FcγRIIa Genotype Predicts Progression of HIV Infection

Abstract

Polymorphisms in FcγR genes are associated with susceptibility to or severity of a number of autoimmune and infectious diseases. We found that HIV-infected men in the Multicenter AIDS Cohort Study with the FcγRIIa RR genotype progressed to a CD4+ cell count of <200/mm3 at a faster rate than individuals with the RH or HH genotypes (relative hazard = 1.6; p = 0.0001). However, progression to AIDS (using the broad definition of either a CD4+ cell count <200/mm3 or development of an AIDS-defining illness) was less impacted by FcγRIIa genotype, largely because HH homozygotes had an increased risk of Pneumocystis jiroveci pneumonia as an AIDS-defining illness. We also showed that chronically infected subjects develop a substantial anti-gp120-specific IgG2 response. Moreover, HIV-1 immune complexes are more efficiently internalized by monocytes from HH subjects compared with RR subjects, likely because of the presence of IgG2 in the complexes. Finally, the FcγRIIIa F/V gene polymorphism was not associated with progression of HIV infection, but, as demonstrated previously, did predict the risk of Kaposi’s sarcoma. These results demonstrate the importance of FcγRs in AIDS pathogenesis and point toward a critical role for interactions between FcγRs and immune complexes in disease progression.

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

“…Two groups separately demonstrated that HIV-infected subjects carrying a CD16 polymorphism, which increases the IgG binding of the receptor and enhances the NK cell ADCC potential (50), exhibit faster disease progression (51,52). It should be noted that an additional study by Forthal et al (53) did not observe an effect of CD16 polymorphisms on HIV disease progression. However, studies revealing a potential role for CD16 polymorphisms in HIV disease progression, in combination with the current study and other studies showing alterations in NK cell phenotype and functional potential as a result of activation through CD16 (26,29), suggest that a critical reassessment of the role of ADCC in chronic HIV infection is essential.…”

FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial

“…Aberrant expression or the presence of certain allelic variations of FcγRs is associated with altered functionality that in turn is associated with susceptibility to, or increased severity of, certain autoimmune and infectious diseases and to outcomes of monoclonal Ab cancer treatments (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Besides IgG Abs, IgA Abs also play an important role in humoral immunity.…”

Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

“…In contrast, less is known about the role of Fc-mediated effector function in the control of HIV-1, although four lines of evidence signal its importance. First, studies in HIV-1-infected people (8)(9)(10)(11)(12)(13)(14) and in macaques infected with simian immunodeficiency virus (15,16) consistently show an inverse correlation between Fc-mediated effector functions, including antibody-dependent cell-mediated cytotoxicity (ADCC) (8,9) or antibody-dependent cell-mediated viral inhibition (ADCVI), and viral loads or decreased disease progression (17). Second, vaccine-elicited protection both in nonhuman primates (18)(19)(20)(21) and in a subset of human subjects in the Vax-004 trial (22) correlates with Fc-mediated effector function often observed in the absence of detectable neutralizing antibodies (18)(19)(20)(21).…”