Our overall strategy in Focus #2 is harnessing CD4+ T cell responses for long-term protective immunity against HIV. This is based on the study of follicular CD4+ T helper (Tfh) cells to gain knowledge that will assist in the design of immunogens and immunization strategies that favor the elicitation of protective broadly neutralizing antibodies. In addition, we will investigate CD4+ T cells for other potential anti-HIV roles, direct cytoxicity and help to CD8+ T cells, that may be exploited through vaccination. As we learn valuable lessons from these T cell studies, they will feed back into Focus #1, most particularly into the evaluation of novel immunogens and immunization strategies.
In the CD4+ T cell area, Tfh cells are newly recognized and have an important role in providing optimal help to B cells. Thus, there is a great untapped potential that may give a major boost to immunogen design and immunization strategies.
1. Develop tools to accurately identify and functionally characterize HIV-specific Tfh cells in humans. It is critical to be able to identify and track HIV-specific Tfh cells to understand their role in the development of bnAb responses in HIV infected humans, (2) quantify Tfh cells elicited by candidate HIV vaccines, and understand and manipulate Tfh cell functions in HIV-specific immune responses. It will be necessary to understand how a human immune response can generate an HIV bnAb response and the characteristics of successful Tfh and B cell responses to pathogens. The ability to track antigen-specific Tfh cells in peripheral blood would be an enormous advantage as a tool in vaccine trials.
2. Describe the mechanisms of Tfh cell generation and identify adjuvants that optimally elicit Tfh cells and potent B cell responses in the context of HIV Env immunization. The identification of Tfh cell activation and differentiation signals will be important for rational vaccine design. This knowledge can then be used to validate Tfh differentiation adjuvants in the context of candidate vaccines.
3. Determine the relationships between Tfh cell specificity and anatomic distribution for control of HIV. It is important to determine the anatomic locations of HIV-specific Tfh cells in the context of natural infection and candidate vaccines to determine their role in mediating systemic humoral immunity and mucosal humoral immunity. The protein specificity of the CD4 T cell responses and in what form B cells see functional Env spikes are critical issues to resolve.
4. Identify effector mechanisms of HIV-specific CD4+ T cells and define their role in viral control at the portal of entry. Small founder populations of HIV infected cells are necessary to establish mucosal transmission, which may offer a window of opportunity for cellular immunity to prevent viral dissemination. Studies of the early kinetics of the T cell will determine whether an initial influx of virus- specific CD4+ T cells precedes robust CD8 or CD4 CTL responses and correlates with early containment.