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Journal of Virology, October 2009, p. 9731-9742, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00570-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Identification of Ongoing Human Immunodeficiency Virus Type 1 (HIV-1) Replication in Residual Viremia during Recombinant HIV-1 Poxvirus Immunizations in Patients with Clinically Undetectable Viral Loads on Durable Suppressive Highly Active Antiretroviral Therapy{triangledown}

Carlum Shiu,1 Coleen K. Cunningham,2 Thomas Greenough,3 Petronella Muresan,4 Victor Sanchez-Merino,3 Vincent Carey,4 J. Brooks Jackson,1 Carrie Ziemniak,1 Lawrence Fox,5 Marvin Belzer,6 Stuart C. Ray,1 Katherine Luzuriaga,3 Deborah Persaud,1* and the Pediatric AIDS Clinical Trials Group P1059 Team

Johns Hopkins University, Baltimore, Maryland,1 Duke University Medical Center, Durham, North Carolina,2 University of Massachusetts, Worcester, Massachusetts,3 Statistical and Data Analysis Center, Boston, Massachusetts,4 NIAID, NIH, Bethesda, Maryland,5 Children's Hospital Los Angeles, Los Angeles, California6

Received 19 March 2009/ Accepted 2 July 2009

In most human immunodeficiency virus type 1 (HIV-1)-infected individuals who achieve viral loads of <50 copies/ml during highly active antiretroviral therapy (HAART), low levels of plasma virus remain detectable for years by ultrasensitive methods. The relative contributions of ongoing virus replication and virus production from HIV-1 reservoirs to persistent low-level viremia during HAART remain controversial. HIV-1 vaccination of HAART-treated individuals provides a model for examining low-level viremia, as immunizations may facilitate virus replication and sequence evolution. In a phase 1 trial of modified vaccinia virus Ankara/fowlpox virus-based HIV-1 vaccines in 20 HIV-infected young adults receiving HAART, we assessed the prevalence of low-level viremia and sequence evolution, using ultrasensitive viral load (<6.5 copies/ml) and genotyping (five-copy sensitivity) assays. Viral evolution, consisting of new drug resistance mutations and novel amino acid changes within a relevant HLA-restricted allele (e.g., methionine, isoleucine, glutamine, or arginine for leucine at position 205 of RT), was found in 1 and 3 of 20 subjects, respectively. Sequence evolution was significantly correlated with levels of viremia of between 6.5 and <50 copies/ml (P = 0.03) and was more likely to occur within epitopes presented by relevant HLA alleles (P < 0.001). These findings suggest that ongoing virus replication contributes to low-level viremia in patients on HAART and that this ongoing replication is subject to CD8+ T-cell selective pressures.

* Corresponding author. Mailing address: Johns Hopkins University School of Medicine, Department of Pediatrics, 200 North Wolfe Street, Room 3151, Baltimore, MD 21287. Phone: (443) 287-3735. Fax: (410) 614-1315. E-mail: dpers{at}jhmi.edu

{triangledown} Published ahead of print on 15 July 2009.

Journal of Virology, October 2009, p. 9731-9742, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00570-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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