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J Virol ; 94(12)2020 06 01.
Article in English | MEDLINE | ID: mdl-32295903

ABSTRACT

Cell entry by HIV-1 is mediated by its principal receptor, CD4, and a coreceptor, either CCR5 or CXCR4, with viral envelope glycoprotein gp120. Generally, CCR5-using HIV-1 variants, called R5, predominate over most of the course of infection, while CXCR4-using HIV-1 variants (variants that utilize both CCR5 and CXCR4 [R5X4, or dual] or CXCR4 alone [X4]) emerge at late-stage infection in half of HIV-1-infected individuals and are associated with disease progression. Although X4 variants also appear during acute-phase infection in some cases, these variants apparently fall to undetectable levels thereafter. In this study, replication-competent X4 variants were isolated from plasma of drug treatment-naive individuals infected with HIV-1 strain CRF01_AE, which dominantly carries viral RNA (vRNA) of R5 variants. Next-generation sequencing (NGS) confirmed that sequences of X4 variants were indeed present in plasma vRNA from these individuals as a minor population. On the other hand, in one individual with a mixed infection in which X4 variants were dominant, only R5 replication-competent variants were isolated from plasma. These results indicate the existence of replication-competent variants with different coreceptor usage as minor populations.IMPORTANCE The coreceptor switch of HIV-1 from R5 to CXCR4-using variants (R5X4 or X4) has been observed in about half of HIV-1-infected individuals at late-stage infection with loss of CD4 cell count and disease progression. However, the mechanisms that underlie the emergence of CXCR4-using variants at this stage are unclear. In the present study, CXCR4-using X4 variants were isolated from plasma samples of HIV-1-infected individuals that dominantly carried vRNA of R5 variants. The sequences of the X4 variants were detected as a minor population using next-generation sequencing. Taken together, CXCR4-using variants at late-stage infection are likely to emerge when replication-competent CXCR4-using variants are maintained as a minor population during the course of infection. The present study may support the hypothesis that R5-to-X4 switching is mediated by the expansion of preexisting X4 variants in some cases.


Subject(s)
HIV Infections/immunology , HIV-1/genetics , Receptors, CCR5/genetics , Receptors, CXCR4/genetics , Receptors, HIV/immunology , Adult , Aged , Amino Acid Sequence , CD4 Lymphocyte Count , Coinfection , Disease Progression , Female , Gene Expression Regulation , HIV Infections/genetics , HIV Infections/virology , HIV-1/classification , HIV-1/immunology , High-Throughput Nucleotide Sequencing , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Male , Middle Aged , Phylogeny , Protein Binding , RNA, Viral/genetics , RNA, Viral/immunology , Receptors, CCR5/immunology , Receptors, CXCR4/immunology , Receptors, HIV/genetics , Viral Tropism/genetics , Viral Tropism/immunology , Virus Attachment , Virus Internalization
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