A major scientific challenge in the development of an effective AIDS vaccine is the identification of clear correlates of immunoprotection. An important component in this search is a more thorugh understanding of the functional profile of recombinant vector-based vaccine-induced T cell responses. Our preliminary findings suggest that both the function and the phenotype of vaccine-induced CD4+ and CD8+ T cell responses undergo significant modification following infection. These modifications are more complex than what can be revealed through analysis of IL2 and/or IFN-gamma production and proliferative capacity. In the proposed studies, we hypothesize that the qualitative aspects of both CD4+ and CD8+ T cell functions are similar in vaccinees and acutely infected individuals but rapidly deteriorate following infection.
In Aim 1, we will determine how the functional profile of recombinant vector-based vaccine-induced CD8+ T cell responses (defined as the pattern of cytokine production, ability to degranulate, and to suppress virus replication) will correlate with the functional and proliferative capacity of CD4+ T cell responses. Moreover, we will define the phenotype of poly-functional (IL2+IFN-gamma+TNF-alpha+) vaccine induced CD4+ T cell responses and their susceptibility to HIV-1 infection. We further hypothesize that vaccine-induced CD4 T cell responses are under the control of regulatory T cell (Treg) populations that could selectively influence the functional profile of vaccine-induced CD4+ T cell subsets and their proliferative capacity.
In Aim 2, we will compare function and regulation of vaccinees' T cell responses to those present during chronic viral infection (i.e. HIV and CMV infections). Lastly, in Aim 3, we will identify the tropism for myeloid and plasmacytoid dendritic cells of different recombinant vectors currently used as vaccine candidates. We will also determine how DC-tropism may bias the amplification of antigen-specific T cells with different functional profiles. These studies will provide new insights on poly-functional aspects of vaccine-induced T cell responses, their changes following HIV infection, and how they compare to those induced by chronic viral infection such as those caused by HIV and CMV infections. Moreover, definition of how vaccine-induced T cell responses can be modulated by Treg cell subsets and biased by the DC-tropism of the recombinant vectors could impact the design of future vaccine strategies.
| Frahm, Marc; Goswami, Neela D; Owzar, Kouros et al. (2011) Discriminating between latent and active tuberculosis with multiple biomarker responses. Tuberculosis (Edinb) 91:250-6 |
