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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, Wilscott E. Naugler,^1, Nicole H. Tobin,¹ and James I. Mullins^2,3,6

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.

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

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

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