Publications

BACKGROUND

While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear.

METHODS

We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4(+) T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency.

RESULTS

Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4(+) T-cell count (all P ≤ .001). A higher percentage of CD38(+)HLA-DR(+) cells in the CD8(+) T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4(+) T-cell count. Frequencies of senescent (defined as CD28(-)CD57(+) cells), exhausted (defined as PD1(+) cells), naive, and CMV-specific T cells did not predict mortality.

CONCLUSIONS

Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.

UNLABELLED

Chronic pain is a major symptom in patients with endometriosis, a common gynecologic condition affecting women in their reproductive years. Although many proalgesic substances are produced by endometriosis lesions, experimental evidence supporting their relative roles is still lacking. Furthermore, it is unclear whether these proalgesic agents directly activate nociceptors to induce endometriosis pain. To determine their relative contribution to pain associated with endometriosis, we evaluated the intrathecal administration of oligodeoxynucleotides (ODNs) antisense to messenger RNA for receptors for 3 pronociceptive mediators known to be produced by the ectopic endometrium. Two weeks after the implant of autologous uterine tissue onto the gastrocnemius muscle, local mechanical hyperalgesia was observed in operated rats. Intrathecal antisense ODN targeting messenger RNA for the interleukin 6 receptor-signaling complex subunit glycoprotein 130 and the nerve growth factor tyrosine kinase receptor A, but not their mismatch ODNs, reversibly attenuated mechanical hyperalgesia at the implant site. In contrast, intrathecal antisense ODN targeting the tumor necrosis factor receptor 1, at a dose that markedly inhibited intramuscularly injected tumor necrosis factor alpha, had only a small antihyperalgesic effect in this model. These results indicate the relative contribution of pronociceptive mediators produced by ectopic endometrial tissue to endometriosis pain. The experimental approach presented here provides a novel method to evaluate for the differential contribution of mediators produced by other painful lesions as well as endometriosis lesions as targets for novel treatment of pain syndromes.

PERSPECTIVE

This article presents evidence for the relative contribution of proalgesic mediators to primary hyperalgesia displayed by rats submitted to a model of endometriosis pain. This approach can be used to identify potential targets for the treatment of endometriosis pain.