HIV-2 mediated effects on target and bystander cells induce plasma proteome remodeling

Abstract

Despite low or undetectable plasma viral load, people living with HIV-2 (PLWH2) typically progress toward AIDS. The driving forces behind HIV-2 disease progression and the role of viremia are still not known, but low-level replication in tissues is believed to play a role. To investigate the impact of viremic and aviremic HIV-2 infection on target and bystander cell pathology, we used data-independent acquisition mass spectrometry to determine plasma signatures of tissue and cell type engagement. Proteins derived from target and bystander cells in multiple tissues, such as the gastrointestinal tract and brain, were detected at elevated levels in plasma of PLWH2, compared with HIV negative controls. Moreover, viremic HIV-2 infection appeared to induce enhanced release of proteins from a broader range of tissues compared to aviremic HIV-2 infection. This study expands the knowledge on the link between plasma proteome remodeling and the pathological cell engagement in tissues during HIV-2 infection.

Keywords: Disease; Human specimen; Proteomics; Virology.

Graphical abstract

Figure 1

HIV-2 infection induces remodeling of the blood plasma proteome (A) Dendrogram illustrating clustering of analyzed proteins into different modules. (B) Comparisons of protein eigenvalues for each module between the different study groups, viremic PLWH1, viremic PLWH2, aviremic PLWH2 and HIV seronegative individuals. (C) Module – trait relationships, where Spearman Rank r- and p values are given for correlations between module protein eigenvalues and CD4⁺ T-cell percentage of all lymphocytes (CD4%), viral load, frequency of exhausted CD8⁺ T-cells, and frequency of hyperactivated B-cells, among PLWH2. Statistically significant group-wise differences were determined by ANOVA test, followed by Benjamini-Hochberg correction for multiple testing (p < 0.05). Statistically significant correlations were determined using the Spearman Rank correlation test, followed by BH correction for multiple testing (p < 0.05). Mean values are depicted in violin plots.

Figure 2

Both HIV-1 and HIV-2 infections induces increased release of proteins enhanced from known HIV-1 replication sites Comparisons between study groups, i.e., viremic PLWH1, viremic PLWH2, aviremic PLWH2, and HIV seronegative individuals, with respect to (A) leakage protein-derived tissue signatures, and (B) secreted protein-derived tissue signatures. Statistically significant group-wise differences were determined by ANOVA test, followed by Benjamini-Hochberg correction for multiple testing (p < 0.05). Mean values are depicted in violin plots.

Figure 3

Viremic HIV-2 infection induced increased leakage of multiple cell types from known virus replication sites (A) Relationships and (B) groupwise comparisons of leakage protein-derived cell types. Statistically significant correlations were determined using the Spearman Rank correlation test, followed by Benjamini-Hochberg (BH) correction for multiple testing (p < 0.05) and group-wise differences were determined by ANOVA test, followed by BH correction for multiple testing (p < 0.05). Mean values are depicted in violin plots.

Figure 4

Viremic HIV-2 infection induced increased secretion of proteins of multiple target and bystander cells (A) Groupwise comparisons and (B) relationships between secreted protein-derived cell types. Statistically significant group-wise differences were determined by ANOVA test, followed by Benjamini-Hochberg (BH) correction for multiple testing (p < 0.05) and correlations were determined using the Spearman Rank correlation test, followed by BH correction for multiple testing (p < 0.05). Mean values are depicted in violin plots.