Oral chemokine interactome unfolds potential anti-HIV mucosal microbicide targets

Abstract

HIV transmission occurs on mucosal surfaces of the gastrointestinal and cervicovaginal tracts. Recent clinical trials using chemokines such as CCL5, as mucosal entry inhibitors show great promise. A combination of several chemokines can be useful to prevent transmission of HIV at mucosal sites. The challenge is to decide which of the wide array of candidate chemokines are likely to be most effective. Oral chemokine profiles may prove useful in identifying the potential targets. Objectives: To analyze 36 oral chemokines of HIV infected individuals and to compare with a HIV negative group. Methods: 52 HIV positive volunteers undergoing antiviral therapy, 20 HIV positive volunteers without antiviral therapy and a healthy control group were investigated. All volunteers with oral pathologies, smoking and acute systemic pathology were excluded. Unstimulated whole saliva and blood were collected. Salivary sub-proteome for chemokines was analyzed using antibody arrays(R&D). Mammalian chemokine interactome was mapped using an automated high-throughput technology(IPA, Ingenuity). Results: No significant difference found between the total salivary proteins of HIV infected group (6.71 +/- 5.3 µg/µl) and healthy group (6.0 +/- 3.7 µg/µl). However, CCL5, CXCL12, TNFSF1A, sTREM-1, IL-32alpha, IL-23, IL-17E, CCL3, CCL4 showed significantly increased expression levels, 36%, 20%, 22%, 12%, 35%, 22%, 24%, 18% and 33% respectively in HIV infected group without therapy compared to little/no expression of these cytokines in healthy (P<0.05). Whereas SERPINE1, LCF, CXCL10 had relative expression levels of 64%, 68.7%, 72.7% in HIV group without therapy and 31.9%, 34.6%, 46.28% in healthy group respectively. Functional profiling in the mammalian system revealed CCL5, TNFSF1A, CXCL12, CCL3 and CCL4 to have anti-HIV properties. Conclusion: Combinations of CXCL12, CCL3 and CCL4 may have potential as anti-HIV mucosal microbicide targets. They may also serve as promising candidates as mucosal adjuvants, for HIV vaccines.