Abstract
Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15–20% of HIV-related mortality. A complication of initiating antiretroviral therapy (ART) following opportunistic infection is immune reconstitution inflammatory syndrome (IRIS). IRIS afflicts 10–30% of HIV-infected patients with cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At meningitis diagnosis, stimulation with cryptococcal capsule component, glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4+ and CD8+ T cell memory subsets expressing intracellular cytokines (IL-2, IFN-γ, and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8+ central memory phenotype. At the onset of CM-IRIS, stimulation more frequently generated polyfunctional IL-2+/IL-17+ CD4+ T cells in patients with CM-IRIS. Moreover, CD8+ central and effector memory T cells from CM-IRIS subjects also demonstrated more robust IL-2 responses to antigenic stimulation vs. controls. Thus, ART during CM elicits distinct differences in T cell cytokine production in response to cryptococcal antigens both prior to and during the development of IRIS, suggesting an immunologic foundation for the development of this morbid complication of CM infection.
Highlights
Cryptococcal meningitis causes 15–20% of AIDS-related mortality worldwide [1]
Baseline CD4 and CD8 T cell counts, cryptococcal antigen (CrAg) titer, HIV viral load, cerebrospinal fluid (CSF) protein, and white blood cells were similar among subjects with cryptococcal meningitis (CM)-immune reconstitution inflammatory syndrome (IRIS) vs. controls (Table 1)
Upon correcting for the cytokine expression in unstimulated samples, we found that mitogen-induced IL-2 responses by total CD8+ (p = 0.034) (Figure 3A) and naïve CD8+ T cells (p = 0.020) (Figure 3B) were significantly elevated among patients with CM-IRIS compared with controls, while there was a trend for higher CD8+ TDEM T cell IL-2 responses among subjects with
Summary
Cryptococcal meningitis causes 15–20% of AIDS-related mortality worldwide [1]. In sub-SaharanAfrican countries with high HIV prevalence (>5%), Cryptococcus is the most common cause of meningitis in adults, accounting for 26% of cases in Malawi, 45% in Zimbabwe, 30% in South Africa [2,3,4,5], and60% in Uganda [3,5,6]. Cryptococcal meningitis causes 15–20% of AIDS-related mortality worldwide [1]. African countries with high HIV prevalence (>5%), Cryptococcus is the most common cause of meningitis in adults, accounting for 26% of cases in Malawi, 45% in Zimbabwe, 30% in South Africa [2,3,4,5], and. 60% in Uganda [3,5,6]. In 2014, an estimated 162,500 cases of cryptococcal meningitis (CM) occurred. J. Fungi 2019, 5, 42; doi:10.3390/jof5020042 www.mdpi.com/journal/jof. J. Fungi 2019, 5, 42 in sub-Saharan Africa resulting in more than 90,000 deaths [1]. Despite improved immune function in antiretroviral therapy (ART)-treated HIV-infected patients in low and middle-income countries, a significant proportion of patients with a new HIV diagnosis still present with advanced disease
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