Genetically Intact but Functionally Impaired HIV-1 Env Glycoproteins in the T-Cell Reservoir
| Autor: | Jacques Dutrieux, François Clavel, Anne de Verneuil, Allan J. Hance, Sébastien Gallien, Julie Migraine, Hugo Mouquet, Jean-Michel Molina, Fabrizio Mammano |
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| Přispěvatelé: | Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP), Mammano, Fabrizio, Institut Pasteur [Paris] |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine reservoir viruses T cell [SDV]Life Sciences [q-bio] Immunology envelope function HIV Infections Biology Virus Replication Microbiology Genome Virus MESH: HIV-1 MESH: Proviruses 03 medical and health sciences Immune system Proviruses Virology medicine Humans Cells Cultured Infectivity chemistry.chemical_classification MESH: Humans MESH: Virus Replication env Gene Products Human Immunodeficiency Virus MESH: Virus Latency virus diseases HIV MESH: CD4-Positive T-Lymphocytes MESH: HIV Infections Virus Latency 3. Good health [SDV] Life Sciences [q-bio] 030104 developmental biology medicine.anatomical_structure Genetic Diversity and Evolution Viral replication chemistry Insect Science HIV-1 MESH: env Gene Products Human Immunodeficiency Virus Glycoprotein Function (biology) MESH: Cells Cultured |
| Zdroj: | Journal of Virology Journal of Virology, 2018, 92 (4), pp.e01684-17. ⟨10.1128/jvi.01684-17⟩ Journal of Virology, American Society for Microbiology, 2018, 92 (4), pp.e01684-17. ⟨10.1128/jvi.01684-17⟩ |
| ISSN: | 0022-538X 1098-5514 |
| DOI: | 10.1128/jvi.01684-17⟩ |
| Popis: | HIV-infected subjects under antiretroviral treatment (ART) harbor a persistent viral reservoir in resting CD4 + T cells, which accounts for the resurgence of HIV replication after ART interruption. A large majority of HIV reservoir genomes are genetically defective, but even among intact proviruses few seem able to generate infectious virus. To understand this phenomenon, we examined the function and expression of HIV envelope glycoproteins reactivated from the reservoir of four HIV-infected subjects under suppressive ART. We studied full-length genetically intact env sequences from both replicative viruses and cell-associated mRNAs. We found that these Env proteins varied extensively in fusogenicity and infectivity, with strongest functional defects found in Envs from cell-associated mRNAs. Env functional impairments were essentially explained by defects in Env protein expression. Our results support the idea that defects in HIV Env expression, preventing cytopathic or immune HIV clearance, contribute to the persistence of the HIV T-cell reservoir in vivo . IMPORTANCE In most individuals, evolution of HIV infection is efficiently controlled on the long-term by combination antiviral therapies. These treatments, however, fail to eradicate HIV from the infected subjects, a failure that results both in resurgence of virus replication and in resumption of HIV pathogenicity when the treatment is stopped. HIV resurgence, in these instances, is widely assumed to emerge from a reservoir of silent virus integrated in the genomes of a small number of T lymphocytes. The silent HIV reservoir is mostly composed of heavily deleted or mutated HIV DNA. Moreover, among the seemingly intact remaining HIV, only very few are actually able to efficiently propagate in tissue culture. In this study, we find that intact HIV in the reservoir often carry strong defects in their capacity to promote fusion to neighboring cells and infection of target cells, a defect related to the function and expression of the HIV envelope glycoprotein. Impaired envelope glycoprotein expression and function could explain why cells harboring these viruses tend to remain undetected and unharmed in the reservoir. |
| Databáze: | OpenAIRE |
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