15th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 3-6, 2008

Conf Retrovir Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 22)

Hendrik Streeck¹, Z Brumme¹, M Anastario², K Cohen¹, J Jolin¹, G Alter¹, A Meier¹, T Allen¹, B Walker¹, and M Altfeld^1
1Partners AIDS Res Ctr, Massachusetts Gen Hosp, Harvard Med Sch, Boston, US and ²Ctr for Disaster and Humantitarian Assistance Med, Univ of the Hlth Sci, Bethesda, MD, US

BACKGROUND: After acute HIV-1 infection CD8+ T cells are responsible for the initial control of viral replication. In later stages CD8+ T cells partly control viral replication but display signs of increasing dysfunction and exhaustion. It remains unclear whether virus-specific CD8+ T cells with a “polyfunctional” profile are more competent in controlling viral replication in chronic infection, or simply a reflection of the level of ongoing viremia.

METHODS: Longitudinal assessment of epitope-specific CD8+ responses by multicolor flow cytometry and longitudinal HIV RNA plasma sequencing of targeted epitopes in 18 subjects with primary HIV-1 Infection. Functional avidity of wild type and variant responses were assessed by interferon-gamma (IFN-γ) ELISpot using serial dilution of respective peptides. PD-1 and CD127 expression was determined on tetramer+ CD8+ T cells.

RESULTS: CD8+ T cells exhibited multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their ability to secrete multiple cytokines and chemokines in response to antigen over time. Epitope-specific CD8+ T cells developed phenotypic signs of exhaustion by up-regulation of PD-1 expression with persistent viremia. This exhausted phenotype was reversible upon removal of stimulation by antigen in response to ART. In addition, the poly-functionality of the epitope-specific CD8+ response was recovered and PD-1 expression decreased even in the presence of ongoing viral replication following in vivo selection of CD8+ T cell escape mutations in the respective epitopes.

CONCLUSIONS: These data suggest that the poly-functionality of CD8+ T cell responses is determined by the persistence of antigen and stress the importance of evaluating autologous viral sequence in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.

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2008-02-03
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