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Journal of Virology, May 2003, p. 5721-5730, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5721-5730.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Multiple Viral Genetic Analyses Detect Low-Level Human Immunodeficiency Virus Type 1 Replication during Effective Highly Active Antiretroviral Therapy

Lisa M. Frenkel,1,2* Yang Wang,3 Gerald H. Learn,3 Jennifer L. McKernan,1 Giovanina M. Ellis,1 Kathleen M. Mohan,1 Sarah E. Holte,4 Shannon M. De Vange,1 Diane M. Pawluk,1 Ann J. Melvin,1 Paul F. Lewis,5 Laura M. Heath,3 Ingrid A. Beck,1 Madhumita Mahalanabis,1,{dagger} Wilscott E. Naugler,1,{ddagger} Nicole H. Tobin,1 and James I. Mullins2,3,6

Departments of Pediatrics,1 Laboratory Medicine,2 Microbiology,3 Biostatistics,4 Medicine, University of Washington, Seattle, Washington,6 Department of Pediatrics, Oregon Health and Science University, Portland, Oregon5

Received 2 December 2002/ Accepted 14 February 2003

To evaluate human immunodeficiency virus type 1 (HIV-1) replication and selection of drug-resistant viruses during seemingly effective highly active antiretroviral therapy (HAART), multiple HIV-1 env and pol sequences were analyzed and viral DNA levels were quantified from nucleoside analog-experienced children prior to and during a median of 5.1 (range, 1.8 to 6.4) years of HAART. Viral replication was detected at different rates, with apparently increasing sensitivity: 1 of 10 by phylogenetic analysis; 2 of 10 by viral evolution with increasing genetic distances from the most recent common ancestor (MRCA) of infection; 3 of 10 by selection of drug-resistant mutants; and 6 of 10 by maintenance of genetic distances from the MRCA. When four- or five-drug antiretroviral regimens were given to these children, persistent plasma viral rebound did not occur despite the accumulation of highly drug-resistant genotypes. Among the four children without genetic evidence of viral replication, a statistically significant decrease in the genetic distance to the MRCA was detected in three, indicating the persistence of a greater number of early compared to recent viruses, and their HIV-1 DNA decreased by >=0.9 log10, resulting in lower absolute DNA levels (P = 0.007). This study demonstrates the variable rates of viral replication when HAART has suppressed plasma HIV-1 RNA for years to a median of <50 copies/ml and that combinations of four or five antiretroviral drugs suppress viral replication even after short-term virologic failure of three-drug HAART and despite ongoing accumulation of drug-resistant mutants. Furthermore, the decrease of cellular HIV-1 DNA to low absolute levels in those without genetic evidence of viral replication suggests that monitoring viral DNA during HAART may gauge low-level replication.

* Corresponding author. Mailing address: 4800 Sand Point Way, NE, 8G-1, Seattle, WA 98105. Phone: (206) 987-5140. Fax: (206) 987-3890. E-mail: lfrenkel{at}u.washington.edu.

{dagger} Present address: Department of Microbiology, University of Washington, Seattle, Wash.

{ddagger} Present address: Department of Medicine, Oregon Health and Science University, Portland, OR 97239.

Journal of Virology, May 2003, p. 5721-5730, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5721-5730.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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