Abstract
The initial infection and transmission of HIV-1 requires C–C chemokine receptor type 5 (CCR5). Here, we report that the membrane-proximal region (MPR, aa 22–38) of CCR5 participates in the infection of HIV-1. First, MPR-specific antibodies elicited in mice dose-dependently inhibited the infection of CCR5-tropic HIV-1. Second, substituting MPR with the same region from other co-receptors significantly impaired HIV-1 infection, while the key residues identified by alanine scanning mutagenesis formed an exposed leucine zipper-like structure. Moreover, a peptide derived from MPR could block the infection of a number of HIV-1 strains only before the formation of gp41 six-helix bundle, coincide with the early interaction between CCR5 and the gp120 protein during HIV-1 infection. These promising results ensured the potential of this previously uncharacterized domain as a starting point for the development of antiviral drugs, blocking antibodies, and HIV vaccines.
Highlights
Identifying novel targets in the infection process of HIV-1 is of great importance for the development of antiviral drugs, antibodies, and vaccines
By using bioinformatic methods, including SVMTrip [32], FBCPred [33], and PAP [34], to identify potential antigenic regions on chemokine receptor type 5 (CCR5), we found a previously unnoticed region located between N-terminus and TM1 (Figure 1B)
In sharp contrast to C17 which showed no inhibitory effect (IC50 > 50 μM) on all 20 min after mixing virus and cells. These results revealed that C17-Chol targeted to a very early event in the viral infection, consistent with the fact that the interaction between CCR5 and gp120 happened before the formation of gp41 fusion complex [45, 46]
Summary
Identifying novel targets in the infection process of HIV-1 is of great importance for the development of antiviral drugs, antibodies, and vaccines. The small molecule drugs against these well-known targets always induced resistant viruses quickly due to the high mutation rate, which is a major obstacle for a successful HIV vaccine [2]. The entry of HIV-1 requires two host proteins, the cluster of differentiation 4 (CD4) and the co-receptor. C–C chemokine receptor type 5 (CCR5) and C–X–C chemokine receptor type 4 (CXCR4) are two main co-receptors for HIV-1 infection, though other chemokine receptors including CCR2b and CCR3 may serve as co-receptors, albeit in rare cases [3]. CCR5 is exclusively utilized in the initial infection of HIV-1, whereas CXCR4-tropic strains are rarely observed in the early infection and only become dominant afterward [4].
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