Abstract
BackgroundMost 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.ResultsWe 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.ConclusionThis 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.
Highlights
IntroductionMost 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
Most currently approved anti-HIV drugs must act inside or on surface of the target cell to inhibit HIV infection, but none can directly inactivate virions away from cells
SCD4 and CD4-mimetics could efficiently induce the formation of the gp41 prehairpin fusion intermediate (PFI) with the exposed grooves on the NHRtrimer [14], which is the target of peptidic HIV fusion inhibitors, such as SJ-2176 [15], T20 [16], C34 [17,18] and T1144 [19,20]. These results suggest that a molecule containing a CD4 or CD4-mimetic and a gp41 PFIbinding domain can inactivate HIV-1 more efficiently than soluble CD4 (sCD4) or CD4-mimetic since T1144 can bind to the exposed gp41 grooves induced by binding of sCD4 or CD4-mimetic to gp120 to speed the virus inactivation
Summary
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. Thirty-two anti-HIV drugs (including five fixed-dose combinations) have been licensed by the United States Food and Drug Administration (FDA) for treatment of HIV infection/AIDS (http://www.hivandhepatitis.com/hiv_and_aids/hiv_treat.html). Most of these drugs act inside the host cell to inhibit viral replication by targeting HIV reverse transcriptase, protease, or integrase. To infect a target cell, HIV-1 first binds to the cellular receptor CD4 and a co-receptor, CXCR4 or CCR5 through its envelope glycoprotein (Env) surface subunit gp120. Mutations in the multiple highly conserved tyrosine and dileucine motifs in gp cytoplasmic domain lead to a loss of HIV-1 Envmediated membrane fusion [8], and several specific amino acid changes in gp120 V3 region and gp are associated together with CXCR4 and/or CCR5 usage [9], suggesting that both gp120 and gp play important roles in HIV-1 entry and are attractive targets for developing an HIV-1 inactivator and/or entry inhibitors [10]
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