Epistatic interactions between Fc (GM) and FcγR genes and the host control of human immunodeficiency virus replication

Abstract

Host genetic factors are thought to contribute to the interindividual differences in the control of HIV replication. The aim of the present investigation was to determine whether genes encoding GM and KM allotypes—genetic markers of immunoglobulin γ and κ chains, respectively—and those encoding Fcgamma receptor (FcγR) IIa and IIIa are associated with the host control of HIV replication. A case-control design was employed amongst HIV-infected subjects, with a group that spontaneously controlled HIV replication (“controllers”) as cases (n=73) and those who did not control replication, as controls (n=100). Genotyping was done by PCR-RFLP, direct DNA sequencing, and TaqMan® genotyping assays. In Caucasian Americans, certain combinations of FcγR and GM genotypes were differentially distributed between controllers and non-controllers. Among the non-carriers of FcγRIIa arginine allele, GM21 non-carriers had over seven-fold greater odds of being controllers than the carriers of this allele (OR=7.47). These GM determinants also interacted with FcγRIIIa alleles. Among the carriers of the FcγRIIIa valine allele, GM21 non-carriers had over three-fold greater odds of being controllers than the carriers of this allele (OR=3.26). These results show epistatic interactions of genes on chromosomes 14 (GM) and 1 (FcγR) in influencing the control of HIV replication.

Immunoglobulin genes and the acquisition of HIV infection in a randomized trial of recombinant adenovirus HIV vaccine

“…The nef-induced antibodies could mediate effector functions, such as ADCC. It is relevant to note that we have found interactive effects of particular GM and FcγR genotypes on the control of HIV1 replication (Deepe et al, 2011). …”

Opportunities to Exploit Non-Neutralizing HIV-Specific Antibody Activity

“…Similarly, the H131 allele of FcγRIIa, which exhibits high affinity for IgG2 has been found to be protective against progression in adults(78), but associated with perinatal infection(81), implying that distinct mechanisms of phagocytosis may mediate antiviral activity at different barriers. Complicating matters further, Fc (GM) allotype diversity and Fc R allotype diversity appear to interact, as in a recent genetic study comparing HIV controllers with infected subjects indicated a strong relationship between genetic background and likelihood of spontaneous control(82). …”

The forgotten tale of immunoglobulin allotypes in cancer risk and treatment

“…Using hypothesis driven candidate gene approaches, numerous studies have identified particular GM genes as risk factors for many malignant [9-13], infectious [14-18], and autoimmune diseases [19-24], but most of these findings have not been confirmed or refuted by modern genome-wide association studies (GWAS). One contributing factor might be the absence of GM gene probes in most genotyping platforms.…”