Several compounds have been identified that inhibit an early stage in the replicative cycle of the human immunodeficiency virus (HIV): i) virus adsorption: polysulfates, polysulfonates, polycarboxylates, polyphosphates, and polyoxometalates; or ii) virus-cell fusion: plant lectins, negatively charged albumins and betulinic acid derivatives; iii) virus fusion/uncoating: bicyclam derivatives; iv) reverse transcription: dideoxynucleoside analogues, acyclic nucleoside phosphonates and non-nucleoside reverse transcriptase inhibitors. In principle, HIV may develop resistance to any of these specific anti-HIV agents. However, virus breakthrough can be completely prevented if these agents, alone or in combination, are added to the HIV-infected cells from the beginning at sufficiently high ('knock-out') concentrations.