Fc gamma Receptor Polymorphisms and Risk of HIV Infection
Donald Forthal, UC Irvine
2006
Fc gamma receptors IIa and IIIa mediate many functions of antibody (Ab) and are encoded by genes with polymorphisms affecting Ab binding. We determined Fc gamma RIIa and IIIa genotypes of participants in a vaccine trial (VaxGen 004) and found that: 1) placebo recipients homozygous for the Fc gamma RIIa H and 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 Fc-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 vitro. Specific aims are: 1. Determine FcγRIIa and IIIa genotypes of infected and uninfected men in the MACS. Allele-specific primers 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 isoforms of Fc gamma RIIa and IIIa will be used in direct infection and transfer assays. Delineating the impact of Fc amma R polymorphisms on infection risk and developing in vitro 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. Fc gamma receptors IIa and IIIa mediate many functions of antibody (Ab) and are encoded by genes with polymorphisms affecting Ab binding. We determined Fc gamma RIIa and IIIa genotypes of participants in a vaccine trial (VaxGen 004) and found that: 1) placebo recipients homozygous for the Fc gamma RIIa H and 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 Fc-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 vitro. Specific aims are: 1. Determine FcγRIIa and IIIa genotypes of infected and uninfected men in the MACS. Allele-specific primers 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 isoforms of Fc gamma RIIa and IIIa will be used in direct infection and transfer assays. Delineating the impact of Fc amma R polymorphisms on infection risk and developing in vitro 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.
