title: HIV-1 transmission patterns in antiretroviral therapy-naïve, HIV-infected North Americans based on phylogenetic analysis by population level and ultra-deep DNA sequencing.
abstract: Factors that contribute to the transmission of human immunodeficiency virus type 1 (HIV-1), especially drug-resistant HIV-1 variants remain a significant public health concern. In-depth phylogenetic analyses of viral sequences obtained in the screening phase from antiretroviral-naïve HIV-infected patients seeking enrollment in EPZ108859, a large open-label study in the USA, Canada and Puerto Rico (ClinicalTrials.gov NCT00440947) were examined for insights into the roles of drug resistance and epidemiological factors that could impact disease dissemination. Viral transmission clusters (VTCs) were initially predicted from a phylogenetic analysis of population level HIV-1 pol sequences obtained from 690 antiretroviral-naïve subjects in 2007. Subsequently, the predicted VTCs were tested for robustness by ultra deep sequencing (UDS) using pyrosequencing technology and further phylogenetic analyses. The demographic characteristics of clustered and non-clustered subjects were then compared. From 690 subjects, 69 were assigned to 1 of 30 VTCs, each containing 2 to 5 subjects. Race composition of VTCs were significantly more likely to be white (72% vs. 60%; p = 0.04). VTCs had fewer reverse transcriptase and major PI resistance mutations (9% vs. 24%; p = 0.002) than non-clustered sequences. Both men-who-have-sex-with-men (MSM) (68% vs. 48%; p = 0.001) and Canadians (29% vs. 14%; p = 0.03) were significantly more frequent in VTCs than non-clustered sequences. Of the 515 subjects who initiated antiretroviral therapy, 33 experienced confirmed virologic failure through 144 weeks while only 3/33 were from VTCs. Fewer VTCs subjects (as compared to those with non-clustering virus) had HIV-1 with resistance-associated mutations or experienced virologic failure during the course of the study. Our analysis shows specific geographical and drug resistance trends that correlate well with transmission clusters defined by HIV sequences of similarity. Furthermore, our study demonstrates the utility of molecular and epidemiological analysis of VTCs for identifying population-specific risks associated with HIV-1 transmission and developing effective local healthcare strategies.
authors.affiliation: ViiV HealthCare, Research Triangle Park, North Carolina, United States of America.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Ross
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Horton
authors.affiliation: GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: Samiul
authors.initials: S
authors.lastname: Hasan
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Clinique Medicale L'Actuel, Montreal, QC, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Orlando Immunology Center, Orlando, Florida, United States of America.
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.affiliation: McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Potter
authors.affiliation: Therafirst Medical Center, Ft Lauderdale, Florida, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: LaMarca
authors.affiliation: Centro Ararat, Ponce, Puerto Rico.
authors.forename: Ivan
authors.initials: I
authors.lastname: Melendez-Rivera
authors.affiliation: Dupont Circle Physicians Group, Washington, DC, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Ward
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, United States of America.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Uy
authors.affiliation: ViiV HealthCare, Research Triangle Park, North Carolina, United States of America.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shaefer
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000188:drug therapy / Q000453:epidemiology* / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009656:North America / Q000453:epidemiology; D010802:Phylogeny; D011379:Prognosis