In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a 
predominant cause of AIDS-related mortality. Understanding virulence and 
improving clinical treatments remain important. To characterize the role of the 
fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus 
isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 
nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans 
var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was 
used to characterize genotypes, yielding 15 sequence types and 4 clonal 
clusters. The largest clonal cluster consisted of 74 isolates. The results of 
Burst and phylogenetic analysis suggested that the C. neoformans var. grubii 
strains could be separated into three nonredundant evolutionary groups (Burst 
group 1 to group 3). Patient mortality was differentially associated with the 
different evolutionary groups (P = 0.04), with the highest mortality observed 
among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 
3 strains, Burst group 1 strains were associated with higher mortality (P = 
0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more 
pronounced Th(2) response during ex vivo cytokine release assays with 
strain-specific capsule stimulation (P = 0.02). The results of these analyses 
suggest that cryptococcal strain variation can be an important determinant of 
human immune responses and mortality.
IMPORTANCE: Cryptococcus neoformans is a common life-threatening human fungal 
pathogen that is responsible for an estimated 1 million cases of meningitis in 
HIV-infected patients annually. Virulence factors that are important in human 
disease have been identified, yet the impacts of the fungal strain genotype on 
virulence and outcomes of human infection remain poorly understood. Using an 
analysis of strain variation based on in vitro assays and clinical data from 
Ugandans living with AIDS and cryptococcal infection, we report that strain 
genotype predicts the type of immune response and mortality risk. These studies 
suggest that knowledge of the strain genotype during human infections could be 
used to predict disease outcomes and lead to improved treatment approaches aimed 
at targeting the specific combination of pathogen virulence and host response.