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The R5 virus is the most prevalent virus detected during transmission, the most abundant in the late stages of disease, and the most commonly encountered virus during the course of HIV-1-associated neurological impairment based on the subsequent trafficking of infected monocytes to the CNS –. Conversely, R5 viruses have a greater preference for cells of the monocyte-macrophage lineage however, R5 viruses also display a propensity to enter and replicate in T cells, although they infect a smaller percentage of CD4 + T cells compared with X4 viruses. The X4 virus plays an important role in accelerating disease progression because it is able to efficiently infect T cells and produces a large amount of viral progeny, resulting in high viral load and death of the infected cell population, eventually leading to T-cell depletion.
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HIV-1 X4 and R5 gp120 engagement of receptor/co-receptors on CD4 + T cells and cells of the monocyte-macrophage lineage has been shown to lead to very different patterns of viral replication and pathogenesis. PSSM scores an Env-V3 sequence with respect to known X4 Env-V3 residues at each amino acid calculated such that the scoring distributions between X4 and R5 sequences are significantly different. The position-specific scoring matrix (PSSM) is a Web-based, sequence-based predictive algorithm that is highly accurate and widely used to predict co-receptor usage –. Using the Env-V3 genotypic sequence in conjunction with computational analysis using in silico prediction paradigms has provided an alternative approach to the traditional in vitro phenotypic assay for co-receptor usage prediction –. These studies have also provided important information with regard to determining which therapeutic strategies would be most effective for treating HIV-1 infection. Several studies have focused on the use of the Env-V3 sequence to predict viral tropism. The HIV-1 gp120 V3 (Env-V3) region is the main, though not the sole, determinant of co-receptor usage selection –. Current nomenclature relating to co-receptor utilization during the viral entry process designates CXCR4-utilizing virus as X4 virus, CCR5-utilizing virus as R5 virus, and dual tropic virus that can utilize either co-receptor as X4R5 virus. These steps lead to the glycoprotein 41 (gp41)-mediated fusion process between the viral envelope and the host cell plasma membrane. The two most commonly used co-receptors for viral entry are CXCR4 and CCR5 –. 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 co-receptors. 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. 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. 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. 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. Specific adaptive changes associated with X4 and R5 viruses were identified in co-linear viral sequences beyond the Env-V3. Additionally, R5 viruses have been associated with viral transmission and CNS disease and are also more prevalent during HIV-1 disease. 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. 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.
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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.