New Biomarker Predicts Likelihood of HIV Patients to Develop Fungal Meningitis

A specific genotype has been identified as a potential biomarker for the likelihood of HIV patients to develop fungal meningitis (cryptococcal disease or CD) from infection by Cryptococcus neoformans.

Cryptococcus neoformans is one of the most common causes of fungal disease in HIV-infected persons due to their low levels of CD4+ T-cells, but not all of those who are infected with C. neoformans develop meningitis.

Although CD4+ T-cell deficiency is a risk factor for HIV-associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, investigators at the Albert Einstein College of Medicine (New York, NY, USA) performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study. These samples included 55 from patients infected with HIV who developed CD and matched control groups of 54 patients who were HIV-infected and 55 men who were HIV-uninfected.

Results of the study revealed that after correcting for demographic factors and T-cell counts, a strong association was found between the gene for the high-affinity FCGR3A 158V allele and the risk of CD in the HIV-infected men.

In binding studies, human IgG (hIgG)-C. neoformans complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F. In cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more C. neoformans-infected monocyte cytotoxicity than those expressing FCGR3A 158F.

"We found that this high affinity Fc receptor polymorphism was very highly overrepresented in the patients that got cryptococcal disease," said senior author Dr. Liise-anne Pirofski, professor of microbiology and immunology at the Albert Einstein College of Medicine. "Patients with two copies of the high affinity Fc receptor gene had an almost 20-fold increased risk of contracting the disease. It is surprising that a receptor involved with a higher capacity to bind immune complexes would be associated with susceptibility in patients with HIV, since phagocytosis of immune complexes is thought of as a mechanism for fighting invading microorganisms."

"This could be the beginning of a predictive test, at least in high-risk people," said Dr. Pirofski. "I think that we are ready to study this receptor further as a risk factor for disease in larger cohorts."

The study was published in the August 27, 2013, online edition of the journal mBio.

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