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Excerpt
Substance P, a potent modulator of neuroimmunoregulation [1–3], stimulates human peripheral blood mononuclear cells to produce inflammatory cytokines [4]. Substance P and its receptor (neurokinin-1) receptor are present in human immune cells, including lymphocytes and monocyte-derived macrophages [2,3]. There is an important relationship between substance P and HIV infection of human immune cells [5]. Substance P and its receptor (neurokinin-1), may be involved in the modulation of HIV infection both in vivo and in vitro. Using in-vitro culture systems, we have demonstrated that substance P upregulates HIV replication in human peripheral blood monocyte-derived macrophages [5]. The substance P inhibitor, CP96-345, inhibits HIV R5 strain replication in mononuclear phagocytes, probably through interaction with CCR5 [6]. HIV-seropositive children had higher plasma levels of substance P in comparison to healthy control children [7]. We investigated whether HIV-infected individuals have elevated substance P levels in plasma using samples from a well-documented cohort of gay men.
Samples were obtained from subjects who were participating in the Coping in Health and Illness Project, a National Institutes of Health sponsored cohort study [8,9] based at the University of North Carolina, USA. The cohort included 65 HIV-seropositive gay men, who were asymptomatic at study entry, and 51 HIV-seronegative gay men who served as controls. The participants were recruited from rural and urban areas of North Carolina, USA
Each subject contributed two samples (a.m. and p.m.). The HIV disease status of the seropositive subjects was: CD4 T cell count 0–199 cells/mm3 (n = 12); 200–499 cells/mm3 (n = 38); and greater than 500 cells/mm3 (n = 15). At the time of blood sampling, of the 65 HIV-seropositive subjects, 29 subjects were receiving monotherapy with zidovudine and 36 subjects were not receiving antiretroviral therapy.
Sample collection procedure: Before each visit, subjects took nothing by mouth starting at midnight on the night before the blood sample collection. Blood was drawn from subjects, who remained recumbent for plasma cortisol, lymphocyte phenotyping, and substance P levels at 9.10 a.m. (a.m. sample) and between 3.30 and 4.30 p.m. (p.m. sample). The plasma samples were stored at −70°C. Substance P was measured using a simple chromotographic procedure for partial purification and sensitive enzyme immunoassay [10]. NK cells were enumerated using flow cytometry [8–10]. The two sample t-test was used to compare the differences in substance P levels between HIV-seronegative and seropositive men with a.m. samples. A paired t-test was used to compare the differences in substance P levels for HIV-seropositive men between a.m. and p.m. samples. Distributions of CD4, CD16, CD56, and CD57 cells and baseline cortisol values also were examined. Pearson correlation coefficients were calculated to investigate the association between substance P and lymphocyte subsets. Multiple linear regression was used to examine the relationship between substance P and lymphocyte subsets, while controlling for baseline cortisol levels.
The measurement of plasma substance P levels for 65 HIV-seropositive men and 51 HIV-seronegative men revealed higher mean substance P levels in HIV-seropositive men (55.6 ± 13.3 pg/ml, mean ± SD) in comparison with HIV-seronegative men (31.5 ± 9.7 pg/ml, mean ± SD) (Fig. 1, P < 0.001).
