R01AI172843

Antibody Dependent Cellular Cytotoxicity and HIV-1 Mother to Child Transmission - Project Summary

Over 150,000 infants acquire HIV-1 from their infected mothers primarily because combination antiretroviral treatment (CART) remains inaccessible in some populations. Surprisingly, even in the absence of CART, only around 20 – 30% of infants get HIV-1 from their mother, although they are constantly exposed to the virus during gestation, birth, and breastfeeding.

Immune factors, such as maternal antibodies, likely prevent transmission. Mother to child transmission (MTCT) cohorts are an ideal way to examine the impact of pre-existing antibodies in preventing HIV-1 transmission in a natural setting because: 1) infants are reliably exposed to the virus; 2) mothers pass their antibodies to the infant; and 3) samples can be obtained from both the mother and the infant prior to and after transmission.

Understanding the role of and the types of antibodies that can prevent HIV-1 transmission remains one of the highest priorities, especially for vaccine efforts. In contrast to all animal models, MTCT investigations and antibody passive infusion clinical trials demonstrate that pre-existing neutralizing antibodies (NAbs) do not provide significant protection against HIV-1 transmission.

The major difference among animal models and HIV-1 transmission is that humans are exposed to a diverse swarm of HIV-1 variants, and some of the strains are neutralization resistant. In settings where the exposed individual already possesses NAbs, they acquire neutralization resistant variants. In contrast, we show that infants with pre-existing antibody dependent cellular cytotoxicity (ADCC) against their mother's neutralization resistant strains are less likely to acquire HIV-1, and they have lower morbidity up to 1 year after birth in the absence of CART.

We have further observed that transmission depends on both the preexisting ADCC breadth and potency in the naïve exposed infant and the ADCC sensitivity of the variants circulating in the maternal variants (exposure strains). We propose to provide more definitive support for the importance of ADCC during MTCT by exploring if newly infected infants acquire ADCC resistant strains. We will further identify host factors and virus characteristics that influence ADCC breadth and potency and ADCC susceptibility.

We further hypothesize that ADCC present in infected infants can eliminate cells with infectious virus that can produce virus. Infants with higher ADCC against their autologous virus have a lower number of residual infected cells. A smaller number of infected cells results in lower viremia and plasma inflammation, which decreases morbidity and mortality in the absence of CART.

Finally, we will use state-of-the-art techniques to isolate and characterize broad and potent ADCC antibodies. These studies will provide insights about the characteristics of these antibodies and the potential novel ways to elicit them using state-of-the-art vaccine methodologies.

The proposed studies will provide clarity about the selection pressure ADCC exerts during transmission, highlight how pre-existing ADCC decreases mortality, and lead to the generation of novel protective antibodies. Cumulatively, this work will provide new strategies for developing an effective HIV-1 vaccine.

Boston Medical Center Corporation

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]

Boston, Massachusetts 021182908 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 402% from $699,829 to $3,515,485.