Cathepsin B/ SAPC inhibition deregulates apoptosis-related proteins in neuronal cells exposed to supernatants from HIV-infected macrophages.

Monocytes infected with Human immunodeficiency virus 1 (HIV-1) can cross the blood-brain barrier to the central nervous system facilitating neuronal damage. Brain monocyte-derived macrophages can induce HIV neurocognitive disorders (HAND) by releasing neurotoxic factors. One of these secreted factors is cathepsin B (CATB), a lysosomal cysteine protease that interacts with serum amyloid P component (SAPC) contributing to HIV-induced neurotoxicity. However, the mechanisms that trigger CATB and SAPC neuronal apoptosis remain unknown. We aimed to elucidate intracellular pathways in neurons exposed to HIV-infected macrophage supernatants after inhibition of CATB or SAPC with specific antibodies and with the cathepsin B inhibitor CA074 using Tandem Mass Tag (TMT) quantitative proteomics and Ingenuity pathways analyses. Based on significant fold change (FC) > |2|and p-value < 0.05 criteria a total of 10, 13, and 48 proteins were deregulated after CATB antibody, SAPC antibody, and CA074 treatment, respectively. Antibodies against CATB and SAPC downregulated two common apoptosis related proteins: Cyclophilin A (CYPA) and Tubulin alpha-1A (TUBA1). CATB, SAPC antibodies and CA074 downregulated a common protein TUBA1A. Quantitative proteomics analyses revealed that treatment of HIV-infected MDM supernatants with antibodies against CATB/SAPC or with CA074 can reverse common and unique apoptotic pathways that deserve further studies as potential targets against HIV-induced neuronal degeneration.