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Transmission of HIV-1 drug resistance mutations within partner-pairs: A cross-sectional study of a primary HIV infection cohort.

ABSTRACT: BACKGROUND:Transmission of human immunodeficiency virus type 1 (HIV-1) drug resistance mutations, particularly that of minority drug-resistant variants, remains poorly understood. Population-based studies suggest that drug-resistant HIV-1 is less transmissible than drug-susceptible viruses. We compared HIV-1 drug-resistant genotypes among partner-pairs in order to assess the likelihood of transmission of drug resistance mutations and investigate the role of minority variants in HIV transmission. METHODS AND FINDINGS:From 1992-2010, 340 persons with primary HIV-1 infection and their partners were enrolled into observational research studies at the University of Washington Primary Infection Clinic (UWPIC). Out of 50 partner-pairs enrolled, 36 (72%) transmission relationships were confirmed by phylogenetic distance analysis of HIV-1 envelope (env) sequences, and 31 partner-pairs enrolled after 1995 met criteria for this study. Drug resistance mutations in the region of the HIV-1 polymerase gene (pol) that encodes protease and reverse transcriptase were assessed by 454-pyrosequencing. In 25 partner-pairs where the transmission direction could be determined, 12 (48%) transmitters had 1-4 drug resistance mutations (23 total) detected in their HIV-1 populations at a median frequency of 6.0% (IQR 1.5%-98.7%, range 1.0%-99.6%). Of 10 major mutations detected in five transmitters at a frequency >95%, 100% (95% CI 69.2%-100%) were detected in recipients. All of these transmitters were antiretroviral (ARV)-naïve at the time of specimen collection. Fourteen mutations (eight major mutations and six accessory mutations) were detected in nine transmitters at low frequencies (1.0%-11.8%); four of these transmitters had previously received ARV therapy. Two (14% [95% CI 1.8%-42.8%]) G73S accessory mutations were detected in both transmitter and recipient. This number is not significantly different from the number expected based on the observed frequencies of drug-resistant viruses in transmitting partners. Limitations of this study include the small sample size and uncertainties in determining the timing of virus transmission and mutation history. CONCLUSIONS:Drug-resistant majority variants appeared to be commonly transmitted by ARV-naïve participants in our analysis and may contribute significantly to transmitted drug resistance on a population level. When present at low frequency, no major mutation was observed to be shared between partner-pairs; identification of accessory mutations shared within a pair could be due to transmission, laboratory artifact, or apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs), and warrants further study.

SUBMITTER: Stekler JD

PROVIDER: S-EPMC5870941 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Transmission of HIV-1 drug resistance mutations within partner-pairs: A cross-sectional study of a primary HIV infection cohort.

Stekler Joanne D JD Milne Ross R Payant Rachel R Beck Ingrid I Herbeck Joshua J Maust Brandon B Deng Wenjie W Tapia Kenneth K Holte Sarah S Maenza Janine J Stevens Claire E CE Mullins James I JI Collier Ann C AC Frenkel Lisa M LM

PLoS medicine 20180327 3

<h4>Background</h4>Transmission of human immunodeficiency virus type 1 (HIV-1) drug resistance mutations, particularly that of minority drug-resistant variants, remains poorly understood. Population-based studies suggest that drug-resistant HIV-1 is less transmissible than drug-susceptible viruses. We compared HIV-1 drug-resistant genotypes among partner-pairs in order to assess the likelihood of transmission of drug resistance mutations and investigate the role of minority variants in HIV trans ...[more]

PMID: 29584723

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Project description:BackgroundMen who have sex with men (MSM) who undergo voluntary HIV counseling and testing (VCT) often report condomless anal sexual intercourse, having many sexual partners, and being exposed to risky sexual networks. Limited research has discussed the application of motivational interviewing and convenience referral platforms to facilitate the referral of sexual partners for HIV testing among MSM.ObjectiveThis study aimed to evaluate the effects of VCT referral by sexual partners through social networking platforms and the test results after elicited interviews with MSM; compare the characteristics and risk behaviors among MSM tested without referral, index subjects, and referred sexual partners; and explore unknown sexual affiliations through visualizing and quantifying the social network graph.MethodsThis was a cross-sectional study. Purposeful sampling was used to recruit index subjects from a community HIV screening station frequented by MSM in Taipei City on Friday and Saturday nights. Respondent-driven sampling was used to recruit sexual partners. Partner-elicited interviews were conducted by trained staff before VCT to motivate MSM to become index subjects and refer sexual partners via the Line app, or to disclose the accounts and profiles of sexual partners on relevant social networking platforms. Referred sexual partners received rapid HIV testing, and the recruitment process was repeated until leads were exhausted.ResultsAfter the interviews, 28.2% (75/266) of MSM were successfully persuaded to become index subjects in the first wave, referring 127 sexual partners via the Line app for rapid HIV testing and disclosing 40 sexual partners. The index subjects and tested sexual partners had more sexual partners (F2=3.83, P=.02), more frequent anal intercourse (F2=10.10, P<.001), and higher percentages of those who had not previously received HIV testing (χ21=6.1, P=.047) compared with MSM tested without referrals. The new HIV-seropositivity rate among tested sexual partners was 2.4%, which was higher than the rate in the other 2 groups. The social network analysis revealed the following 4 types of sexual affiliation: chain, Y, star, and complicated. Among the HIV-negative sexual partners, 26.9% (43/160) had sexual affiliations with HIV-positive nodes, and 40% (10/25) were untested sexual partners with a direct sexual affiliation with an HIV-positive node. Four transmission bridges were found in the network graph.ConclusionsPartner-elicited interviews can effectively promote referral for HIV testing and case identification via Line, and can clarify unknown sexual affiliations of MSM to facilitate the development of a tailored prevention program. Social network analysis is needed for an insightful understanding of the different network structures.

