Abstract
Macaques are a potentially useful non-human primate model to compare memory T-cell immunity to acute virus pathogens such as influenza virus and effector T-cell responses to chronic viral pathogens such as SIV. However, immunological reagents to study influenza CD8+ T-cell responses in the macaque model are limited. We recently developed an influenza-SIV vaccination model of pigtail macaques (Macaca nemestrina) and used this to study both influenza-specific and SIV-specific CD8+ T-cells in 39 pigtail macaques expressing the common Mane-A*10+ (Mane-A01*084) MHC-I allele. To perform comparative studies between influenza and SIV responses a common influenza nucleoprotein-specific CD8+ T-cell response was mapped to a minimal epitope (termed RA9), MHC-restricted to Mane-A*10 and an MHC tetramer developed to study this response. Influenza-specific memory CD8+ T-cell response maintained a highly functional profile in terms of multitude of effector molecule expression (CD107a, IFN-γ, TNF-α, MIP-1β and IL-2) and showed high avidity even in the setting of SIV infection. In contrast, within weeks following active SIV infection, SIV-specific CD8+ effector T-cells expressed fewer cytokines/degranulation markers and had a lower avidity compared to influenza specific CD8+ T-cells. Further, the influenza specific memory CD8 T-cell response retained stable expression of the exhaustion marker programmed death-marker-1 (PD-1) and co-stimulatory molecule CD28 following infection with SIV. This contrasted with the effector SIV-specific CD8+ T-cells following SIV infection which expressed significantly higher amounts of PD-1 and lower amounts of CD28. Our results suggest that strategies to maintain a more functional CD8+ T-cell response, profile may assist in controlling HIV disease.
Highlights
IntroductionCD8 T cell responses partially control viral replication in both the acute and chronic phase of HIV and SIV infections
Chronic viral pathogens such as HIV pose a major challenge to immune control
Improved primate models are needed to directly compare CD8 T cell immunity that assist in resolving acute viral pathogens and CD8+ T cell immunity that fails to resolve chronic viral pathogens within the one host
Summary
CD8 T cell responses partially control viral replication in both the acute and chronic phase of HIV and SIV infections. Evidence demonstrating the partial role of CD8 T cells in HIV/SIV include: depletion of CD8 T-cells in SIV-infected macaques increasing viral replication [1,2,3,4], control of viral replication coinciding with the expansion of HIV/SIV-specific CD8 T cells [5,6], immune pressure exerted by CD8 T cells leads to viral escape [7] and MHC alleles such as HLA-B*57 and HLAB*27 being overrepresented long term non-progressor subjects [8,9,10,11]. Recent studies have included the measurements of quality and avidity. HIV-specific CD8 T cells present during chronic infection tend to express an ‘‘exhausted’’ phenotype with high PD-1 and low CD28 expression and are unable to proliferate in response to high concentrations of antigen [22,23,24,25,26]
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