P21-19. Characteristic pattern of soluble biomarkers in HIV-1 elite controllers

Maike Sperk [1,2], Wang Zhang [1,3], Anders Sönnerborg [1], Ujjwal Neogi [1,3]
Affiliates: [1] Karolinska Institutet, Huddinge, Stockholm, Sweden. [2] University of Tuebingen, Tuebingen, Germany. [3] KTH Royal Institute of Technology, Solna, Stockholm, Sweden.

Background
A small subset of HIV-1 positive individuals, the “Elite Controllers” (EC), is able to control viral replication and to restrain progression of immunodeficiency without antiretroviral therapy . It has been suggested that EC can hold the key to how functional HIV-cure can be reached. As soluble biomarkers are used to understand HIV-1 immunopathogenesis, they might also help us identify the underlying mechanisms, which ensure that disease progression is prevented in EC. In this study, we aimed to explore plasma proteomics data in a well-defined Swedish cohort of HIV-1 positive ECs with up to 20 years of clinical follow-up data.

Method
Plasma samples were obtained from three categories of individuals; unbiased untreated HIV-1-positive EC (n=19), and two background populations of treatment naïve patients with viremia (VP, n=32) and HIV-1-negative persons (HC, n=23) and analyzed using the proximity extension assay (PEA) and the Proseek Multiplex Immuno-oncology panel I (Olink Bioscience AB, Uppsala, Sweden) targeting 92 soluble factors. The differential profile (heatmap) of the soluble factors (proteome) was analysed using Qlucore Omics Explorer version 3.2.

Result
Among the 92 proteins, 82 were detectable in >50% of the samples and were further used for the analysis. Multi-group analysis by ANOVA identified clustering of 90% (29/32) of VPs together while EC and HC clustered separately from VP, but intermingled with each other (Fig 1). Among the factors, 28 were distinctive to be statistically significant at a false discover rate (FDR) adjusted p (q)<0.001 using ANOVA. Soluble factors belonging to the chemokines, TNFSF/TNFRSF or immune checkpoint molecules (or its receptors) have specific patterns in the respective three groups and could determine the disease status collectively. Interestingly, the death receptors ligands TNFSF6 (FasL), TNFSF10 (TRAIL), and TNFSF12 (TWEAK) do not show the same expression patterns between the groups. While EC had lower levels of FasL and TRAIL compared to VP (significantly) and HC (significantly for FasL, but not significantly for TRAIL), TWEAK was significantly decreased in VP and EC compared to HC, but no significant difference was seen between the two of them.

Conclusions
The plasma proteomics profile of the soluble factors analysis strongly indicated that cell surface receptor signaling pathway, programmed cell death, response to cytokine and cytokine-mediated signaling may synergistically play important role in virus replication control in EC.