This invention provides novel methods for identifying agents that inhibit HIV infection. The anti-HIV agents are identified by screening test compounds for ability to modulate a biological activity of isopeptidase T (IsoT), e.g., its isopeptidase activity or its binding to another molecule such as viral protein R (Vpr). Such IsoT modulators can be further examined for their activity in inhibiting an activity indicative of HIV infection or HIV replication. These novel anti-HIV agents are useful in the prevention or treatment of HIV infection and conditions associated with or caused by HIV infection.