Background:  Transmission of HIV drug resistance is well recognized and compromises

response to first-line therapy. However, the population dynamics of transmitted resistance remains unclear, although previous models have assumed that such transmission reflects direct infection from treated individuals. We wished to ask whether population-based phylogenetic analyses would uncover lineages of resistant viruses circulating in

untreated individuals.

Methods:  The phylogeny of 14,061 HIV-1 pol gene sequences generated in the United Kingdom from both treatment-naïve and -experienced individuals was reconstructed. To characterize drug-resistant virus lineages in epidemiologically linked drug-naïve individuals, the ancestral states of 37 resistance-associated codon positions was then reconstructed along the phylogeny, and resistance-associated polymorphisms present at internal nodes linking patients with no known treatment history were identified. The phylogenetic clustering of ≥3 sequences from drug-naïve patients sharing ≥1 resistance-associated polymorphism was considered as evidence for the existence of a drug-resistant viral lineage. The time of emergence and persistence of these drug-resistant lineages was finally estimated by Bayesian MCMC inference.

Results:  We have identified 5 treatment-independent viral clusters containing mutations conferring cross-resistance to antiretroviral drugs prescribed today in the United Kingdom. These viral lineages included 19, 9, 4, 3, and 3 patients, respectively, and represent sustainable reservoirs of resistance amongst new HIV infections, independent of treatment. Dated-phylogenies indicated that these reservoirs originated between 1997 and 2003, and have persisted in the HIV infected population for as long as 8 years.

Conclusions:  The existence of sustained reservoirs of resistance in the absence of treatment has the capacity to threaten the long-term efficacy of ART and suggests there is a limit to the decline of transmitted drug resistance. Given the current decrease in resistance transmitted from treated individuals in the United Kingdom, a greater proportion of resistance is likely to come from drug-naïve lineages. These findings provide new insights for the planning and management of treatment programs in resource-rich and developing countries.