R01AI162094

Neutralizing antibody responses during natural control of acute hepatitis B with and without HIV-1 coinfection - Summary

This proposal aims to understand the effects of HIV on the humoral immune response to hepatitis B by focusing on HBV-specific neutralizing antibodies (NAB), B cell repertoire, and monoclonal antibodies that develop after an acute hepatitis B infection.

This proposal will study 185 men (74 HIV+) in the MACS-WIHS combined cohort study who had acute hepatitis B while in follow-up and whose outcome of either natural recovery (N=163) or viral persistence (N=22) was previously determined.

The first aim focuses on comparing the prevalence and magnitude of the anti-HBS NAB responses over 30 months after natural control of an acute HBV infection in people living with and without HIV. We hypothesize that in persons living with HIV (PLWH), the NAB responses will be weaker and less durable than in persons without HIV infection. Decreased durability of NAB responses could contribute to the increased risk of HBV reactivation with HIV infection.

In the second aim, we will tag HBV specific B cells isolated from participants' specimens obtained during their acute infection period. We will then determine and compare the molecular features of HBV-specific B cell receptors during the acute infection period between those with natural recovery and those who develop chronic hepatitis B. We will also determine the effects of HIV on these molecular features and on frequency of B cells specific for HBV.

In the third aim, we will clone monoclonal antibodies (MABS) from these HBV-specific B cells and determine the MABS' functional characteristics and binding affinities. We expect that the MABS from persons with natural recovery will bind with higher affinity and neutralize more potently than those who develop chronic infection. We also expect that HIV will decrease the affinity and potency of the MABS.

Innovative aspects of this project include: 1) the unique cohort of a large number of incident HBV infections where both natural recovery and viral persistence occur in prospectively-followed people living with and without HIV infection, 2) the ability to detect NAB responses in plasma from human subjects using the HEPG2-NTCP infection model system, and 3) the ability to isolate HBV-specific B cells for ex vivo study. To date, such studies have not been possible explaining why there is little information on NAB responses to HBV obtained directly from infected humans.

The results from this proposal will contribute to our understanding of the effects of HIV on the immune response to hepatitis B and could facilitate future research to develop a functional cure for hepatitis B, which is the leading cause of cirrhosis and hepatocellular carcinoma worldwide.

The Johns Hopkins 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]

Baltimore, Maryland 212051832 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 316% from $766,615 to $3,186,484.