Type

Range

Units

Status

Start Date

End Date

Financing

Keywords

Brief description/objective

Rationale: Accumulating evidence underlines the importance of a functional highly avid CD8+ HIV-specific T-cell response in the initial containment of human immunodeficiency virus (HIV) infection. During the time course of infection HIV-specific but also T-cell responses directed towards other persistent infections and recall antigens are functionally impaired or lost. Nevertheless it is still a matter of debate whether CD8+ T-cell functionality can be restored after highly active antiretroviral therapy (HAART) initiation. Recently published observations imply an important role of the time of treatment initiation (reflected by CD4-nadir) in the preservation of a functional cellular immune response. Furthermore preserved HIV-specific CD8+ T-cell responses directed towards viral immune escape polymorphisms may play an important role in persistent viral containment even in the HAART area.

Hypothesis: HAART-initiation at an earlier time point at a higher CD4-nadir will preserve HIV- & recall antigen-specific, and elicit de novo CD8+ T-cell response of high functional avidity directed towards wild-type epitopes and epitope polymorphisms.

Methods: In this preliminary observational cross-sectional pilot study we will describe in detail the HIV- and cytomegalovirus (CMV)- and influenza (A/H1N1 2009)- specific CD8+ T-cell response in HIV-infected patients with fully suppressed HI-viral load under HAART stratified by CD4-nadir <100 and >400 CD4 cells/μl. In particular the focus will be the assessment of the functional CD8+ T-cell avidity dependent on CD4-nadir evaluated by affinity-modified tetramer technology in wild-type (consensus) and newly emerged CD8+ T-cell responses elicited by epitope polymorphisms.

Significance: The proposed project will enhance our understanding of the mechanisms leading to the preservation of functional immune responses against HIV and other persistent viruses dependent on HAART-initiation. The findings will provide some immunological evidence guiding the recommendations of HAART-initiation and guide the set-up of a larger study not only evaluating the HIV-specific immune responses but also the responses to other persistent infections – e.g. hepatitis C – and its clinical implications.