Background: VSSP (very small sized proteoliposomes) is a new approach to enhance immune restoration and control HIV replication. Properties of VSSP as immunopotentiator have been reported. VSSP is a potent adjuvant for dendritic cells activation and Th1 differentiation. VSSP induced a faster repopulation of immune cells in cyclophosphamide-receiving animals, also enhanced the recovery of memory T-lymphocytes and abrogated the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs).VSSP was obtained through the incorporation of NAcGM3 (an strong immunosuppressive ganglioside) into the outer membrane protein complex of Neisseria meningitidis (Nm). Recently, role of GM3 ganglioside in the incorporation of HIV in mature dendritic cells was shown essential of HIV reservoir.  Method and Results: Three Clinical trials have performed on patients with AIDS or in HIV population. The first trial (phase I) proved the safety of the formulation NAcGM3/VSSP/Montanide ISA 51, concomitant with HAART in 43 patients with HIV. Similarly, story-based evidence showed the recovery of the viral load and the CD4s. A second trial (phase II) of the proof of concept, involving 104 patients controlled and double-blinded, is still underway in Cuba and Argentina. In the same, it will be evaluated whether VSSP delays the start of triple therapy in people with HIV where there is a high risk of it becoming AIDS in the two-year treatment period. So far, the toxicity studies have proved to be safe in both treatment groups (The interim analysis will be presented). Recently, we presented the third trial to the Cuban regulatory agency to evaluate the formulation NAcGM3/VSSP in patients with a resistance to antiretroviral therapies available in low-income countries or in patients with discordances (low T CD4 and low Viral Load). This trial intends to measure the delay in the appearance of new opportunistic disease or death after the administration of NAcGM3/VSSP. The design is based on experience with six patients without a therapeutic option in Cuba, who were treated with the formulation outside protocol and a delay in opportunistic diseases was observed. Conclusion Our findings support the safety of VSSP with or without antiretroviral treatment in HIV/AIDS patients and some evidence of disease control.