What Constitutes a Protective CTL Response in HIV-1 Infection?
Lead Research Organisation:
Imperial College London
Department Name: Div of Investigative Science
Abstract
What constitutes a good immune response? Why do some HIV-infected people develop AIDS in months whilst others remain healthy for decades? How do your genes affect your outcome of infection? These are the fundamental questions that we are trying to answer.
The size of the HIV pandemic is staggering. In some areas of sub-Saharan Africa 1 in every 3 adults are infected. A cheap effective vaccine is desperately needed. The first step in designing an HIV vaccine is understanding the type of immunity that it should induce, i.e. what exactly is a good immune response?
Answering this question is complicated by the fact that HIV destroys immune cells. Consequently we cannot tell if immune response attributes associated with good viral control are a cause or an effect of low levels of virus. This means that many traditional methods of investigating the immune response are redundant.
A clue as to what determines the efficacy of the human immune response lies in the observation that some people naturally control HIV infection much better than others and that this is, in part, related to the person’s genetic makeup. The aim of this project is to understand what a good immune response is by understanding why some genes result in better immune control than others.
The research will be conducted by a novel mathematical analysis of existing HIV-infected patient databases. Our results will contribute to our understanding of what constitutes a good immune response. This could have direct implications for human health and HIV vaccine development. More generally, severity of illness for all 3 of the world’s most devastating diseases: AIDS, malaria and TB is partially determined by host genetics. We hope that the methods and insights our research generates will be applicable in all of these cases.
The size of the HIV pandemic is staggering. In some areas of sub-Saharan Africa 1 in every 3 adults are infected. A cheap effective vaccine is desperately needed. The first step in designing an HIV vaccine is understanding the type of immunity that it should induce, i.e. what exactly is a good immune response?
Answering this question is complicated by the fact that HIV destroys immune cells. Consequently we cannot tell if immune response attributes associated with good viral control are a cause or an effect of low levels of virus. This means that many traditional methods of investigating the immune response are redundant.
A clue as to what determines the efficacy of the human immune response lies in the observation that some people naturally control HIV infection much better than others and that this is, in part, related to the person’s genetic makeup. The aim of this project is to understand what a good immune response is by understanding why some genes result in better immune control than others.
The research will be conducted by a novel mathematical analysis of existing HIV-infected patient databases. Our results will contribute to our understanding of what constitutes a good immune response. This could have direct implications for human health and HIV vaccine development. More generally, severity of illness for all 3 of the world’s most devastating diseases: AIDS, malaria and TB is partially determined by host genetics. We hope that the methods and insights our research generates will be applicable in all of these cases.
Technical Summary
AIM: To determine what constitutes a protective CTL response in HIV-1 infection.
APPROACH.
Host HLA class I genotype is significantly associated with the outcome of HIV-1 infection. We will perform a meta-analysis of existing experimental data from 3 patient cohorts to determine the mechanisms underlying this association.
RATIONALE.
Recent data has shown that HIV-1 damages the immune system within weeks of infection. Consequently, it is difficult to ascertain if many of the CTL attributes previously associated with good immune control e.g. proliferative capacity are the cause, or simply a passive consequence, of low viral load. With host genetic effects the direction of causality is unequivocal. Consequently, by investigating the mechanisms underlying HLA associations we directly investigate the attributes of a protective CTL response.
BACKGROUND.
HIV-1 continually evolves to escape the host CTL response. It has been hypothesised that escape contributes to AIDS progression but no clear relationship has been demonstrated. Consequently, it is not known whether HIV-1 escape from CTL is an epiphenomenon that might exacerbate disease progression in a few atypical cases or whether it is a significant driving force that leads to AIDS in the majority.
PRELIMINARY DATA.
We have demonstrated a relationship between HLA protection and viral escape. We found that CTLs restricted by alleles associated with slow progression to AIDS recognised epitopes where escape variants were weakly selected (P=0.008) and occurred infrequently (P=0.017). Epitopes presented by protective alleles were more likely to elicit a CD8+ T cell response (P=0.001, P=0.0007) and less likely to contain sequence variation (P=0.006). A third of HLA-associated AIDS risk was explained by the net selective advantage of escape variants. These results were found across all alleles and epitopes studied, suggesting a universal CTL-dependent mechanism of protection.
PROJECT.
These data are promising. They show that the strength of selection for escape is a significant determinant of CTL protection and describe why different HLA alleles are associated with different rates of AIDS progression. However, they do not explain what determines CTL selection and consequently cannot be used to guide vaccine design. Here we test hypotheses regarding the basis of the CTL protective effect we have observed; including the contribution of epitope plasticity, CTL breadth and viral attenuation.
SIGNIFICANCE.
A prerequisite for rational vaccine design is an understanding of the attributes of protective immunity. More generally, what constitutes a good CTL response and how HLA genotype impacts on CTLs are fundamental questions in biomedicine.
APPROACH.
Host HLA class I genotype is significantly associated with the outcome of HIV-1 infection. We will perform a meta-analysis of existing experimental data from 3 patient cohorts to determine the mechanisms underlying this association.
RATIONALE.
Recent data has shown that HIV-1 damages the immune system within weeks of infection. Consequently, it is difficult to ascertain if many of the CTL attributes previously associated with good immune control e.g. proliferative capacity are the cause, or simply a passive consequence, of low viral load. With host genetic effects the direction of causality is unequivocal. Consequently, by investigating the mechanisms underlying HLA associations we directly investigate the attributes of a protective CTL response.
BACKGROUND.
HIV-1 continually evolves to escape the host CTL response. It has been hypothesised that escape contributes to AIDS progression but no clear relationship has been demonstrated. Consequently, it is not known whether HIV-1 escape from CTL is an epiphenomenon that might exacerbate disease progression in a few atypical cases or whether it is a significant driving force that leads to AIDS in the majority.
PRELIMINARY DATA.
We have demonstrated a relationship between HLA protection and viral escape. We found that CTLs restricted by alleles associated with slow progression to AIDS recognised epitopes where escape variants were weakly selected (P=0.008) and occurred infrequently (P=0.017). Epitopes presented by protective alleles were more likely to elicit a CD8+ T cell response (P=0.001, P=0.0007) and less likely to contain sequence variation (P=0.006). A third of HLA-associated AIDS risk was explained by the net selective advantage of escape variants. These results were found across all alleles and epitopes studied, suggesting a universal CTL-dependent mechanism of protection.
PROJECT.
These data are promising. They show that the strength of selection for escape is a significant determinant of CTL protection and describe why different HLA alleles are associated with different rates of AIDS progression. However, they do not explain what determines CTL selection and consequently cannot be used to guide vaccine design. Here we test hypotheses regarding the basis of the CTL protective effect we have observed; including the contribution of epitope plasticity, CTL breadth and viral attenuation.
SIGNIFICANCE.
A prerequisite for rational vaccine design is an understanding of the attributes of protective immunity. More generally, what constitutes a good CTL response and how HLA genotype impacts on CTLs are fundamental questions in biomedicine.
