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CTL and HIV- super Infection


HIV/AIDS (INCO)

CTL-Mediated Protection from HIV-1 Infection in a High-Risk Cohort in Tanzania: Persistent Seronegativity, Persistent Single-Subtype Infection, and Cross-Subtype Superinfection
Framework programme:
5
Project number:
ICA4-CT-2002-10048
EC contribution:
€ 1 050 000
Duration:
36 months
Type:
RS
Starting date:
Autumn 2002

Summary:

Cytotoxic T-lymphocytes will be a primary effecter in any successful HIV-1 vaccine. Knowledge of the protective CTL epitopes and their cross-subtype effectiveness is incomplete. The study proposes to use the setting of natural infection in individuals, multiply exposed to HIV subtypes A, C and D, to gain understanding of a protective CTL response. From a high-risk cohort in Tanzania, three groups will be identified: persistently seronegative, persistently infected with a single HIV subtype or recombinant, and superinfected with a second subtype. CTL ELISPOT and epitope mapping, viral load and diversity, HLA typing, and MHA (a new subtyping tool) will be employed. This study will be the first to define the CTL response capable of protecting from new HIV infections in persistent seronegatives and, in the same population and setting, to identify the flawed CTL responses that permit superinfection of already infected individuals. Personnel and infrastructure development will facilitate future vaccine trials.

Objectives:

The broad objective of this proposal is to investigate the hypothesis that the quality, breadth, and specificity of the CTL response against HIV-1 is a key determinant in protection, both from an initial HIV-1 infection, and from superinfection with a second HIV-1 subtype. The study will assess the quality of the CTL response, together with related parameters, such as viral load and diversity, HLA type, and, in the case of superinfection, the recognised CTL epitopes in the strains causing the initial infection and superinfection, respectively. A high-risk cohort in Tanzania exposed to HIV-1 subtypes A, C, and D will provide the clinical materials for evaluation. After three years of longitudinal follow-up, 30 individuals in each of the three categories will be studied: highly exposed uninfected, persistently singly infected and superinfected. Definition of protective CTL responses, and a direct evaluation of cross-subtype immunity, will guide the design and evaluation of candidate vaccines in the region. Infrastructure and personnel development in Tanzania during this project will also materially support preparation for candidate vaccine evaluation.

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