Globally, over 38 million people are infected with HIV. Currently, nearly 70% of all infected individuals now have access to antiretroviral therapy turning what was previously a death sentence to a lifelong chronic disease. Still, this represents a massive financial burden on society, and more importantly a continuous personal and financial burden to those infected and their loved ones. A functional cure for HIV is direly needed to free people from these life-long drug regimens. To this end, my research focuses on harnessing the unique features of Major Histocompatibility Complex (MHC)-E-restricted CD8+ T cells as an immunotherapeutic to achieve HIV remission or a functional cure.

MHC-E-Restricted CD8+ T cells

Typically, CD8+ T cells use their T cell receptors (TCR) to recognize pathogen-infected cells via antigens presented on MHC-Ia molecules. The profound diversity of human MHC-Ia, with over 13,000 distinct molecules identified, in turn drives profound diversity among TCR. Therefore, to any given pathogen, each individual possesses a unique set of pathogen-recognizing TCR. Conversely, MHC-Ib molecule, MHC-E, is nearly monomorphic in the human population. As a consequence, the TCR from an HIV-specific MHC-E-restricted CD8+ T cell could theoretically recognize HIV-infected cells from any HIV infected person. This highlights their potential as a universal immunotherapeutic. However, vital questions remain as to how these cells function:

How are MHC-E-restricted T cells induced?

1. How do MHC-E-restricted CD8+ T cells recognize antigen?
2. Is the TCR necessary and sufficient for antigen recognition?
3. How long do MHC-E-restricted CD8+ T cells persist in vivo?

To address these questions, we utilize rhesus macaques vaccinated with Strain 68-1 RhCMV expressing SIV antigens. This vector induces high frequency MHC-E-restricted CD8+ T cells and has been shown to elicit 50% protection from SIV in vaccinated macaques. This work is critical to further our understanding of these unique CD8+ T cells and this promising vaccine platform.

Ex Vivo Gene Therapy

Ex vivo gene therapy involves altering or correcting the genome of a patient’s cells before re-introducing them back to the patient. Recently, the FDA approved the two first immunotherapies using this approach to express chimeric antigen receptors (CAR) on a patient’s CD8+ T cells to target Non-Hodgkins lymphoma. The power of this approach is within the universal nature of the CAR which targets antigens expressed in all forms of these Non-Hodgkin’s lymphomas. We seek to use the universal nature of MHC-E-restricted TCRs to target HIV. However key questions remain as to how best to use these TCR in vivo to achieve remission:

TCR targeting which HIV antigens will be the most effective?

1. Which HIV reservoir site(s) should be targeted?
2. How long does the infused TCR-altered CD8+ T cell need to persist?
3. How many treatments will be required to see an effect?

For these studies, we will utilize the rhesus macaque model and examine how MHC-E-restricted TCR transduced cells respond and function during various stages of SIV infection. This work will inform how best to utilize MHC-E-restricted TCR as an HIV immunotherapeutic.

BIOGRAPHY

Dr. Abdulhaqq graduated from Philadelphia University (currently Thomas Jefferson University) in 2008 with a B.S. in Biological Science. He received his Ph.D. with an emphasis in Gene Therapy and Vaccines from the Cell & Molecular Biology at the University of Pennsylvania in 2014 with Dr. Luis Montaner. In 2015, he joined Dr. Jonah Sacha's laboratory at the Vaccine & Gene Therapy Institute as a Postdoctoral Researcher. He was promoted to Research Assistant Professor in 2020.

Selected Publications:

1. Abdulhaqq SA, Wu H, Schell JB, Hammond KB, Reed JS, Legasse AW, Axthelm MK, Park BS, Asokan A, Früh, Hansen SG, Picker LJ, Sacha JB. Vaccine-mediated Inhibition of the Transporter Associated with Antigen Processing is Insufficient to Induce MHC-E Restricted CD8+ T cells in Nonhuman Primates. Journal of Virology.  2019 Jul 17. PMID: 31315990
2. Walters LC, Harlos K, Brackenridge S, Rozbesky D, Barrett JR, Jain V, Walter TS, O'Callaghan CA, Borrow P, Toebes M, Hansen SG, Sacha J, Abdulhaqq SA, Greene JM, Früh K, Marshall E, Picker LJ, Jones EY, McMichael AJ, Gillespie GM. Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nature Communications. 2018 Aug 7;9(1):3137. PMCID: PMC6081459

Wu HL, Wiseman RW, Hughes CM, Webb GM, Abdulhaqq SA, Bimber BN, Hammond KB, Reed JS, Gao L, Burwitz BJ, Greene JM, Ferrer F, Legasse AW, Axthelm MK, Park BS, Brackenridge S, Maness NJ, McMichael AJ, Picker LJ, O'Connor DH, Hansen SG, Sacha JB. The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques. Journal of Immunology. 2018 Jan 1. PMCID: PMC5736429