Polymorphisms in FcgammaR 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
FcgammaRIIa RR genotype progressed to a CD4(+) cell count of <200/mm(3) 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/mm(3) or development of an
AIDS-defining illness) was less impacted by
FcgammaRIIa 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 FcgammaRIIIa 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 FcgammaRs in
AIDS pathogenesis and point toward a critical role for interactions between FcgammaRs and
immune complexes in
disease progression.