POTENT INHIBITION OF HIV TYPE-1 INFECTION OF MONONUCLEAR PHAGOCYTES BY SYNTHETIC PEPTIDE ANALOGS OF HIV TYPE-1 PROTEASE SUBSTRATES

The HIV-1 genome encodes a protease that is required for viral process ing of the precursor polyproteins Pr55(gag) and Pr-160gag-pol. Interfe rence with this process in human lymphocytes inhibits production of in fectious virus. We tested the ability of several protease inhibitors t o decrease replication of HIV-1(BaL) in human monocytes and peritoneal macrophages. The compounds tested are oligopeptide analogs of HIV-1 p rotease substrates in which the scissile dipeptide has been replaced b y a hydroxyethylene isostere. The protease inhibitors were added only once, 1 hr prior to inoculation with virus. Every 3-5 days, half the m edium was replaced with fresh medium. Inhibition of virus production w as assessed by measuring reverse transcriptase (RT) activity in supern atant medium 14 days after infection. The concentration of drug requir ed to inhibit infection by 50% (IC50) in monocytes ranged from 0.17 to 2.99 mu M; IC50 values for peritoneal macrophages ranged from 0.21 to 1.9 mu M. The IC50 values for these compounds were 1.1- to 10-fold hi gher when tested in monocytes compared to their inhibitory effect in l ymphocytes, although still potently effective in the dosage range that appeared nontoxic to cells. Cell toxicity was seen only at concentrat ions greater than 10 mu M, and varied among the drugs tested. Immunobl ot analysis of two of the drugs (SB205700 and SB108922) confirmed inhi bition of polyprotein processing. In control cells, 22% of viral prote in pr55 was processed to p24 by 24 hr, and 51% was processed by 48 hr. In cells treated with the protease inhibitors (2 mu M), pr55 processi ng was inhibited 77% at 24 hr and 89% at 48 hr. Thus, these synthetic peptide analogs potently inhibit productive infection of mononuclear p hagocytes by HIV-1. Drugs of this class may be useful for the treatmen t of HIV-1 infection in humans.