Demonstration of sustained drug-resistant human immunodeficiency virus type 1 lineages circulating among treatment-naïve individuals

Abstract

Transmission of human immunodeficiency virus (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 investigated whether population-based phylogenetic analyses would uncover lineages of resistant viruses circulating in untreated individuals. Through the phylogenetic analysis of 14,061 HIV type 1 (HIV-1) pol gene sequences generated in the United Kingdom from both treatment-naïve and -experienced individuals, we identified five treatment-independent viral clusters containing mutations conferring cross-resistance to antiretroviral drugs prescribed today in the United Kingdom. These viral lineages represent sustainable reservoirs of resistance among new HIV infections, independent of treatment. Dated phylogenies reconstructed through Bayesian Markov chain Monte Carlo inference indicated that these reservoirs originated between 1997 and 2003 and have persisted in the HIV-infected population for up to 8 years. Since our cohort does not represent all infected individuals within the United Kingdom, our results are likely to underestimate the number and size of the resistant reservoirs circulating among drug-naïve patients. The existence of sustained reservoirs of resistance in the absence of treatment has the capacity to threaten the long-term efficacy of antiretroviral therapy and suggests there is a limit to the decline of transmitted drug resistance. Given the current decrease in resistance transmitted from treated individuals, 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.

FIG. 1.

Schematic distribution of DRMs found in the reconstructed HIV-1 pol gene phylogenies. Circles and squares at the tips of the branches represent drug-naïve and -experienced patients, respectively. Sequences with drug resistance mutations are indicated in red. Three distribution patterns were distinguished: sporadic acquisition of DRMs (a), treatment-dependent transmission of DRMs (b), and treatment-independent transmission of DRMs (c). Lineages of drug-resistant viruses circulating among newly infected individuals were defined as clusters of resistant viruses that included three or more drug-naïve individuals (c).

FIG. 2.

Phylogenies of the five resistant HIV-1 clusters circulating among drug-naïve individuals. The clusters were extracted from a Bayesian MCMC maximum clade credibility tree generated under the GTR + Γ model of evolution and a relaxed molecular clock. Branch lengths are expressed in nucleotide substitutions per site, and Bayesian posterior probabilities are shown when above 0.5. Terminal branches are labeled with the resistance mutations found in the respective sequences. Circles and squares symbolize drug-naïve and -experienced patients, respectively. Labels at internal nodes or tips of the trees correspond to the branches listed in Table 2.

FIG. 3.

Bayesian MCMC phylogenetic trees of the resistant lineages compared to 100 HIV-1 pol sequences after exclusion of 59 codon positions associated with drug resistance (a) or based on third-codon positions only (b). Branch lengths are expressed as the number of nucleotide substitutions per site. Boxes indicate the position of the five resistant clusters in the trees. Nodes with a posterior probability of 1.00 are labeled with a star.

FIG. 4.

(a) Estimated time of origin of the five resistant clusters circulating among drug-naïve individuals. The time of the most recent common ancestor of each cluster was estimated under a relaxed molecular clock model. (b) Relaxed clock dated phylogenies of the five resistant clusters circulating among drug-naïve individuals. Branch lengths are expressed in calendar years.