This new grant application is in response to the ?Martin Delaney Collaboratories for HIV Cure Research (UM1)? RFA. We call our application ?BELIEVE?, short for ?Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication?. One individual, known as the ?Berlin patient?, is considered to be cured of HIV, with no evidence for active replication competent virus in the absence of antiretroviral (ARV) therapy. The ?Mississippi? baby initially appeared to be another cure, but virus re-emerged a couple of years after ARV cessation. ARV therapy prolongs life, but a life expectancy gap shows patients on viral suppressive therapies live a shorter life, and have more co-morbidities. To help end the epidemic, an HIV cure is needed. Current ?shock and kill? strategies are limited in harnessing the power of immunity in seeking and removing latent cells. Augmentation of immunity could be performed through vaccination, although therapeutic vaccination in HIV infection has had limited efficacy to date. In addition, immune effectors in HIV infected persons are not fully recovered with ARV treatment. There are at least three mechanisms which lead to the inability of the immune system to remove virus completely: (1) a weakened and exhausted cytotoxic T- lymphocyte (CTL) response from which epitope escape has occurred, (2) over activated but under performing Natural Killer cells, and (3) inability of effector cells to reach the right sites where latent virus reside. Our proposal has objectives, broadly defined, that are aimed at understanding how to enhance the killing ability of HIV specific cytotoxic T lymphocytes, to augment NK cell functions, and to harness T-cell, NK cell and antibody mediated effectors in the context of adult and pediatric HIV infections. First, we will immediately initiate a pilot clinical study with our most promising combination of T-cell infusion and latency-reversing agents. We will compare this combination to enhanced natural and engineered T-cells to eradicate HIV reservoirs (in vitro, in mice, in non-human primates, and in additional human clinical studies), in association with novel HIV Nef small molecule inhibitors. Second, we will develop and test enhanced Natural Killer cells with or without broadly neutralizing antibodies (in mice, in non human primates, and in humans). Third, we will target sites of viral latency which CTL cannot reach, by targeting CTL to home to reservoir sites. We have gathered a group of accomplished investigators, with strong collaborative histories, along with community advisors. Around 40% of the scientific leadership positions are women, and there are representatives of early stage and minority investigators, and two corporate partners, all driven by the belief that a cure will depend on enhancing anti-HIV immunity in association with latency reversal.

Public Health Relevance

We hypothesize that enhancing patients' autologous lymphocytes ex vivo and and re-infusing them, along with latency reversing agents, and specific targeting to sites where latent virus resides, could lead to eradication of latently infected cells and potentially a cure for HIV infected patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
5UM1AI126617-02
Application #
9315726
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Kuo, Lillian S
Project Start
2016-07-14
Project End
2018-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
George Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Webb, Gabriela M; Li, Shengbin; Mwakalundwa, Gwantwa et al. (2018) The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles. Blood Adv 2:76-84
Huang, Szu-Han; Ren, Yanqin; Thomas, Allison S et al. (2018) Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells. J Clin Invest 128:876-889
Ogunshola, Funsho; Anmole, Gursev; Miller, Rachel L et al. (2018) Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants. Nat Commun 9:5023
Colonna, Lucrezia; Peterson, Christopher W; Schell, John B et al. (2018) Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation. Nat Commun 9:4438
Clutton, Genevieve Tyndale; Jones, R Brad (2018) Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure. Front Immunol 9:1452
Natesampillai, Sekar; Cummins, Nathan W; Nie, Zilin et al. (2018) HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome. J Virol 92:
Barrett, A John; Prockop, Susan; Bollard, Catherine M (2018) Reprint of: Virus-Specific T Cells: Broadening Applicability. Biol Blood Marrow Transplant 24:S1-S6
Bronnimann, Matthew P; Skinner, Pamela J; Connick, Elizabeth (2018) The B-Cell Follicle in HIV Infection: Barrier to a Cure. Front Immunol 9:20
Moroco, Jamie A; Alvarado, John Jeff; Staudt, Ryan P et al. (2018) Remodeling of HIV-1 Nef Structure by Src-Family Kinase Binding. J Mol Biol 430:310-321
Jones, Bradley R; Kinloch, Natalie N; Horacsek, Joshua et al. (2018) Phylogenetic approach to recover integration dates of latent HIV sequences within-host. Proc Natl Acad Sci U S A 115:E8958-E8967

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