R01AI165079

Targeting Siglec-9/Sialoglycan Interactions to Enhance NK Functions During HIV Infection - Project Summary:

The functions of natural killer (NK) cells can be influenced by the cell-surface glycosylation of their target cells. A subset of CD56dim NK cells expresses the sialic acid-binding protein Siglec-9. This subset has a high cytolytic activity; however, Siglec-9 itself is an inhibitory receptor that restrains the cytolytic ability of this otherwise highly cytotoxic population. Harnessing the cytotoxic capacity of this population has not been evaluated as an approach for eradicating HIV.

In our preliminary studies, focusing first on NK cells, we found that levels of Siglec-9+ CD56dim NK cells inversely correlate with CD4+ T cell-associated HIV DNA during antiretroviral therapy (ART)-suppressed HIV infection. Furthermore, Siglec-9+ CD56dim NK cells exhibited higher cytotoxicity towards HIV+ cells compared to Siglec-9- NK cells. These data are consistent with the highly cytotoxic nature of the Siglec-9+ NK cells. However, consistent with the known inhibitory function of the Siglec-9 molecule itself, blocking Siglec-9 enhanced NK cells' ability to kill HIV+ cells in vitro.

Focusing next on target cells, we found that HIV latently-infected CD4+ T cells exhibit high levels of the Siglec-9 ligand, A2-3 sialic acid, compared to HIV productively-infected or uninfected cells. We also developed a novel approach to block Siglec/sialic acid interactions during HIV infection by conjugating sialidase (enzyme that cleaves sialic acid) to four HIV broadly neutralizing antibodies (BNABs). These conjugates (in hand) can be used in conjunction with drugs that reactivate HIV latently-infected cells to achieve a functional HIV cure. We pilot tested one of these conjugates and found it able to selectively desialylate the surface of HIV+ cells and enhance NK capacity to kill these infected cells in vitro.

Together, our data support our central hypothesis that Siglec/sialoglycan interactions contribute to the ability of HIV-infected cells to evade NK immune surveillance and that blocking these interactions, via selective desialylation of HIV-infected cells, will enhance the capacity of NK cells to clear HIV-infected cells.

Aim 1: We will test the hypothesis that Siglec-9/sialic acid interactions contribute to the ability of HIV latently-infected cells to evade NK immune surveillance. In (1A), we will determine the role of Siglec-9 in the ability of NK cells to kill HIV+ cells, and in (1B), we will determine the role of A2-3 sialic acid in the ability of HIV latently-infected CD4+ T cells to evade killing by NK cells.

Aim 2: We will test the hypothesis that HIV BNAB-sialidase conjugates reduce the size of the HIV reservoir (2A) in vitro and (2B) ex vivo, and (2C) delay viral rebound in vivo using a modified version of the splenic-injected primary HIV-infected reservoir (SPHIR-IL15) non-fetal humanized mouse model with high NK longevity. We will also confirm the mechanism by which BNAB-sialidase conjugates enhance NK cell antiviral function by examining the role of Fc-mediated functions and Siglec-binding in NK targeting.

Our interdisciplinary approach is taking advantage of recent advances in the emerging field of glyco-immunology to enhance NK cell capacity to kill HIV+ cells in ART-suppressed individuals. Our goal is to provide a novel mechanism and approach that can be harnessed to functionally cure HIV infection.

Northwestern University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Chicago, Illinois 60611 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 410% from $616,815 to $3,144,475.