Toward Identification of the Genetic Risk Profile for Cryptococcal Disease in HIV-Infected Patients

Cryptococcus spp. are important fungal pathogens that represent a major cause of morbidity and mortality in both immunocompetent and immunodeficient patients. Although cryptococcal disease is one of the major causes of death in HIV-infected patients, especially in sub-Saharan Africa, not all patients at risk with low CD4 counts develop the disease. It has been thus hypothesized that host genetic variation may represent an important susceptibility risk factor for this infection. In their recent study in mBio, Rohatgi et al. [S. Rohatgi et al., mBio 4(5):e00573-13, 2013, doi:10.1128/mBio.00573-13] present an important piece of evidence to support this hypothesis, by demonstrating that the FCGR3A 158 F/V polymorphism has an important impact on susceptibility to cryptococcal disease in HIV-infected patients. The authors present both genetic evidence and immunological validation for the hypothesis that humoral immunity in general and FCGR3A-mediated uptake and antibody-dependent cellular cytotoxicity (ADCC) in particular play important roles in the pathogenesis of Cryptococcus infection. Their discovery that the 158V allele of this polymorphism can increase the risk of Cryptococcus infections up to 20-fold in homozygous individuals opens the possibility for risk stratification and personalized treatment of HIV-infected patients.