Combining Phylogenetic and Network Approaches to Identify HIV-1 Transmission Links in San Mateo County, California

Abstract

The HIV epidemic in San Mateo County is sustained by multiple overlapping risk groups and is an important hub for HIV transmission in northern California. Limited access to care has led historically to delayed clinical presentation, higher rates of opportunistic infections, and an increased prevalence of antiretroviral drug resistance. The virologic and clinical consequences of treatment within these multiple ethnic and behavioral groups are poorly understood, highlighting the need for efficient surveillance strategies that are able to elucidate transmission networks and drug resistance patterns. We obtained sequence data from a group of 316 HIV-positive individuals in the San Mateo AIDS Program over a 14-year period and integrated epidemiologic, phylogenetic, and network approaches to characterize transmission clusters, risk factors and drug resistance. Drug resistance mutations were identified using the Stanford HIV Drug Resistance Database. A maximum likelihood tree was inferred in RAxML and subjected to clustering analysis in Cluster Picker. Network analysis using pairwise genetic distances was performed in HIV-TRACE. Participants were primarily male (60%), white Hispanics and non-Hispanics (32%) and African American (20.6%). The most frequent behavior risk factor was male-male sex (33.5%), followed by heterosexual (23.4%) and injection drug use (9.5%). Nearly all sequences were subtype B (96%) with subtypes A, C, and CRF01_AE also observed. Sequences from 65% of participants had at least one drug resistance mutation. Clustered transmissions included a higher number of women when compared to non-clustered individuals and were more likely to include heterosexual or people who inject drugs (PWID). Detailed analysis of the largest network (N = 47) suggested that PWID played a central role in overall transmission of HIV-1 as well as bridging men who have sex with men (MSM) transmission with heterosexual/PWID among primarily African American men. Combined phylogenetic and network analysis of HIV sequence data identified several overlapping risk factors in the epidemic, including MSM, heterosexual and PWID transmission with a disproportionate impact on African Americans and a high prevalence of drug resistance.

Keywords: California; HIV; network; phylogenetics; transmission links.

FIGURE 1

Maximum likelihood HIV-1 pol transmission clusters in San Mateo County, California. Colored semi-circles indicate HIV subtypes. Black branches represent sequences obtained from 316 HIV-positive adults receiving antiretroviral treatment as part of the publicly funded San Mateo County AIDS Program. Gray branches denote reference sequences. Clades highlighted in blue indicate transmission clusters identified in Cluster Picker (TBE ≥ 90 and genetic distance threshold of 8%). Asterisks indicate transmission pairs mutually identified as transmission links in Cluster Picker and HIV-TRACE. The scale bar at the bottom represents the number of substitutions per site along branches in the tree topology.

FIGURE 2

Inferred genetic network structure of a major cluster (N = 47 individuals) in the San Mateo HIV-1 subtype B epidemic identified by HIV-TRACE using a genetic distance threshold of 2%. Shape codes gender, colors denote the reported mode of transmission for each individual and line width represents the bootstrap confidence for linkage. ^∗are indicating African-American individuals. MSM, men who have sex with men; PWID, people who inject drugs, injection drug users.