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

• Downstream catabolite 3-Hydroxyanthralinic Acid (HAA) causes Th17 depletion

Favre, Mold et al, Science TM, 2010

IDO

KynurenineTryptophan

(K/T Ratio) = Marker of Tryptophan Catabolism

Impact of IDO Inductionon HIV Pathogenesis

IFN-γLPS

IDOInductionin DC/MØ

↓TryptophanT Cell

Proliferative Defect

MicrobialTranslocation

↑HAA Th17 Depletion

Does the Extent of Tryptophan Catabolism Predict Subsequent Clinical Events During Treated HIV Infection?

• Cohort of 500 HIV-infected Ugandans starting first ART regimen (UARTO)

• Assessed plasma tryptophan and kynurenine levels through 1st year of ART

• Assessed impact on subsequent CD4 recovery and mortality

Characteristics of HIV-infected Ugandans Starting ART

Characteristic Median (IQR)N=435

Age, years 34 (28-39)

Female gender, % 70

Pre-ART CD4+ T cell count, cells/mm3 133 (79-201)

Pre-ART Plasma HIV RNA level, log10 copies/ml 5.0 (4.6-5.3)

Months of observation on ART 38 (22-47)

8% Lost to follow up by month 36

Higher Baseline Tryptophan Catabolism Associated with Greater Early CD4 Recovery

Though Largely Explained by Pre-ART VL

No evidence for an association between K/T ratio and early CD4 recovery after adjustment for pre-ART VL (P=0.95)

But Higher Baseline Tryptophan Catabolism Predicts Diminished Late CD4 Recovery

Higher pre-ART K/T ratio predicted diminished late CD4 recovery after adjustment for age, gender, and pre-ART VL and CD4 count (P=0.008)

Low Pre-ART CD4 Count Predicts Earlier Mortality

Higher Tryptophan Catabolism(K/T ratio) Predicts Earlier Mortality

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.

AcknowledgementsMUST-UARTOThe participantsAnnet KembabaziDerrick MusingaSimone Hausammann-KigoziBosco BwanaConrad Muzoora

UCSF - UARTOElvin GengSteven DeeksJohn BennettRain MocelloJeffrey Martin

MGH/Harvard - UARTOAnna BaylorJessica HabererPeggy BartekDavid Bangsberg

UARTO Team

UCSF – Food InsecurityKathleen RaglandSheri Weiser

UCSF – LaboratoryYong HuangHuyen CaoJoseph M. McCune

Doris Duke CSDA, 1R21AI078774,R01MH054097