Gene therapy holds considerable promise for the functional cure of HIV-1 infection. A number of clinical trials have assessed the safety and the feasibility of modifying CD4+ T lymphocytes and their precursor to express anti-HIV genetic inhibitors. Despite these achievements, further optimization of HIV gene therapy approaches is required, starting from the selection of new therapeutic targets and the design of innovative genetic platforms. To increase the potency of the antiviral approach and to accomplish long-term control of HIV-1 replication, multiple inhibitory agents blocking different steps in the viral life cycle should be simultaneously delivered into target cells. In this context, small interfering RNA (siRNAi)-based approaches represent powerful strategies. The immediate aim of this project is to combine innovative combinatorial platforms expressing siRNAs along with the fusion inhibitor membrane-anchored C (maC)-peptide within the same lentiviral vector and assess its efficiency to inhibit the infection of target T lymphocyte by HIV-1 virus.