Persistence of multidrug-resistant HIV-1 in primary infection leading to superinfection

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Abstract
The authors previous studies documented persistence of multidrug resistance (MDR) acquired in five primary HIV-1infection (PHI) cases for 1–2 years in the absence of antiretroviral treatment. This study characterizes the evolution of transmitted wild-type (WT) (n = 15), resistant (n = 10), and MDR (n = 6) infections. Long-term persistence of MDR infections (2–7 years), leading to one observed MDR superinfection is documented. Genotypic changes in circulating viral quasi-species were evaluated over 1.5–7 years in patients (n = 31) enrolled in the PHI study. Sequencing of reverse transcriptase and protease regions identified nucleotide substitutions in the viral quasi-species and mutations at sites implicated in resistance to antiretroviral drugs. Phylogenetic and clonal analysis were performed to confirm one observed superinfection. Patients acquiring WT, drug-resistant and MDR infections showed little quasi-species evolution (> 99.6% homology) for more than 1.5 years, regardless of route of transmission. Transmitted resistance mutations (other than 184V) persisted for 2–7 years. MDR persistence in two PHI cases contrasted with the corresponding rapid reversion of MDR infections to WT in their partners following treatment interruption. One MDR transmission eliciting low-level viremia resulted in clearance of the original MDR infection followed by re-infection with a second heterologous MDR strain from a different partner. Phylogenetic and clonal analysis of source and index partner confirmed the superinfection. Both MDR species showed approximately 13-fold reductions in replication capacity relative to the homologous WT strain isolated from the source partner. Genotypic analysis in PHI may identify superinfection and MDR infections that represent important determinants of virological and treatment outcome.