2-3 Days Attenuated viruses Example: Sidney blood bank cohort Virus had a “mistake” in the nef gene

Attenuated viruses Host genetic factors

CD4 CCR5 Co-receptor polymorphisms can prevent entry of virus into cells 32 base pair deletion in CCR5

B27 B57 Migueles, PNAS 97:2709, 2000 Some molecules on the cell of an individual are associated with improved viral control and slow disease progression

Attenuated viruses Host immune responses Host genetic factors

New virus assembly Humoral Immune System: Neutralizing Antibodies B cell

New virus assembly CTL Soluble factors Cellular immune system: Killer T cells Cytotoxic T cell

New virus assembly CTL Soluble factors B cell Th

B cell Th CTL

The Generals (T helper cells trained to target HIV)

Generals (T Helper cells) Infantry (CTL) Enemy Infected cell

Why are the generals absent in most infected persons?

Generals (T Helper cells) Infantry (CTL) Enemy Infected cell

Virus-Specific T Helper Cells: Essential for Maintenance of Effective CTL Th cells absent Th cells present Relative magnitude CTL Viremia CTL

Is there any way to enhance the immune response against HIV?

Generals (T helper cells) Infantry (CTL) Enemy (Infected cells)

HAART Generals (T Helper cells) Infantry (CTL) Enemy (Infected cell)

Magnitude of Helper Cells Effect of Early Treatment on the Generals (HIV-Specific T Helper Cells) Weeks on Treatment

What happens if you stop treatment?

Weeks after first treatment interruption viral load (copies RNA/mL) HAART Early treatment of acute HIV infection followed by treatment interruption

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 ? n 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 n Individuals with high levels of Killer T cells have been shown to have low viral loads n Two interesting groups of individuals —HIV-1 long-term nonprogressors (LTNP) —HIV-1 exposed, but uninfected individuals (HEPS)

Infected 21 years Normal T cells Undetectable viral load Never on anti-HIV meds LTNP LTNP have strong and broadly directed killer cell responses and helper cell responses

HEPS n 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 n 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 n 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) n Many vaccine approaches/trials currently in study

Our current Research n Understanding of total the killer T cell and helper cell response against HIV, not only to single proteins like previous studies. n 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 n Durban, RSA n Immune responses in Clade C-Infection n Mother to child transmission and pediatric treatment and treatment interruption studies n NIH contract Epitope mapping in Non-Caucasians

Nelson Mandela School of Medicine University of Natal Lab

Why is HIV not controlled by the immune system like other chronic viral infections? Mono Chicken pox Herpes simplex

Problems n VIRAL ESCAPE n VIRAL DIVERSITY

How HIV mutates to escape Killer T-cells

Examples: n Goulder et al, Nature 2001 —Viral escape mutants can be transmitted from mother to child n Barouch et al, Nature 2002 —Loss of viral control in a vaccinated animal associated with viral escape in one epitope Viral escape

Viral Diversity Comparing Viruses: How much does HIV evolve compared to Flu? Less Variation More Variation

Influenza variation compared to HIV variation Canadian Flu 1996 Global Flu

Influenza variation compared to HIV variation Amsterdam 1997 Dem Rep of Congo Canadian Flu 1996 Global Flu

The extreme variability of HIV over time is a major impediment to immune control, effective drug therapy and vaccine development

Acknowledgements n Marcus Altfeld n Xu Yu n Almas Rathod n Cecily Fitzpatrick n Paul Lee n Philip Goulder n Christian Brander n Eric Rosenberg n Bruce Walker Funding Sources: German Research Council (DFG) amfAR Concerned Parents for AIDS Research (CPFA)

HLA-B27 is associated with slow progression to AIDS Viral Load n = 10 HLA-B27+

HLA B27 molecule I W K I L K G L The dominant CTL response in HLA-B27+ individuals: HIV Gag p24 KK10 epitope L R

B27-KK10 escape is associated with elevated viral load Non-controllers p=0.025 All Arg/Lys at P Controllers Viral Load

HIV Gag p24 KK10 epitope HLA B27 molecule I W K I L K G L R L K M I W K I L K G L

100% 80% 60% 40% 20% 0% n=21 86% n=6 33% p=0.02 PediatricAdult 2.73% CD8s 1.55% pbmc IFN-  CD8 B27-KK10 is recognized more frequently in adult than in pediatric HIV infection

B27-ve motherB27+ve mothers C C048-C 049-C IFN-  SFC/ million PBMC 1925 B27-KK10 is not recognized in children of B27-positive mothers

B27-ve motherB27+ve mothers 043-C C048-C049-C B27-KK10 non-recognition associated with P2 anchor mutation IFN-  SFC/ million PBMC P2 anchor mutation shared with mother No P2 anchor mutation