Impact of Tryptophan Catabolism on CD4+ T Cell Recovery and Mortality in HIV- infected Ugandans Initiating ART Peter W. Hunt , Sheri Weiser, Yong Huang, Conrad Muzoora, Annet Kembabazi, Kathleen Ragland, John Bennett, Elvin Geng, Steven G. Deeks, David R. Bangsberg, Jeffrey N. Martin, and Joseph M. McCune
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Impact of Tryptophan Catabolism on CD4+ T Cell Recovery and Mortality in HIV-infected Ugandans Initiating ART Peter W. Hunt, Sheri Weiser, Yong Huang,
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Impact of Tryptophan Catabolism on CD4+ T Cell Recovery
and Mortality in HIV-infected Ugandans Initiating ART
Peter W. Hunt, Sheri Weiser, Yong Huang, Conrad Muzoora, Annet Kembabazi, Kathleen Ragland, John Bennett, Elvin
Geng, Steven G. Deeks, David R. Bangsberg, Jeffrey N. Martin, and Joseph M. McCune
Background
• Immune activation persists in most HIV+ patients despite ART-mediated viral suppression
• This inflammatory state may contribute to morbidity/mortality during treated HIV infection.
• Demonstrating that specific inflammatory pathways predict subsequent clinical events is critical step in identifying therapeutic targets.
IDO-induced Tryptophan Catabolism
• IFN-γ and LPS stimulate Indoleamine 2,3-dioxygenase -1 (IDO) production in DCs/MØ
• Causes tryptophan catabolism • Tryptophan depletion may impair
T cell proliferation– Maternal tolerance of fetal antigens– Cancer evasion of immune response
• Catabolites may be neurotoxic– Neurodegenerative diseases, ADC
Each tertile increase in baseline K/T ratio associated with a 2.1-fold greater hazard of death after adjustment for pre-ART BMI and CD4 count (P=0.01).
Tryptophan Catabolism Decreases During ART
Tryptophan Levels K/T Ratio
Tryptophan Catabolism Continues to Predict Mortality during Suppressive ART
(VL<400 at Month 6 of ART)
Each tertile increase in month 6 K/T ratio associated with a 2.9-fold increased hazard of death after adjusting for BMI, CD4 count, and %CD38+HLA-DR+ CD8+ T cells (P=0.042).
Does dietary protein intake modify the relationship between
tryptophan catabolism and mortality?
Low Protein Diet Might ExacerbateT Cell Proliferative Defects but Ameliorate Th17 Depletion
LowDietary
Tryptophan
IDO-induced
Catabolism
MoreTryptophanDepletion
More T Cell Proliferative
Defects
LessMicrobial
Translocation
LessHAA
LessTh17
Depletion
HighDietary
Tryptophan
IDO-induced
Catabolism
LessTryptophanDeficiency
Less T Cell Proliferative
Defects
More Microbial
Translocation
MoreHAA
MoreTh17
Depletion
High Protein Diet Might AmeliorateT Cell Proliferative Defects but
Exacerbate Th17 Depletion
Gal, J. Neurochemistry, 1978
Ugandan Diet is Low in Protein
See also: Crawford et al, British Journal of Nutrition, 1970
Low Dietary Protein Intake Is Associated with Low Plasma Tryptophan
Relationship remains significant even after adjustment for VL, CD4 count, gender, and BMI (P=0.021)
No Evidence for an Association Between Dietary Protein Intake and Mortality
Low Dietary Protein Does Not Appear to Exacerbate the Impact of Tryptophan Catabolism on Mortality
Low Dietary Protein Does Not Appear to Exacerbate the Impact of Tryptophan Catabolism on Mortality
P for interaction = 0.34
Conclusions• Among HIV-infected Ugandans, greater pre-ART
tryptophan catabolism predicts a diminished rate of late CD4+ T cell recovery during suppressive ART.
• Tryptophan catabolism is a major independent predictor of mortality in HIV-infected Ugandans both pre-ART and during ART-mediated viral suppression.
• Interventions designed to block IDO induction (or the root causes of IDO induction) may hold promise in this setting.