Potent suppression of viral infectivity by the peptides that inhibit multimerization of human immunodeficiency virus type 1 (HIV-1) Vif proteins.
Virion infectivity factor (Vif) is essential for the replication of human immunodeficiency virus type 1 (HIV-1) in vivo, but its function remains uncertain. Recently, we have shown that Vif proteins are able to form multimers, including dimers, trimers, or tetramers. Because the multimerization of Vif proteins is required for Vif function in the viral life cycle, we propose that it could be a novel target for anti-HIV-1 therapeutics. Through a phage peptide display method, we have identified a set of 12-mer peptides containing a PXP motif that binds to HIV-1 Vif protein. These proline-enriched peptides potently inhibited the Vif-Vif interaction in vitro. We have also screened a set of synthesized Vif peptides (15-mer), which covers all the amino acids of the HIV-1 Vif protein sequence, for their ability to inhibit the Vif-Vif interaction in vitro. We demonstrated that Vif-derived proline-enriched peptides that contain the (161)PPLP(164) domain are able to inhibit the Vif-Vif interaction. Conversely, the deletion of the (161)PPLP(164) domain of Vif protein will significantly impair the capability of Vif proteins to interact with each other, indicating that the (161)PPLP(164) domain plays a key role in Vif multimerization. All these results demonstrate that the proline-enriched peptides block the multimerization of Vif through interfering with the polyproline interfaces of Vif formed by (161)PPLP(164) domain. Moreover, these peptides which inhibit the Vif-Vif interaction in vitro potently inhibit HIV-1 replication in the "nonpermissive" T-cells. We propose that this study starts a novel strategy to develop structural diverse inhibitors of Vif such as peptidomimetics or small organic molecules.
Yang
Bin
B
The Dorrance H. Hamilton Laboratories, Center for Human Virology, Division of Infectious Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Gao
Ling
L
Li
Lin
L
Lu
Zhixian
Z
Fan
Xuejun
X
Patel
Charvi A
CA
Pomerantz
Roger J
RJ
DuBois
Garrett C
GC
Zhang
Hui
H
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D016346:Gene Products, vif / Q000737:chemistry* / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D010957:Plasmids; D013329:Structure-Activity Relationship; D054320:vif Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D016346:Gene Products, vif; D009842:Oligopeptides; D054320:vif Gene Products, Human Immunodeficiency Virus