Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor Usage
The tropism of the Human Immunodeficiency Virus type 1 (HIV-1) is determined by the use of either or both chemokine coreceptors CCR5 (R5) and CXCR4 (X4) for entry into the target cell. The ability of HIV-1 to bind R5 or X4 is determined primarily by the third variable loop (V3) of the viral envelope...
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2025-02-01
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| author | Angelo Pavesi Fabio Romerio |
| author_facet | Angelo Pavesi Fabio Romerio |
| author_sort | Angelo Pavesi |
| collection | DOAJ |
| description | The tropism of the Human Immunodeficiency Virus type 1 (HIV-1) is determined by the use of either or both chemokine coreceptors CCR5 (R5) and CXCR4 (X4) for entry into the target cell. The ability of HIV-1 to bind R5 or X4 is determined primarily by the third variable loop (V3) of the viral envelope glycoprotein gp120. HIV-1 strains of pandemic group M contain an antisense gene termed <i>asp</i>, which overlaps <i>env</i> outside the region encoding the V3 loop. We previously showed that the ASP protein localizes on the envelope of infectious HIV-1 virions, suggesting that it may play a role in viral entry. In this study, we first developed a statistical method to predict coreceptor tropism based on Fisher’s linear discriminant analysis. We obtained three linear discriminant functions able to predict coreceptor tropism with high accuracy (94.4%) when applied to a training dataset of V3 sequences of known tropism. Using these functions, we predicted the tropism in a dataset of HIV-1 strains containing a full-length <i>asp</i> gene. In the amino acid sequence of ASP proteins expressed from these <i>asp</i> genes, we identified five positions with substitutions significantly associated with viral tropism. Interestingly, we found that these substitutions correlate significantly with substitutions at six amino acid positions of the V3 loop domain associated with tropism. Altogether, our computational analyses identify ASP amino acid signatures coevolving with V3 and potentially affecting HIV-1 tropism, which can be validated through in vitro and in vivo experiments. |
| format | Article |
| id | doaj-art-d6bd21d30d4340d5b8ca27dbc2d27ab6 |
| institution | DOAJ |
| issn | 1999-4915 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-d6bd21d30d4340d5b8ca27dbc2d27ab62025-08-20T02:43:10ZengMDPI AGViruses1999-49152025-02-0117332310.3390/v17030323Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor UsageAngelo Pavesi0Fabio Romerio1Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 23A, I-43124 Parma, ItalyDepartment of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USAThe tropism of the Human Immunodeficiency Virus type 1 (HIV-1) is determined by the use of either or both chemokine coreceptors CCR5 (R5) and CXCR4 (X4) for entry into the target cell. The ability of HIV-1 to bind R5 or X4 is determined primarily by the third variable loop (V3) of the viral envelope glycoprotein gp120. HIV-1 strains of pandemic group M contain an antisense gene termed <i>asp</i>, which overlaps <i>env</i> outside the region encoding the V3 loop. We previously showed that the ASP protein localizes on the envelope of infectious HIV-1 virions, suggesting that it may play a role in viral entry. In this study, we first developed a statistical method to predict coreceptor tropism based on Fisher’s linear discriminant analysis. We obtained three linear discriminant functions able to predict coreceptor tropism with high accuracy (94.4%) when applied to a training dataset of V3 sequences of known tropism. Using these functions, we predicted the tropism in a dataset of HIV-1 strains containing a full-length <i>asp</i> gene. In the amino acid sequence of ASP proteins expressed from these <i>asp</i> genes, we identified five positions with substitutions significantly associated with viral tropism. Interestingly, we found that these substitutions correlate significantly with substitutions at six amino acid positions of the V3 loop domain associated with tropism. Altogether, our computational analyses identify ASP amino acid signatures coevolving with V3 and potentially affecting HIV-1 tropism, which can be validated through in vitro and in vivo experiments.https://www.mdpi.com/1999-4915/17/3/323HIV-1antisense gene aspcell tropismcoevolutioncoreceptor usageenvelope protein |
| spellingShingle | Angelo Pavesi Fabio Romerio Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor Usage Viruses HIV-1 antisense gene asp cell tropism coevolution coreceptor usage envelope protein |
| title | Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor Usage |
| title_full | Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor Usage |
| title_fullStr | Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor Usage |
| title_full_unstemmed | Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor Usage |
| title_short | Covariation of Amino Acid Substitutions in the HIV-1 Envelope Glycoprotein gp120 and the Antisense Protein ASP Associated with Coreceptor Usage |
| title_sort | covariation of amino acid substitutions in the hiv 1 envelope glycoprotein gp120 and the antisense protein asp associated with coreceptor usage |
| topic | HIV-1 antisense gene asp cell tropism coevolution coreceptor usage envelope protein |
| url | https://www.mdpi.com/1999-4915/17/3/323 |
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