Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2003 Apr 15;100(8):4819-24.
doi: 10.1073/pnas.0736332100. Epub 2003 Apr 8.

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

M C Strain  1 , H F Günthard, D V Havlir, C C Ignacio, D M Smith, A J Leigh-Brown, T R Macaranas, R Y Lam, O A Daly, M Fischer, M Opravil, H Levine, L Bacheler, C A Spina, D D Richman, J K Wong
Affiliations

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

M C Strain et al. Proc Natl Acad Sci U S A. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Fate of infected lymphocytes with M184V mutant and 184M wild-type viruses based on different models of cell clearance and under different treatment conditions. Cells harboring 184M virus are shown as open circles, and cells harboring 184V virus are shaded circles. The expected results shown are theoretical outcomes in isolation from all other processes. (a) Uniform decay predicted by current models which assume a homogeneous population and in the absence of effects due to disproportionate reseeding. (b) Replenishment of reservoir on HAART with lamivudine. (c) Replenishment of reservoir on HAART without lamivudine. (d) Cell loss caused by senescent death. (e) Preferential loss of latently infected cells that were more recently established.
Figure 2
Figure 2
Plasma RNA response in representative patients, M2 and M1, during suppressive and nonsuppressive therapy. Interval of replication exclusively of 184M virus occurred before therapy (solid bar, lower portion of graph). Interval of preferential replication of 184V genomes began during nonsuppressive treatment and continued during HAART (broken bar, lower portion of graph). (a) Patient M2 experienced rapid and sustained suppression of plasma viremia. (b) Patient M1 received similar treatment but experienced intermittently detectable viremia during HAART.
Figure 3
Figure 3
Rise of M184V mutants in plasma RNA and PBMC DNA. (a) In all six patients, more than 90% of plasma RNA genotypes contained the 184V codon after 12 weeks of treatment with ZDV/3TC. Although the accumulation of 184V in PBMC DNA was slower, the mutant accounted for a majority of genotypes before or at the time HAART was initiated. (b and c) Decay of HIV DNA in representative patients receiving HAART with lamivudine. (b) Patient M1. Viral DNA with the 184V or 184M markers both decay very slowly in this patient, who experienced episodic viremia up to 700 copies per ml during HAART. (c) Patient M2. Viral DNA containing 184M is relatively stable, whereas 184V DNA decays rapidly.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Wei X, Ghosh S K, Taylor M E, Jonson V A, Emini E A, Deutsch P, Lifson J D, Bonhoeffer S, Nowak M A, Hahn B H, et al. Nature. 1995;373:117–122. - PubMed
    1. Ho D D, Neumann A U, Perelson A S, Chen W, Leonard J M, Markowitz M. Nature. 1995;373:123–126. - PubMed
    1. Perelson A S, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, Markowitz M, Ho D D. Nature. 1997;387:188–191. - PubMed
    1. Cavert W, Notermans D W, Staskus K, Wietgrefe S, Zupancic M, Gebhard K, Henry K, Zhang Z Q, Mills R, McDade H, et al. Science. 1997;276:960–964. - PubMed
    1. Hlavacek W S, Wofsy C, Perelson A S. Proc Natl Acad Sci USA. 1999;96:14681–14686. - PMC - PubMed

Publication types

LinkOut - more resources