The neurokinin-1 antagonists (SP antagonist) CP96,345 and aprepitant inhibit HIV infectivity of monocytederived macrophages, derived from healthy individuals and studied in ex vivo cell cultures. We have extended these findings to a two-week in vivo setting in a Phase IB clinical trial (IND 75558 Clinical Trial NCT00428519) in HIV-infected subjects with detectable viral loads and CCR5 HIV strains, and we are awaiting the results of this ongoing blinded clinical trial. The proposed study of NKIR antagonists will be performed using peripheral blood samples to be obtained through recruitment with another NIMH funded study (R01-MH082670, 2008-2013, """"""""Depression, Antidepressants and HIV infectivity"""""""") in ex vivo cells obtained from depressed and non-depressed HlV-negative men and women. The goal is to determine whether depression alters susceptibility of cells to HIV infectivity ex vivo. In our long-standing investigations, we have observed differences in resopnise to NKIR antagonists (CP96,345 and aprepitant) related to susceptibility of monocyte-derived macrophages (MDMs) from healthy donors to viral challenge. In this project, we will further investigate anti-viral activity of selected NKI R antagonists targeted against cells from HIV-infected individuals and cells investigated ex viVo from individuals with different levels of depression as determined by Hamilton Depression scales and other standard psychiatric measures. We hypothesize that aprepitant inhibits HIV entry and replication in MDMs. We further hypothesize that this effect is mediated through CCR5 down-regulation. We predict that MDMs from subjects with depression will be infected with an HIV ex vivo model more readily and will demonstrate better responses to NKIR antagonists compared with cells from non-depressed subjects. We further propose that Natural Killer cells from subjects with depression will have impaired Natural Killer cell functions relative to impaired ligation of inhibitory Natural Killer cell receptors and that treatment with NK1R antagonists will restore these functions. The ex vivo efficiacy of NKIR antagonists in cells from depressed subjects will be determined.
The effects of a neurokinin-1 drug receptor antagonist (substance P preferring receptor), aprepitant, an HIVantiviral active and Natural Killer cell function improving drug, will be investigated in cells from depressed and non-depressed subjects. The potential anti-HIV activity and natural killer cell functional improvement in depression will be determined.
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|Barrett, Jeffrey S; Bajaj, Gaurav; McGuire, Jennifer et al. (2014) Modeling and simulation approach to support dosing and study design requirements for treating HIV-related neuropsychiatric disease with the NK1-R antagonist aprepitant. Curr HIV Res 12:121-31|
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