Abstract
The most predominant HIV-1 strains in China's current epidemic is the Circulating Recombinant Form 07_BC (CRF07_BC). CRF07_BC is mainly considered as a CCR5-tropic (R5) virus, since CXCR4-tropic (X4) viruses have thus far not been found in this subtype, and the molecular determinants of coreceptor switching remain unknown. To investigate the mechanisms underlying coreceptor requirement in CRF07_BC viruses, we characterized a panel of pNL4-3-based chimeric viruses with mutated V3 loop regions derived from an HIV-1 CRF07_BC infectious clone pXJDC13. Among 17 chimeric viruses, seven were dual-tropic and induced syncytium formation in MT-2 cells. Two amino acid insertions between positions 13 and 14, as well as arginine substitution at position 11 or 16 (IG insertion and P16R mutation or MG insertion and S11R mutation), conferred the chimeric viruses CXCR4-tropic features, which were same as subtype C X4 viruses. Next, to construct CRF07_BC X4 variants, mutated V3 loops were cloned into the CRF07_BC infectious clone pXJDC13. These V3 loops, which in the pNL4-3 backbone conferred chimeric viruses with CXCR4-using ability, abrogated infectivity completely in the CRF07_BC pXJDC13 genetic background. Similarly, IG insertion or MG insertion and S11R mutation dramatically diminished or completely abolished viral infectivity in other envelopes of subtype C or CRF07_BC. These results suggest that the effects of IG insertion and P16R mutation or MG insertion and S11R mutation on CXCR4 usage are context dependent, and additional mutations elsewhere in the envelope are needed to compensate for these fitness-reducing alterations.
Highlights
The envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) serve to mediate viral entry into cells
R5 viruses typically persist into late stages of disease, CXCR4- or dual-tropic viruses emerge in approximately 50% of individuals infected with subtype B viruses, and coreceptor switching is reported in subtype A, C, D, CRF01_AE, and CRF02_AG infections [8,9,10,11,12]
Does the coreceptor prediction methods developed on other subtypes work in CRF07_BC? Do CRF07_BC CXCR4tropic viruses share the same characteristics in the V3 region with X4 variants in other subtypes? Can CRF07_BC X4 variants be constructed by mutagenesis according to the V3 characteristics of subtype B and C X4 viruses? Here we systematically studied the impact of X4-like V3 features on the CRF07_BC infectious clone pXJDC13
Summary
The envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) serve to mediate viral entry into cells. This process requires the sequential interaction of gp120 with the CD4 receptor and coreceptors, such as CCR5 or CXCR4 [1]. HIV-1 infection is almost always established with R5 viruses, which predominate during the acute and asymptomatic phases of infection [2]. R5 viruses typically persist into late stages of disease, CXCR4- or dual-tropic viruses emerge in approximately 50% of individuals infected with subtype B viruses, and coreceptor switching is reported in subtype A, C, D, CRF01_AE, and CRF02_AG infections [8,9,10,11,12]
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