Fc gamma Receptor Polymorphisms and Risk of HIV Infection
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Many cells of the immune system, including natural killer cells, macrophages, and dendritic cells, have receptors for the Fc part of antibody. These Fc receptors (FcRs) mediate many of the functions of IgG antibody including ingestion and degradation of virus, killing of virus-infected cells, and presentation of viral peptides to cytotoxic T lymphocytes. Infectious virus can also use the FcRs to enter and infect susceptible cells. Two FcRs, known as Fc gamma RIIa and Fc gamma RIIIa are encoded by genes having two different alleles. In the case of Fc gamma RIIa, one allele results in a histidine (H) and the other in an arginine (R) in the part of the receptor that serves to bind the antibody. Thus, individuals can have receptors with two Hs (HH genotype), with two Rs (RR genotype) or with one H and one R (RH genotype). IgG antibody binds best to individuals with HH receptors, intermediately to RH receptors, and poorest to RR receptors. A similar polymorphism occurs for Fc gamma RIIIa, resulting in either a valine (V) or phenylalanine (F); the VV genotype demonstrates the highest binding to IgG antibody, FF the poorest, and FV intermediate binding. We determined Fc gamma RIIa and IIIa genotypes of participants in a vaccine trial (VaxGen 004) and found that: 1) placebo recipients who had two Fc gamma RIIa H alleles and two IIIa V alleles (i.e., HHVVs) had a lower risk of HIV infection than placebo recipients with other Fc gamma RIIa/IIIa genotypes and; 2) vaccine recipients with the Fc gamma RIIIa VV genotype, including HHVVs, had a higher risk than vaccinees with other genotypes. Infection risk in HHVVs was 12.8 times higher for vaccinees than placebo recipients. Given the vast implications for HIV vaccines, it is imperative that these findings be confirmed. Using subjects from the Multicenter AIDS Cohort Study (MACS), we will investigate the apparent protective effect of the HHVV genotype. We will also develop assays to measure the effect of Fc gamma R genotypes on HIV-1 replication. Our long-term goal is to inform vaccine development by elucidating how antibody-Fc gamma R interactions impact HIV infection. We will test two hypotheses: 1) in the absence of pre-existing anti-HIV antibody, the HHVV genotype is more common among uninfected individuals than among infected individuals; and 2) relationships between Fc gamma R polymorphisms and HIV infection can be modeled in the test tube. Specific aims are: 1. Determine Fc gamma RIIa and IIIa genotypes of infected and uninfected men in the MACS. Polymerase chain reaction (PCR) will be used to genotype 560 infected and 560 uninfected men; and 2) Develop in vitro models of Fc gamma R genotype-dependent differences in HIV-1 replication. Macrophages and dendritic cells expressing the different forms of Fc gamma RIIa and IIIa will be used in direct infection and transfer assays. Delineating the impact of Fc gamma R polymorphisms on infection risk and developing systems to model genotype dependency will be critical to understanding early events in HIV infection, lead to improved vaccination strategies that take advantage of Fc gamma R biology, and provide ways to avoid future harm.