Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: Intrinsic stability predicts lifelong persistence

doi:10.1073/pnas.0736332100

Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: Intrinsic stability predicts lifelong persistence

Departments of ^*Medicine and Pathology and ^†Physics, University of California at San Diego, La Jolla, CA 90293; ^‡Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zürich, 8091 Zürich, Switzerland; ^§Positive Health Program, San Francisco General Hospital, San Francisco, CA 94110; ^¶School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom; ^‖Bristol Myers Squibb, Wilmington, DE 19805; and ^**Veterans Affairs San Diego Healthcare System, San Diego, CA 92161

Edited by John M. Coffin, Tufts University School of Medicine, Boston, MA, and approved February 12, 2003 (received for review October 27, 2002)

Abstract

Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of treatment and to identify cells replenished by ongoing replication. Decay rates of subsets of latently HIV-infected cells paradoxically decreased with time since establishment, reflecting heterogeneous lymphocyte activation and clearance. Residual low-level replication can replenish cellular reservoirs; however, it does not account for prolonged clearance rates in patients without detectable viremia. In patients receiving potent antiretroviral therapy, the latent pool has a heterogeneous and dynamic composition that comprises a progressively increasing proportion of stable lymphocytes. Eradication will not be achieved with complete inhibition of viral replication alone.

Footnotes

↵ ‡‡ To whom correspondence should be addressed. E-mail: j2wong{at}ucsd.edu.
This paper was submitted directly (Track II) to the PNAS office.
↵ †† Ruiz, N. & Ridler, S. (1997) 4th International Conference on Retrovirus and Opportunistic Infections, Jan. 22–26, Washington, DC LB1, 206 (abstr.).
↵ §§ Strain, M., Little, S., Daar, E., Günthard, H., Spina, C., Lam, R. Y., Daly, O. A., Ignacio, C., Macaranas, T., Kwok, S., et al. (2002) 9th International Conference on Retrovirus and Opportunistic Infections, February 24–28, Seattle, WA, 97 (abstr.).
Abbreviations:

HAART,

highly active antiretroviral therapy;

FDC,

follicular dendritic network;

PBMC,

peripheral blood mononuclear cells