Project description:ObjectivesTo assess HIV-1 diversity, transmission dynamics and prevalence of transmitted drug resistance (TDR) in Angola, five years after ART scale-up.MethodsPopulation sequencing of the pol gene was performed on 139 plasma samples collected in 2009 from drug-naive HIV-1 infected individuals living in Luanda. HIV-1 subtypes were determined using phylogenetic analysis. Drug resistance mutations were identified using the Calibrated Population Resistance Tool (CPR). Transmission networks were determined using phylogenetic analysis of all Angolan sequences present in the databases. Evolutionary trends were determined by comparison with a similar survey performed in 2001.Results47.1% of the viruses were pure subtypes (all except B), 47.1% were recombinants and 5.8% were untypable. The prevalence of subtype A decreased significantly from 2001 to 2009 (40.0% to 10.8%, P = 0.0019) while the prevalence of unique recombinant forms (URFs) increased > 2-fold (40.0% to 83.1%, P < 0.0001). The most frequent URFs comprised untypable sequences with subtypes H (U/H, n = 7, 10.8%), A (U/A, n = 6, 9.2%) and G (G/U, n = 4, 6.2%). Newly identified U/H recombinants formed a highly supported monophyletic cluster suggesting a local and common origin. TDR mutation K103N was found in one (0.7%) patient (1.6% in 2001). Out of the 364 sequences sampled for transmission network analysis, 130 (35.7%) were part of a transmission network. Forty eight transmission clusters were identified; the majority (56.3%) comprised sequences sampled in 2008-2010 in Luanda which is consistent with a locally fuelled epidemic. Very low genetic distance was found in 27 transmission pairs sampled in the same year, suggesting recent transmission events.ConclusionsTransmission of drug resistant strains was still negligible in Luanda in 2009, five years after the scale-up of ART. The dominance of small and recent transmission clusters and the emergence of new URFs are consistent with a rising HIV-1 epidemics mainly driven by heterosexual transmission.

Project description:BackgroundMucosal HIV-1 transmission predominantly results in a single transmitted/founder (T/F) virus establishing infection in the new host despite the generally high genetic diversity of the transmitter virus population. To what extent HIV-1 transmission is a stochastic process or driven by selective forces that allow T/F viruses best to overcome bottlenecks in transmission has not been conclusively resolved. Building on prior investigations that suggest HIV-1 envelope (Env) features to contribute in the selection process during transmission, we compared phenotypic virus characteristics of nine HIV-1 subtype B transmission pairs, six men who have sex with men and three male-to-female transmission pairs.ResultsAll recipients were identified early in acute infection and harbored based on extensive sequencing analysis a single T/F virus allowing a controlled analysis of virus properties in matched transmission pairs. Recipient and transmitter viruses from the closest time point to transmission showed no signs of selection for specific Env modifications such as variable loop length and glycosylation. Recipient viruses were resistant to circulating plasma antibodies of the transmitter and also showed no altered sensitivity to a large panel of entry inhibitors and neutralizing antibodies. The recipient virus did not consistently differ from the transmitter virus in terms of entry kinetics, cell-cell transmission and replicative capacity in primary cells. Our paired analysis revealed a higher sensitivity of several recipient virus isolates to interferon-α (IFNα) which suggests that resistance to IFNα cannot be a general driving force in T/F establishment.ConclusionsWith the exception of increased IFNα sensitivity, none of the phenotypic virus properties we investigated clearly distinguished T/F viruses from their matched transmitter viruses supporting the notion that at least in subtype B infection HIV-1 transmission is to a considerable extent stochastic.

Dataset Information

Transmission of HIV-1 drug resistance mutations within partner-pairs: A cross-sectional study of a primary HIV infection cohort.

Publications

Transmission of HIV-1 drug resistance mutations within partner-pairs: A cross-sectional study of a primary HIV infection cohort.

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