Abstract
BackgroundIn approximately 10% of newly diagnosed individuals in Europe, HIV-1 variants harboring transmitted drug resistance mutations (TDRM) are detected. For some TDRM it has been shown that they revert to wild type while other mutations persist in the absence of therapy. To understand the mechanisms explaining persistence we investigated the in vivo evolution of frequently transmitted HIV-1 variants and their impact on in vitro replicative capacity.ResultsWe selected 31 individuals infected with HIV-1 harboring frequently observed TDRM such as M41L or K103N in reverse transcriptase (RT) or M46L in protease. In all these samples, polymorphisms at non-TDRM positions were present at baseline (median protease: 5, RT: 6). Extensive analysis of viral evolution of protease and RT demonstrated that the majority of TDRM (51/55) persisted for at least a year and even up to eight years in the plasma. During follow-up only limited selection of additional polymorphisms was observed (median: 1).To investigate the impact of frequently observed TDRM on the replication capacity, mutant viruses were constructed with the most frequently encountered TDRM as site-directed mutants in the genetic background of the lab strain HXB2. In addition, viruses containing patient-derived protease or RT harboring similar TDRM were made. The replicative capacity of all viral variants was determined by infecting peripheral blood mononuclear cells and subsequently monitoring virus replication. The majority of site-directed mutations (M46I/M46L in protease and M41L, M41L + T215Y and K103N in RT) decreased viral replicative capacity; only protease mutation L90M did not hamper viral replication. Interestingly, most patient-derived viruses had a higher in vitro replicative capacity than the corresponding site-directed mutant viruses.ConclusionsWe demonstrate limited in vivo evolution of protease and RT harbouring frequently observed TDRM in the plasma. This is in line with the high in vitro replication capacity of patient-derived viruses harbouring TDRM compared to site-directed mutant viruses harbouring TDRM. As site-directed mutant viruses have a lower replication capacity than the patient-derived viruses with similar mutational patterns, we propose that (baseline) polymorphisms function as compensatory mutations improving viral replication capacity.
Highlights
In approximately 10% of newly diagnosed individuals in Europe, HIV-1 variants harboring transmitted drug resistance mutations (TDRM) are detected
Patients diagnosed with a transmitted drug resistant HIV-1 variant To investigate the in vivo evolution of transmitted drug resistant HIV variants, we selected 31 patients from four European countries (Belgium, NL the Netherlands (Greece), the Netherlands, Slovenia) who were diagnosed in 2001 to 2008 with an HIV variant harboring a frequently observed TDRM
In this study we strived to explain the in vivo persistence of the majority of TDRM in patients diagnosed with a drug-resistant HIV-1 variant
Summary
In approximately 10% of newly diagnosed individuals in Europe, HIV-1 variants harboring transmitted drug resistance mutations (TDRM) are detected. In resource-rich settings, drug resistance mutations in protease and RT are detected in 10-15% of newly diagnosed HIV patients [2,3]. Nucleoside RT inhibitor (NRTI) mutations are the most frequently observed transmitted drug resistance mutations (TDRM). Thymidine analogue mutations (TAMs) M41L and T215 variants, that have been selected by drugs extensively used in the past, are often observed in newly diagnosed patients [4]. A worrying trend is the increased prevalence of non-nucleoside RT inhibitor (NNRTI) related mutations in newly diagnosed patients [3,5], as single NNRTI mutations, such as the frequently observed K103N mutation, can result in high levels of resistance against first generation NNRTIs [6]. When present in combination with other protease drug resistance mutations, both M46I/L and L90M are related to reduced susceptibility to several protease inhibitors (PIs) [6]
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