Abstract
The adaptation of human immunodeficiency virus type-1 (HIV-1) to an array of physiologic niches is advantaged by the plasticity of the viral genome, encoded proteins, and promoter. CXCR4-utilizing (X4) viruses preferentially, but not universally, infect CD4+ T cells, generating high levels of virus within activated HIV-1-infected T cells that can be detected in regional lymph nodes and peripheral blood. By comparison, the CCR5-utilizing (R5) viruses have a greater preference for cells of the monocyte-macrophage lineage; however, while R5 viruses also display a propensity to enter and replicate in T cells, they infect a smaller percentage of CD4+ T cells in comparison to X4 viruses. Additionally, R5 viruses have been associated with viral transmission and CNS disease and are also more prevalent during HIV-1 disease. Specific adaptive changes associated with X4 and R5 viruses were identified in co-linear viral sequences beyond the Env-V3. The in silico position-specific scoring matrix (PSSM) algorithm was used to define distinct groups of X4 and R5 sequences based solely on sequences in Env-V3. Bioinformatic tools were used to identify genetic signatures involving specific protein domains or long terminal repeat (LTR) transcription factor sites within co-linear viral protein R (Vpr), trans-activator of transcription (Tat), or LTR sequences that were preferentially associated with X4 or R5 Env-V3 sequences. A number of differential amino acid and nucleotide changes were identified across the co-linear Vpr, Tat, and LTR sequences, suggesting the presence of specific genetic signatures that preferentially associate with X4 or R5 viruses. Investigation of the genetic relatedness between X4 and R5 viruses utilizing phylogenetic analyses of complete sequences could not be used to definitively and uniquely identify groups of R5 or X4 sequences; in contrast, differences in the genetic diversities between X4 and R5 were readily identified within these co-linear sequences in HIV-1-infected patients.
Highlights
The initial step of infection with human immunodeficiency virus type 1 (HIV-1) involves the interaction of the viral envelope glycoprotein, gp120, with the host cellular CD4 receptor, followed by the subsequent interaction with one of the chemokine coreceptors
R5 viruses have a greater preference for cells of the monocyte-macrophage lineage; R5 viruses display a propensity to enter and replicate in T cells, they infect a smaller percentage of CD4+ T cells compared with X4 viruses [26]
viral protein R (Vpr) and Tat amino acid residues, and long terminal repeat (LTR) nucleic acid sequences to identify X4- and R5-specific signature sequences in the Vpr, Tat, and LTR. These studies demonstrated the presence of specific nucleotide and amino acid residues within Vpr, Tat, and LTR that differentially define regions consistent with CXCR4 and CCR5 co-receptor usage as defined by position-specific scoring matrix (PSSM) scoring of co-linear Env-V3 sequences
Summary
The initial step of infection with human immunodeficiency virus type 1 (HIV-1) involves the interaction of the viral envelope glycoprotein, gp120, with the host cellular CD4 receptor, followed by the subsequent interaction with one of the chemokine coreceptors. These studies demonstrated the presence of specific nucleotide and amino acid residues within Vpr, Tat, and LTR that differentially define regions consistent with CXCR4 and CCR5 co-receptor usage as defined by PSSM scoring of co-linear Env-V3 sequences.
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