Abstract: Methods are provided for the treatment of a HIV infection. The methods can include administering to a subject with an HIV infection a therapeutically effective amount of an agent that interferes with the interaction of gp120 and ?4 integrin, such as a ?4?1 or ?4?7 integrin antagonist, thereby treating the HIV infection. In several examples, the ?4 integrin antagonist is a monoclonal antibody that specifically binds to a ?4, ?1 or ?7 integrin subunit or a cyclic hexapeptide with the amino acid sequence of CWLDVC. Methods are also provided to reduce HIV replication or infection. The methods include contacting a cell with an effective amount of an agent that interferes with the interaction of gp120 and ?4 integrin, such as a ?4?1 or ?4?7 integrin antagonist. Moreover, methods are provided for determining if an agent is useful to treat HIV.