In this study, high molecular weight dextran only or combination with gp120 was used to stimulate human monocyte-derived macrophages to study the immune response to treatments and to elucidate the preliminary possibly related pathways. Our data demonstrated that 40 µg/ml of dextran did not induce a significant alteration of important immune-related gene expressions but decreased the gene expressions of CXCR4 and CCR5 mediated with reactive oxygen stress (ROS) generated by mitochondria. Cell viability measured by flow cytometry indicated that HIV induced 84% of macrophage deaths but combination of dextran with gp120 restored 48% of the mortality rate. Interestingly, a combination of dextran with gp120 can improve the enhancement of CD244 and perforin expressions induced by HIV, indicating that HIV infection is mediated to cytotoxicity. In addition, PI13 K and NFκB pathway played a very important role in the HIV-infected cell viability and ROS generation had partially influenced the cell viability. Regarding Toll-like receptors, dextran stimulated TLR1 increase, TLR9 decrease via PI13K pathway; however the alterations were restored by HIV-1 gp 120. Our data also showed that PI13K, mitochondrial ETC and NFκB pathways play very key roles in regulating perforin, CD244 and CD260. In conclusion, combination of dextran with gp120 is a good conjugate of polysaccharides to develop an HIV vaccine.