HIV-1 is equipped with the envelope gp160 glycoprotein for interaction with Langerhans cells (LCs) and dendritic cells (DCs), the members of the innate immune system, which confront the virus at the portal of virus entry in the human body. These cells are equipped with receptors by which they bind and endocytose the virus. The gp120 glycoprotein is used for binding to CD4 receptor and CCR5 co-receptor of T helper 2 (Th2) cells and the virions shed gp120 is able to induce FcepsilonRI+ hematopoietic cells to produce IL-4, which inactivate the host adaptive immune response. The properties of gp120s various functional domains are analyzed together with the regulatory viral proteins, which are involved in the damage to T and B cells during HIV-1 replication. The interaction of HIV-1 virions through their gp120 with LCs and DCs at the portal of virus entry will be discussed. A hypothesis will be presented that the understanding of the role of the different functional domains of gp120 in the life cycle of the virus and during AIDS will help in the design of approaches to prevent and abrogate HIV-1 infection and AIDS.