The Kynurenine Pathway of Tryptophan Catabolism and AIDS-Associated Kaposi Sarcoma in Africa

Abstract

Background Other than Kaposi's sarcoma (KS)-associated herpesvirus and CD4+ T cell lymphopenia, the mechanisms responsible for KS in the context of HIV are poorly understood. One recently explored pathway of HIV pathogenesis involves induction of the enzyme indoleamine 2,3 dioxygenase-1 (IDO), which catabolizes tryptophan into kynurenine and several other immunologically active metabolites that suppress T cell proliferation. We investigated the role of IDO in the development of KS in HIV disease. Methods In a case-control study among untreated HIV-infected Ugandans, cases were adults with KS and controls were without KS. IDO activity was assessed by the ratio of plasma kynurenine to tryptophan levels (KT ratio), measured by liquid chromatography tandem mass spectrometry. Results We studied 631 HIV-infected subjects: 222 KS cases and 409 controls. Non-KS controls had a higher median plasma KT ratio (130, IQR: 90 to190 nM/μM) than cases (110, IQR: 90 to 150 nM/μM) (p = 0.004). After adjustment for age, sex, CD4 count and plasma HIV RNA level, subjects with the highest (fourth quartile) plasma KT ratios had a 59% reduction (95% CI: 27% to 77%) in the odds of KS compared to those with the lowest (first quartile) levels. KS was also independently associated with lower CD4+ count, higher plasma HIV RNA, and men. Conclusions Among HIV-infected individuals, greater activity of the kynurenine pathway of tryptophan catabolism, as evidenced by higher levels of plasma KT ratio, was associated with lower occurrence of KS. Some consequences of immune activation in HIV infection might actually suppress certain cancers.

Role of immune activation in progression to AIDS

“…For example, among ART-suppressed HIV-infected individuals in North America, innate immune activation and inflammatory markers were much more strongly predictive of mortality than T cell activation (the opposite inference from the pre-ART era) [19, 20], presumably because most of the causes of death were non-infectious in etiology (e.g., cardiovascular, non-AIDS cancer, etc). Conversely, among ART-suppressed individuals in resource-limited settings, where infectious complications remain much more important causes of death [16, 17], T cell activation and pathways conferring adaptive immune defects are much stronger predictors of mortality [21–23]. Thus, it would not be surprising if the final common immunologic pathways driving disease vary by end-organ complication.…”

“…The tryptophan catabolite 3-hydroxyanthralinic acid (3-HAA) also promotes regulatory T cell expansion (further impairing T cell function) while suppressing Th17 and Th22 cells, resulting in impaired gut epithelial barrier integrity and potentially contributing to microbial translocation and further innate immune activation [37]. Recently, three cohort studies have now linked systemic IDO activity (typically assessed as the plasma kynurenine/tryptophan ratio) to increased mortality during suppressive ART, suggesting that this pathway may well be clinically relevant [19–21]. This pathway might also contribute to neurologic morbidity.…”

Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans

“…First, we had limited data on non-genetic factors, such as co-infections. We were able to adjudicate potential TB diagnoses [16] and found little change in effect estimates after excluding these individuals. We also performed post-hoc analyses of SNPs in relation to month 6 and 12 KT ratios separately.…”

“…For this study, deaths due to trauma, injury, or suicide were excluded. Self-reported diagnoses of tuberculosis (TB) and/or TB medication history were adjudicated by reviewing clinical records and laboratory smear/culture results [16]. These data were only available for UARTO since TB diagnosis was an exclusion criterion for the ARKS study [16].…”

“…Only SNPs with minor allele frequencies (MAF)>1% were included in the analyses. The final model included covariates for gender, pregnancy, and cohort (to account for KS diagnosis[16] and other unmeasured cohort-specific differences), as well as the first ten principal components to control for population stratification.…”