A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains.

Abstract

BACKGROUND:

Most currently approved anti-HIV drugs (e.g., reverse transcriptase inhibitors, protease inhibitors and fusion/entry inhibitors) must act inside or on surface of the target cell to inhibit HIV infection, but none can directly inactivate virions away from cells. Although soluble CD4 (sCD4) can inactivate laboratory-adapted HIV-1 strains, it fails to reduce the viral loads in clinical trials because of its low potency against primary isolates and tendency to enhance HIV-1 infection at low concentration. Thus, it is essential to design a better HIV inactivator with improved potency for developing new anti-HIV therapeutics that can actively attack the virus in the circulation before it attaches to and enter into the target cell.

RESULTS:

We engineered a bivalent HIV-1 inactivator, designated 2DLT, by linking the D1D2 domain of CD4 to T1144, the next generation HIV fusion inhibitor, with a 35-mer linker. The D1D2 domain in this soluble 2DLT protein could bind to the CD4-binding site and induce the formation of the gp41 prehairpin fusion-intermediate (PFI), but showed no sCD4-mediated enhancement of HIV-1 infection. The T1144 domain in 2DLT then bound to the exposed PFI, resulting in rapid inactivation of HIV-1 virions in the absence of the target cell. Beside, 2DLT could also inhibit fusion of the virus with the target cell if the virion escapes the first attack of 2DLT.

CONCLUSION:

This bivalent molecule can serve as a dual barrier against HIV infection by first inactivating HIV-1 virions away from cells and then blocking HIV-1 entry on the target cell surface, indicating its potential for development as a new class of anti-HIV drug.

• Authors: Lu Lu, Chungen Pan, Yuan Li, Hong Lu, Wu He, Shibo Jiang
• Journal: Retrovirology (Retrovirology) Vol. 9 Pg. 104 (Dec 07 2012) ISSN: 1742-4690 [Electronic] England
• PMID: 23217195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD4 Antigens
• HIV Envelope Protein gp120
• HIV Envelope Protein gp41
• HIV Fusion Inhibitors
• Receptors, CCR5
• Recombinant Fusion Proteins
• Recombinant Proteins
• recombinant soluble CD4

Topics

• Amino Acid Sequence
• CD4 Antigens (chemistry, metabolism)
• Cell Line
• HIV Envelope Protein gp120 (metabolism)
• HIV Envelope Protein gp41 (antagonists & inhibitors, chemistry)
• HIV Fusion Inhibitors (chemistry, pharmacology)
• HIV-1 (drug effects, metabolism)
• Humans
• Membrane Fusion (drug effects)
• Molecular Sequence Data
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Multimerization (drug effects)
• Receptors, CCR5 (metabolism)
• Recombinant Fusion Proteins (chemistry, pharmacology)
• Recombinant Proteins (chemistry, metabolism)
• Virion (drug effects)
• Virus Replication (drug effects)