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HIV-1 resistance to CCR5 antagonists associated with highly efficient use of CCR5 and altered tropism on primary CD4+ T cells.
- Source :
-
Journal of virology [J Virol] 2010 Jul; Vol. 84 (13), pp. 6505-14. Date of Electronic Publication: 2010 Apr 21. - Publication Year :
- 2010
-
Abstract
- We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4(+) T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N' terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a tropism shift toward effector memory cells upon infection of primary CD4(+) T cells in the presence of APL, with relative sparing of the central memory CD4(+) T cell subset. If such a tropism shift proves to be a common feature of CCR5-antagonist-resistant viruses, then continued use of CCR5 antagonists even in the face of virologic failure could provide a relative degree of protection to the T(CM) subset of CD4(+) T cells and result in improved T cell homeostasis and immune function.
- Subjects :
- Benzoates pharmacology
CCR5 Receptor Antagonists
Diketopiperazines
HIV Envelope Protein gp120 genetics
HIV Envelope Protein gp41 genetics
HIV-1 physiology
Humans
Mutation, Missense
Piperazines pharmacology
Receptors, HIV antagonists & inhibitors
Spiro Compounds pharmacology
Virus Attachment
Anti-HIV Agents pharmacology
CD4-Positive T-Lymphocytes virology
Drug Resistance, Viral
HIV-1 drug effects
Receptors, CCR5 physiology
Receptors, HIV physiology
Viral Tropism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 84
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 20410277
- Full Text :
- https://doi.org/10.1128/JVI.00374-10