The kynurenine pathway of tryptophan catabolism and AIDS-associated kaposi sarcoma in Africa

Helen Byakwaga, Peter W. Hunt, Miriam Laker-Oketta, David V. Glidden, Yong Huang, Bosco M. Bwana, A. Rain Mocello, John Bennett, Victoria Walusansa, Sheila C. Dollard, David Bangsberg, Edward K. Mbidde, Jeffrey N. Martin

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Other than Kaposi 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, interquartile range: 90 to 190 nM/mM) than KS cases (110, interquartile range: 90 to 150 nM/mM) (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% confidence interval: 27% to 77%) in the odds of KS compared with 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.

Original languageEnglish (US)
Pages (from-to)296-303
Number of pages8
JournalJournal of Acquired Immune Deficiency Syndromes
Volume70
Issue number3
StatePublished - 2015
Externally publishedYes

Fingerprint

Kynurenine
Kaposi's Sarcoma
Tryptophan
Acquired Immunodeficiency Syndrome
HIV
Indoleamine-Pyrrole 2,3,-Dioxygenase
CD4 Lymphocyte Count
RNA
T-Lymphocytes
Human Herpesvirus 8
Lymphopenia
Enzyme Induction
Tandem Mass Spectrometry
Liquid Chromatography
Sarcoma
HIV Infections
Case-Control Studies
Cell Proliferation
Confidence Intervals

Keywords

  • Africa
  • HIV
  • Indoleamine 2 3-dioxygenase-1
  • Kaposi sarcoma
  • Kynurenine
  • Plasma HIV RNA
  • Tryptophan

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Byakwaga, H., Hunt, P. W., Laker-Oketta, M., Glidden, D. V., Huang, Y., Bwana, B. M., ... Martin, J. N. (2015). The kynurenine pathway of tryptophan catabolism and AIDS-associated kaposi sarcoma in Africa. Journal of Acquired Immune Deficiency Syndromes, 70(3), 296-303.

The kynurenine pathway of tryptophan catabolism and AIDS-associated kaposi sarcoma in Africa. / Byakwaga, Helen; Hunt, Peter W.; Laker-Oketta, Miriam; Glidden, David V.; Huang, Yong; Bwana, Bosco M.; Mocello, A. Rain; Bennett, John; Walusansa, Victoria; Dollard, Sheila C.; Bangsberg, David; Mbidde, Edward K.; Martin, Jeffrey N.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 70, No. 3, 2015, p. 296-303.

Research output: Contribution to journalArticle

Byakwaga, H, Hunt, PW, Laker-Oketta, M, Glidden, DV, Huang, Y, Bwana, BM, Mocello, AR, Bennett, J, Walusansa, V, Dollard, SC, Bangsberg, D, Mbidde, EK & Martin, JN 2015, 'The kynurenine pathway of tryptophan catabolism and AIDS-associated kaposi sarcoma in Africa', Journal of Acquired Immune Deficiency Syndromes, vol. 70, no. 3, pp. 296-303.
Byakwaga H, Hunt PW, Laker-Oketta M, Glidden DV, Huang Y, Bwana BM et al. The kynurenine pathway of tryptophan catabolism and AIDS-associated kaposi sarcoma in Africa. Journal of Acquired Immune Deficiency Syndromes. 2015;70(3):296-303.
Byakwaga, Helen ; Hunt, Peter W. ; Laker-Oketta, Miriam ; Glidden, David V. ; Huang, Yong ; Bwana, Bosco M. ; Mocello, A. Rain ; Bennett, John ; Walusansa, Victoria ; Dollard, Sheila C. ; Bangsberg, David ; Mbidde, Edward K. ; Martin, Jeffrey N. / The kynurenine pathway of tryptophan catabolism and AIDS-associated kaposi sarcoma in Africa. In: Journal of Acquired Immune Deficiency Syndromes. 2015 ; Vol. 70, No. 3. pp. 296-303.
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abstract = "Background: Other than Kaposi 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, interquartile range: 90 to 190 nM/mM) than KS cases (110, interquartile range: 90 to 150 nM/mM) (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{\%} confidence interval: 27{\%} to 77{\%}) in the odds of KS compared with 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.",
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AU - Hunt, Peter W.

AU - Laker-Oketta, Miriam

AU - Glidden, David V.

AU - Huang, Yong

AU - Bwana, Bosco M.

AU - Mocello, A. Rain

AU - Bennett, John

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AU - Mbidde, Edward K.

AU - Martin, Jeffrey N.

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N2 - Background: Other than Kaposi 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, interquartile range: 90 to 190 nM/mM) than KS cases (110, interquartile range: 90 to 150 nM/mM) (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% confidence interval: 27% to 77%) in the odds of KS compared with 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.

AB - Background: Other than Kaposi 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, interquartile range: 90 to 190 nM/mM) than KS cases (110, interquartile range: 90 to 150 nM/mM) (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% confidence interval: 27% to 77%) in the odds of KS compared with 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.

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