Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy.
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 > or =0.9 log(10), 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.
Department of Pediatrics, University of Washington, Seattle, Washington, USA. lfrenkel@u.washington.edu
Lisa M
LM
Frenkel
Yang
Y
Wang
Gerald H
GH
Learn
Jennifer L
JL
McKernan
Giovanina M
GM
Ellis
Kathleen M
KM
Mohan
Sarah E
SE
Holte
Shannon M
SM
De Vange
Diane M
DM
Pawluk
Ann J
AJ
Melvin
Paul F
PF
Lewis
Laura M
LM
Heath
Ingrid A
IA
Beck
Madhumita
M
Mahalanabis
Wilscott E
WE
Naugler
Nicole H
NH
Tobin
James I
JI
Mullins
D023241:Antiretroviral Therapy, Highly Active; D002648:Child; D002675:Child, Preschool; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D010802:Phylogeny; D012367:RNA, Viral / Q000097:blood; D017422:Sequence Analysis, DNA; D014779:Virus Replication
D004279:DNA, Viral; D012367:RNA, Viral