期刊
AIDS
卷 28, 期 8, 页码 1091-1099出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0000000000000223
关键词
genetic marker; integration; replication-incompetent; provirus; in-vivo persistence of CD4-positive T lymphocytes; HIV-1
资金
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Bethesda, Maryland)
- National Cancer Institute, National Institutes of Health [HHSN261200800001E]
Objective: Determining the precise lifespan of human T-cell is challenging due to the inability of standard techniques to distinguish between dividing and dying cells. Here, we measured the lifespan of a pool of T cells that were derived from a single cell 'naturally' labelled with a single integrated clone of a replication-incompetent HIV-1 provirus. Design/methods: Utilizing a combination of techniques, we were able to sequence/map an integration site of a unique provirus with a stop codon at position 42 of the HIV-1 protease. In-vitro reconstruction of this provirus into an infectious clone confirmed its inability to replicate. By combining cell separation and integration site-specific PCR, we were able to follow the fate of this single provirus in multiple T-cell subsets over a 20-year period. As controls, a number of additional integrated proviruses were also sequenced. Results: The replication-incompetent HIV-1 provirus was solely contained in the pool of effector memory CD4(+) T cells for 17 years. The percentage of the total effector memory CD4(+) T cells containing the replication-incompetent provirus peaked at 1% with a functional half-life of 11.1 months. In the process of sequencing multiple proviruses, we also observed high levels of lethal mutations in the peripheral blood pool of proviruses. Conclusion: These data indicate that human effector memory CD4(+) T cells are able to persist in vivo for more than 17 years without detectably reverting to a central memory phenotype. A secondary observation is that the fraction of the pool of integrated HIV-1 proviruses capable of replicating may be considerably less than the 12% currently noted in the literature.
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