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Latent HIV-1 can be reactivated by cellular superinfection in a Tat-dependent manner, which can lead to the emergence of multidrug-resistant recombinant viruses.
- Source :
-
Journal of virology [J Virol] 2013 Sep; Vol. 87 (17), pp. 9620-32. Date of Electronic Publication: 2013 Jun 26. - Publication Year :
- 2013
-
Abstract
- The HIV-1 latent reservoir represents an important source of genetic diversity that could contribute to viral evolution and multidrug resistance following latent virus reactivation. This could occur by superinfection of a latently infected cell. We asked whether latent viruses might be reactivated when their host cells are superinfected, and if so, whether they could contribute to the generation of recombinant viruses. Using populations of latently infected Jurkat cells, we found that latent viruses were efficiently reactivated upon superinfection. Pathways leading to latent virus reactivation via superinfection might include gp120-CD4/CXCR4-induced signaling, modulation of the cellular environment by Nef, and/or the activity of Tat produced upon superinfection. Using a range of antiviral compounds and genetic approaches, we show that gp120 and Nef are not required for latent virus reactivation by superinfection, but this process depends on production of functional Tat by the superinfecting virus. In a primary cell model of latency in unstimulated CD4 T cells, superinfection also led to latent virus reactivation. Drug-resistant latent viruses were also reactivated following superinfection in Jurkat cells and were able to undergo recombination with the superinfecting virus. Under drug-selective pressure, this generated multidrug-resistant recombinants that were identified by unique restriction digestion band patterns and by population-level sequencing. During conditions of poor drug adherence, treatment interruption or treatment failure, or in drug-impermeable sanctuary sites, reactivation of latent viruses by superinfection or other means could provide for the emergence or spread of replicatively fit viruses in the face of strong selective pressures.
- Subjects :
- CD4 Antigens physiology
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes virology
Drug Resistance, Multiple, Viral genetics
Genes, tat
Genetic Variation
HEK293 Cells
HIV Envelope Protein gp120 physiology
HIV Infections drug therapy
HIV Infections virology
HIV-1 drug effects
HeLa Cells
Humans
Jurkat Cells
Reassortant Viruses drug effects
Receptors, CXCR4 physiology
Recombination, Genetic
Selection, Genetic
Superinfection drug therapy
Superinfection virology
Virus Activation genetics
Virus Activation physiology
Virus Latency genetics
HIV-1 genetics
HIV-1 physiology
Reassortant Viruses genetics
Reassortant Viruses physiology
tat Gene Products, Human Immunodeficiency Virus physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 87
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 23804632
- Full Text :
- https://doi.org/10.1128/JVI.01165-13