Factors influencing immunodominance of the cytotoxic T lymphocyte response in C clade HIV infection

Lead Research Organisation: University of Oxford
Department Name: Unknown

Abstract

The immune response plays a central role in influencing the rate of progression to HIV disease. The particular immune cells critical in the immune response against HIV are termed cytotoxic T lymphocytes (CTL). These cells can recognise fragments of HIV proteins presented on the surface of infected cells. In this way CTL can recognise and kill HIV-infected cells.
These investigators have, since 1998, studied the CTL response against HIV in South Africa, an epicentre of the epidemic. Recently published studies by this group highlighted the dominant role of particular CTL, which play the major part in influencing disease outcome. However, whilst certain CTL are associated with slow progression to HIV disease, other CTL are associated with particularly poor control of HIV.
The hypothesis underlying these proposed studies is that these differences in outcome relate principally to the particular fragments of HIV that are recognised by the CTL. The aim of this proposed research is, therefore, to determine, first, the precise identity of these fragments of HIV proteins that may play a key part in shaping the effectiveness of immune control of HIV; and, second, what are the factors that influence whether or not responses to these protein fragments are made.

Technical Summary

The cytotoxic T lymphocyte (CTL) response against HIV plays a central role in control of viral replication and in influencing the rate of progression to HIV disease. The work of this group of investigators has since 1998 focused its efforts on characterising the anti-clade C CTL response in infected Zulu/Xhosa from Durban, South Africa, an epicentre of the epidemic. Initial analysis of the HIV-specific responses in 375 adults with chronic infection in Durban demonstrated that HLA-B alleles play the dominant role in the CTL response, in mediating selection pressure on the virus, and in influencing disease outcome. However, certain HLA-B alleles are associated with effective control, whilst other HLA-B alleles are associated with particularly poor control of HIV.

The hypothesis underlying these proposed studies is that these differences in outcome relate principally to the specific HLA-B-restricted CTL epitopes that are targeted by individual study subjects. The aim of this proposed research is, therefore, to determine, first, what are the particular epitopes that may play a key part in shaping the efficacy of the CTL response; and, second, what are the factors that influence whether or not responses to these epitopes are initially generated and subsequently maintained.

Publications

10 25 50
 
Description WHO Infant Treatment guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact As a result of data presented at the Conference on Retroviruses and Opportunistic Infections (Feb 2008), I was invited to present these data at a WHO meeting in Geneva and joined the Technical Reference Group on HIV/ART Care as a result. Discussions held at this meeting resulted in a change in international HIV treatment guidelines for infants, to recommend universal treatment of HIV-infected infants due to the impact on morbidity and mortality.
 
Description WHO Paediatric Guidelines 2013
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact I was a member of the WHO guidelines group for antiretroviral treatment of HIV infection in adults, pregnant women and children, published 2013. Guidelines now recommend earlier treatment thresholds, and have extended universal treatment for children to <5 years of age,and extended treatment of pregnant women to all women
 
Description NIH Scholarship
Amount £800 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 03/2007 
End 03/2007
 
Description Wellcome Trust Intermediate Clinical Fellow
Amount £926,528 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2011 
End 05/2015
 
Description Young Investigator CROI
Amount £1,000 (GBP)
Organisation Conference on Retroviruses and Opportunistic Infections (CROI) 
Sector Charity/Non Profit
Country United States
Start 03/2010 
End 03/2010
 
Title Clade C HIV sequences 
Description A database of 710 clade C HIV sequences was generated as a result of work partly carried out under this grant, which has been shared with other research groups addressing questions of viral sequence change in HIV infection 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact The following publications resulted from this database of viral sequences: 19244334 19242411 18596105 18434400 18426987 17409157 17251285 17173051 
 
Description Boston 
Organisation Ragon Institute of MGH, MIT and Harvard
Country United States 
Sector Academic/University 
PI Contribution Study of HIV-infected infants and cohort of HIV-infected adults was established jointly between Oxford and Harvard
Collaborator Contribution Collaboration on studies in Durban
Impact The following manuscripts resulted from this collaboration: 19828603 19605475 19244334 18580613 18434400 18426987 18284325 17881456 17617274 17545701 17409157 17251285 17173051
 
Description Durban 
Organisation University of KwaZulu-Natal
Country South Africa 
Sector Academic/University 
PI Contribution Collaboration on a clinical trial of treatment strategies for HIV-infected infants in Durban. Financial and academic support, plus clinical support from our team. Study run in collaboration between Boston, Durban and Oxford. Collaboration on establishing a cohort of HIV-infected adults for studies of CTL-mediated control of HIV infection
Collaborator Contribution Establishment of an adult and paediatric HIV cohort
Impact The following manuscripts were published as a result of the collaboration with the Durban lab: 19828603 19605475 19244334 18580613 18434400 18426987 18284325 17881456 17617274 17545701 17409157 17251285 17173051
 
Description Great Ormond Street Hospital 
Organisation Great Ormond Street Hospital (GOSH)
Department Department of Infectious Diseases
Country United Kingdom 
Sector Hospitals 
PI Contribution We established a paediatric HIV cohort to study immune responses in children. Several children were recruited from this site.
Collaborator Contribution Recruitment of patients leading to research findings and publications
Impact Two publications (PubMed ID 21834749 and 21505296) The collaboration involves with doctors and Clinical Nurse Specialists working in the paediatric HIV clinic
Start Year 2006
 
Description St Mary's Hospital, London 
Organisation Imperial College Healthcare NHS Trust
Department Paediatric Infectious Diseases Imperial College
Country United Kingdom 
Sector Academic/University 
PI Contribution We established a paediatric HIV cohort to study immune responses in children, several of whom were recruited from this clinic
Collaborator Contribution Recruitment of patients leading to research findings and publications
Impact Two publications (PubMed ID 21834749 and 21505296) The collaboration involves with doctors and Clinical Nurse Specialists working in the paediatric HIV clinic
Start Year 2006
 
Description University of Alabama 
Organisation University of Alabama at Birmingham
Department School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Sharing of viral sequencing data leading to publication
Collaborator Contribution Sharing of data for publication
Impact Publication: 18426987
 
Description Univsersity of Washington 
Organisation University of Washington
Department Department of Microbiology
Country United States 
Sector Academic/University 
PI Contribution Shared viral sequencing data for use in manuscript
Collaborator Contribution Sharing of research data leading to publication
Impact Publications: 18596105 18434400
 
Description Zvitambo Project 
Organisation Johns Hopkins University
Department Johns Hopkins Bloomberg School of Public Health
Country United States 
Sector Academic/University 
PI Contribution We have fostered a new collaboration between the University of Oxford and the Zvitambo Project, Harare, Zimbabwe. We are exploring potential collaborative projects currently.
Collaborator Contribution The Zvitambo Project has a unique archive of clinical trial samples and we are currently formulating research ideas to explore disease progression in HIV-infected infants (using HLA typing to determine alleles associated with rapid or slow disease progression)
Impact None yet; discussions are ongoing and projects being planned
Start Year 2011