MOAA0105 - Oral Abstract
Impact of tryptophan catabolism on CD4+ T cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy
Presented by Peter W. Hunt (United States).
P. Hunt1, S. Weiser1, Y. Huang1, C. Muzoora2, A. Kembabazi2, K. Ragland1, J. Bennett1, S. Deeks1, D. Bangsberg3, J. Martin1, J. McCune1
1University of California - San Francisco, San Francisco, United States, 2Mbarara University of Science and Technology, Mbarara, Uganda, 3Massachusetts General Hospital, Center for Global Health, Boston, United States
Background: HIV-induced indoleamine 2,3-dioxygenase (IDO) expression in activated monocytes results in tryptophan catabolism, which may inhibit T cell proliferation and IL-17 production. However, its impact on mortality has never been assessed in HIV infection.
Methods: HIV-infected adults initiating antiretroviral therapy (ART) were sampled from the Uganda AIDS Rural Treatment Outcomes cohort. Levels of IDO-induced tryptophan catabolism (ratio of the downstream catabolite kynurenine to tryptophan in plasma, KT ratio) were assessed before and during ART, and related to subsequent mortality and the rate of subsequent CD4 recovery during confirmed viral suppression with linear mixed models.
Results: Of 435 evaluable participants, 70% were women and median pre-ART values were: age, 34 years; CD4 count, 133 cells/mm3; plasma HIV RNA level (VL), 5.0 log10 copies/ml; tryptophan, 18 uM; and KT ratio, 0.13. Higher pre-ART KT ratio was associated with higher VL (rho: 0.38, P< 0.001), lower CD4+ T cell count (rho: -0.16, P< 0.001), and after adjustment for VL and CD4 count, female gender (P=0.038). Through month 12 of ART-mediated viral suppression, plasma tryptophan increased (P< 0.001) and KT ratio decreased (P< 0.001), but pre-ART levels remained strongly predictive of month 12 levels (rho: 0.42 and 0.54, P< 0.001 for both). After adjustment for pre-ART CD4 count, VL, age, and gender, higher pre-ART KT ratio predicted a slower rate of CD4 recovery after month 12 (P=0.008). Thirty-nine participants died. After adjustment for pre-ART CD4 count and BMI, lower tryptophan and higher KT ratio both pre-ART and at month 6 of viral suppression predicted earlier mortality (P≤0.022 for all). While lower self-reported dietary protein sources were associated with lower tryptophan levels (P=0.007), adjustment for dietary protein strengthened the association between tryptophan levels and mortality.
Conclusion: The extent of tryptophan catabolism is a major predictor of both CD4+ T cell recovery and mortality among HIV-infected Ugandans initiating ART.
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