Episodic sexual transmission of HIV revealed by molecular phylodynamics

Abstract

Background: The structure of sexual contact networks plays a key role in the epidemiology of sexually transmitted infections, and their reconstruction from interview data has provided valuable insights into the spread of infection. For HIV, the long period of infectivity has made the interpretation of contact networks more difficult, and major discrepancies have been observed between the contact network and the transmission network revealed by viral phylogenetics. The high rate of HIV evolution in principle allows for detailed reconstruction of links between virus from different individuals, but often sampling has been too sparse to describe the structure of the transmission network. The aim of this study was to analyze a high-density sample of an HIV-infected population using recently developed techniques in phylogenetics to infer the short-term dynamics of the epidemic among men who have sex with men (MSM).

Methods and findings: Sequences of the protease and reverse transcriptase coding regions from 2,126 patients, predominantly MSM, from London were compared: 402 of these showed a close match to at least one other subtype B sequence. Nine large clusters were identified on the basis of genetic distance; all were confirmed by Bayesian Monte Carlo Markov chain (MCMC) phylogenetic analysis. Overall, 25% of individuals with a close match with one sequence are linked to 10 or more others. Dated phylogenies of the clusters using a relaxed clock indicated that 65% of the transmissions within clusters took place between 1995 and 2000, and 25% occurred within 6 mo after infection. The likelihood that not all members of the clusters have been identified renders the latter observation conservative.

Conclusions: Reconstruction of the HIV transmission network using a dated phylogeny approach has revealed the HIV epidemic among MSM in London to have been episodic, with evidence of multiple clusters of transmissions dating to the late 1990s, a period when HIV prevalence is known to have doubled in this population. The quantitative description of the transmission dynamics among MSM will be important for parameterization of epidemiological models and in designing intervention strategies.

Figure 1. Distribution of Genetic Distance Among All Pairwise Comparisons of 2,126 Patient-Derived HIV Sequences

Key indicates the number of comparisons for each datapoint by colour. Sequences were compared at all 499 third-base sites and recorded for an exact difference or an ambiguous difference (see text for details). Two major peaks reflect within subtype (30–60 differences) and between subtype (100–110 differences) comparisons, respectively. The third smaller region of density close to the origin identifies patients with at least one other closely related sequence in the dataset.

Figure 2. HIV Transmission Clusters Defined by Genetic Distance

Patients included in major clusters are represented by a red node, and connecting lines between red nodes represent a genetic distance of less than 4.8% (24 differences). Sensitivity of the clusters to the distance criterion shown by additional nodes in green (5.0%), blue (5.2%), and orange (5.4%).

Figure 3. Bayesian MCMC Phylogenetic Tree of All Sequences Closely Linked to At Least One Other (N = 402)

Clusters with ≥10 members (and a posterior probability of 1) are shown in red. Letters indicate the position of identified clusters. Scale bar indicates number of substitutions.

Figure 4. Distribution of Cluster Size from MrBayes Phylogenetic Tree of Closely Related Sequences (N = 402)

A cluster is defined by nodes with a posterior probability of 1. Letters indicate the six largest clusters phylogenetically defined.

Figure 5. Relaxed-Clock Time-Scaled Phylogenies for the Six Largest Clusters

Time-scaled phylogenies were generated using the partitioned SRD06 model. (A) Full trees with scale bar graduations in years. (B) Terminal branches removed with scale in calendar years to show timing of transmission events.

Figure 6. Histogram of Internal Branch Lengths (N = 88) from All Six N ≥ 10 Clusters Estimated Using the Partitioned SRD06 Model

Median branch length was 13.14 mo, and the 25th percentile was 5.8 mo. Similar results were obtained using the GTR + I + Γ model (unpublished data).