Methods and compositions are provided for treating HIV infection and for inhibiting HIV infection, and for identifying purinergic receptor antagonists or Panx 1 hemi-channel blockers useful therefor. The invention provides a method of treating a mammalian subject having an HIV infection, or suspected of having been exposed to HIV, comprising administering to the mammalian subject an amount of (i) an antagonist of a Panx 1 hemichannel, or (ii) of an inhibitor of a purinergic receptor, effective to inhibit (a) HIV fusion with a target cell, or (b) HIV replication, or (c) HIV entry into a target cell, or two or more of (a), (b) and (c).