Modulation of HIV immune control by HLA-E-VL9 and HLA-E-VL9 binding antibodies

. Introduction: HLA-E is a non-classical HLA class Ib molecule, which like classical HLA class Ia (HLA-A/B/C) presents intracellular virus-derived peptides. Unlike class Ia molecules, HLA-E is limited in polymorphisms and has an additional major role in presenting a conserved self peptide “VL9” that is derived from the leader sequence of other HLA molecules. HLA-E in complex with VL9 (HLA-E-VL9) binds the inhibitory receptor NKG2A on a subset of natural killer (NK) and CD8+ T cells, downmodulating their cytotoxicity. The Haynes Lab discovered HLA-E-VL9 binding B cells among the natural antibody pool of mice and humans and used these as substrates to develop the first HLA-E-VL9 high-affinity antibodies. I have demonstrated that high affinity HLA-E-VL9 specific antibodies can mediate checkpoint release of NK and CD8+ T cell killing of HLA-E-VL9 overexpressing targets and, as well, mediate NK antibody-dependent cellular cytotoxicity. Furthermore, I demonstrated for the first time that HLA-E-VL9 is expressed on the HIV-infected cell surface. I hypothesize that HLA-E-VL9 expression mediates HIV-1 evasion from NKG2A+ NK and T cells, and that this inhibition can be countered by anti-HLA-E- VL9 antibodies derived from the natural antibody repertoire. Research: In Aim 1, I will determine functional consequences of HLA-E-VL9 expression on HIV-infected CD4+ T cells on NK/T cell killing of HIV-infected target cells. In Aim 2 , I will evaluate the role of endogenous HLA-E- VL9/Mamu-E-VL9 binding antibodies in responding to retroviral infection. Training: I will continue my training with Dr. Haynes at Duke University to further my skillsets in assessing immune responses from human and non-human primate samples, and as well, fill gaps in my skillsets with regard to T cell functional assays and complex NK phenotyping. With co-mentor Dr. Azoitei at Duke University, I will develop new skillsets in structural antibody modelling and engineering. I will also pursue training in scientific writing, effective collaboration, and laboratory management, to further facilitate my success as an independent investigator. Environment: The Duke Human Vaccine Institute (DHVI) is a well-resourced, collaborative, and productive environment in which to train in translational immunology. Both the DHVI and Duke University are committed to the success of early stage investigators. I have assembled a mentoring team of advisors and collaborators who are leaders in the fields of probing immune function and regulation and HLA biology. Impact on Public Health. The results of this work will define strategies to safely harness HLA-E-VL9 mediated enhancement of NK and CD8+ T cell activity to inform the development of a new anti-viral or anti-cancer immunotherapy, and yield new insights into mechanisms of viral evasion and roles of the natural antibody pool. Project Number: 1K99AI197913-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Joyce Hwang | Institution: DUKE UNIVERSITY, DURHAM, NC | Award Amount: $106,164 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 IIDA-R (83)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99AI19791301