Although HIV-1 can induce strong antigen-specific T- and B-cells in almost all infected individuals, most of these adaptive immune responses are not protective against HIV-1 disease progression. Only in the very rare cases of """"""""elite controllers"""""""", effective T cell immune activity against HIV-1 is generated that can effectively block HIV-1 replication to undetectable levels. Similarly, B-cell responses that are able to broadly neutralize the majority of circulating viral species and effectively prevent HIV-1 transmission in animal models only emerge in a very small number of individuals. Yet, the mechanisms that support induction of such effective T- and B-cell immune responses in this small number of infected individuals, but not in the majority of alternative patients, are largely unclear. Dendritic cells (DCs) represent the most effective naturally-occurring antigen-presenting cells with critical roles for inducing antigen-specific T cell responses, and their decisive impact on the evolution of humoral immune responses is also increasingly being recognized. However, specific functional characteristics of DCs that are instrumental in generating protective HIV-1-specific T- and B- cell responses are unclear, despite the fact that almost all HIV-1 vaccine candidates rely on DCs for induction of adaptive immune responses. This application seeks to explore such mechanisms using a panel of novel, interdisciplinary methodological approaches.
In specific aim 1, we propose to investigate the immunogenetic network between HLA class I molecules and Leukocyte Immunoglobulin-Like Receptors (LILR), a group of immunomodulatory MHC class I receptors expressed on DCs. We hypothesize that specific combinations of HLA class I and LILR allotypes result in improved functional activities of DCs, and their abilities to generate protective immune responses against HIV-1.
In specific aim 2, we will explore cell-intrinsic immune responses against HIV-1 infection in DCs from elite controllers, and evaluate the influence of such innate immune activity on the function of ensuing HIV-1-specific T cell responses. These investigations are based on a large set of preliminary data demonstrating unique abilities of DCs from these patients to mount cell-intrinsic type I interferon responses against HIV-1, and may reveal a previously unrecognized network between innate and adaptive immune mechanisms in DCs that is critical for the induction of highly-protective HIV-1-specific T cell responses.
In specific aim 3, we will explore functional properties of DCs in the small number of individuals who naturally develop broadly-neutralizing antibodies (bNAb)/neutralizing breadth (NB) against HIV-1, and investigate molecular signals in DCs that support bNAb/NB development through priming of specific populations of T follicular helper cell responses. By identifying specific functional aspects of DCs that are critical for the generation of effective immune responses against HIV-1 during natural infection, this work will contribute to the design of strategies to induce such immune responses in larger patient populations.

Public Health Relevance

Effective T- and B-cell immune responses against HIV-1 are only generated in a small number of patients during natural infection, for reasons that remain unknown. Here, we propose to investigate functional characteristics of dendritic cells that support the development of such immune responses, which may critically help to induce such immune responses in broader patient populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI078799-06A1
Application #
8732047
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Stansell, Elizabeth H
Project Start
2008-04-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Martin-Gayo, Enrique; Buzon, Maria Jose; Ouyang, Zhengyu et al. (2015) Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers. PLoS Pathog 11:e1004930
Vigano, Selena; Negron, Jordi; Ouyang, Zhengyu et al. (2015) Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties. J Virol 89:7829-40
Buzon, Maria J; Martin-Gayo, Enrique; Pereyra, Florencia et al. (2014) Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells. J Virol 88:10056-65
Leng, Jin; Ho, Hsin-Pin; Buzon, Maria J et al. (2014) A cell-intrinsic inhibitor of HIV-1 reverse transcription in CD4(+) T cells from elite controllers. Cell Host Microbe 15:717-28
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Bashirova, Arman A; Martin-Gayo, Enrique; Jones, Des C et al. (2014) LILRB2 interaction with HLA class I correlates with control of HIV-1 infection. PLoS Genet 10:e1004196
Walker, Bruce D; Yu, Xu G (2013) Unravelling the mechanisms of durable control of HIV-1. Nat Rev Immunol 13:487-98
Li, Chun; Toth, Ilona; Schulze Zur Wiesch, Julian et al. (2013) Functional characterization of HLA-G⁺ regulatory T cells in HIV-1 infection. PLoS Pathog 9:e1003140
Huang, Jinghe; Al-Mozaini, Maha; Rogich, Jerome et al. (2012) Systemic inhibition of myeloid dendritic cells by circulating HLA class I molecules in HIV-1 infection. Retrovirology 9:11
Yang, Yue; Al-Mozaini, Maha; Buzon, Maria J et al. (2012) CD4 T-cell regeneration in HIV-1 elite controllers. AIDS 26:701-6

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