HIV type 1 fitness evolution in antiretroviral-experienced patients with sustained CD4+ T cell counts but persistent virologic failure.
BACKGROUND
Over recent years, treatment guidelines for human immunodeficiency virus (HIV) infection have evolved from monotherapy to combination regimens that include > or = 3 active drugs, resulting in a sharp decrease in morbidity and mortality. In the present article, we evaluated changes in HIV type 1 viral fitness associated with the sequential introduction of antiretroviral treatment strategies in 4 chronically infected patients with sustained CD4 cell count despite having a persistently detectable viral load.


METHODS
Plasma samples were obtained before and during treatment to construct recombinant virus containing the 3'-end of gag, the protease and the reverse-transcriptase coding region. Drug susceptibility phenotype was evaluated with a panel of multiple reverse-transcriptase and protease inhibitors. Replicative capacity (RC) and infectivity were measured, and production of p24 was monitored after transfection.


RESULTS
Multidrug-resistant (MDR) viruses selected during long-term antiretroviral therapy were less fit and infectious than their wild-type or monotherapy-selected counterparts, with the exception of viruses recovered from patient B. In 3 of 4 cases, p24 kinetics after transfection showed a delay in viral production of recombinant viruses containing MDR mutations. Data from the RC and infectivity assays showed good correlation (P < .03) and corroborated the p24 kinetics data.


CONCLUSIONS
This study shows that accumulation of MDR mutations during long-term antiretroviral treatment results, albeit not in all cases, in reductions of viral fitness.
Prado
Julia G
JG
IrsiCaixa Foundation, Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain.
Parkin
Neil T
NT
Clotet
Bonaventura
B
Ruiz
Lidia
L
Martinez-Picado
Javier
J
D019380:Anti-HIV Agents / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D024921:Drug Resistance, Multiple, Viral; D019143:Evolution, Molecular; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D013997:Time Factors
D019380:Anti-HIV Agents; D012367:RNA, Viral