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Minority quasispecies of drug-resistant HIV-1: Emergence, transmission, dynamics, and clinical relevance in acute and chronic HIV-1 infection

English title Minority quasispecies of drug-resistant HIV-1: Emergence, transmission, dynamics, and clinical relevance in acute and chronic HIV-1 infection
Applicant Günthard Huldrych Fritz
Number 120793
Funding scheme Project funding (special)
Research institution Klinik für Infektionskrankheiten und Spitalhygiene Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Infectious Diseases
Start/End 01.11.2008 - 31.10.2012
Approved amount 450'000.00
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All Disciplines (3)

Discipline
Infectious Diseases
Medical Statistics
Clinical Immunology and Immunopathology

Keywords (13)

HIV-1; primary infection; genetic diversity; transmission; population dynamics; minority quasispecies; drug resistance; acute infection; chronic infection; HIV transmission; antiretroviral therapy; large nested project; Swiss HIV Cohort Study

Lay Summary (English)

Lead
Lay summary
HIV drug resistance is a major obstacle in the fight against HIV-1. New technologies allow to detect minority quasispecies of drug resistant viruses. In this project we will investigate the impact of virus diversity and quasispecies dynamics on selection, persistence, and transmission of drug-resistant viruses. Firstly, we will determine to what extent transmission of drug-resistant viruses is underestimated using conventional direct sequencing. Secondly, we will determine what impact the presence of minority quasispecies of drug-resistant HIV-1 do have on subsequent antiretroviral treatment responses. Thirdly, we aim at identifying cellular populations in which residual repolication of HIV-1 may occur despite suppressive ART and will investigate the possible impact of a cellular host factor (ABPOBEC-3G) on HIV-1 diversity, and potentially on the emergence of HIV-1 drug resistant quasispecies. The combination of new technologies such as allele-specific PCR and ultradeep sequencing with carefully defined patient collectives from the Zurich Primary HIV infection Study and the Swiss HIV Cohort Study will allow us to generate meaningful results. In conclusion, this study will guide us to further optimize antiretroviral long-term treatment strategies and will give us insight into better understanding the emergence of viral diversity, one of the key features of HIV-1 infection.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A suicide gene approach using the human pro-apoptotic protein tBid inhibits HIV-1 replication.
Huelsmann Peter M, Hofmann Andreas D, Knoepfel Stefanie A, Popp Jasmin, Rauch Pia, Di Giallonardo Francesca, Danke Christina, Gueckel Eva, Schambach Axel, Wolff Horst, Metzner Karin J, Berens Christian, A suicide gene approach using the human pro-apoptotic protein tBid inhibits HIV-1 replication., in BMC biotechnology, 11, 4-4.
Efficient suppression of minority drug-resistant HIV type 1 (HIV-1) variants present at primary HIV-1 infection by ritonavir-boosted protease inhibitor-containing antiretroviral therapy.
Metzner Karin J, Rauch Pia, von Wyl Viktor, Leemann Christine, Grube Christina, Kuster Herbert, Böni Jürg, Weber Rainer, Günthard Huldrych F, Efficient suppression of minority drug-resistant HIV type 1 (HIV-1) variants present at primary HIV-1 infection by ritonavir-boosted protease inhibitor-containing antiretroviral therapy., in The Journal of infectious diseases, 201(7), 1063-71.
Impact of Minority Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Resistance Genotype After Virologic Failure.
Li Jonathan et al., Impact of Minority Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutations on Resistance Genotype After Virologic Failure., in The Journal of Infectious Diseases, 207(4), 1-5.
In-depth analysis of G-to-A hypermutation rate in HIV-1 env DNA induced by endogenous APOBEC3 proteins using massively parallel sequencing.
Knoepfel Stefanie A, Di Giallonardo Francesca, Däumer Martin, Thielen Alexander, Metzner Karin J, In-depth analysis of G-to-A hypermutation rate in HIV-1 env DNA induced by endogenous APOBEC3 proteins using massively parallel sequencing., in Journal of virological methods, 171(2), 329-38.
Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis.
Li Jonathan Z, Paredes Roger, Ribaudo Heather J, Svarovskaia Evguenia S, Metzner Karin J, Kozal Michael J, Hullsiek Kathy Huppler, Balduin Melanie, Jakobsen Martin R, Geretti Anna Maria, Thiebaut Rodolphe, Ostergaard Lars, Masquelier Bernard, Johnson Jeffrey A, Miller Michael D, Kuritzkes Daniel R, Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis., in JAMA : the journal of the American Medical Association, 305(13), 1327-35.
Minority K65R Variants and Early Failure of Antiretroviral Therapy in HIV-1-infected Eritrean Immigrant.
Bansal Vineeta, Metzner Karin J, Niederost Barbara, Leemann Christine, Boni Jurg, Gunthard Huldrych F, Fehr Jan S, Minority K65R Variants and Early Failure of Antiretroviral Therapy in HIV-1-infected Eritrean Immigrant., in Emerging infectious diseases, 17(10), 1966-8.
Prevalence of key resistance mutations K65R, K103N, and M184V as minority HIV-1 variants in chronically HIV-1 infected, treatment-naïve patients.
Metzner Karin J, Rauch Pia, Braun Patrick, Knechten Heribert, Ehret Robert, Korn Klaus, Kaiser Rolf, Sichtig Nadine, Ranneberg Britta, van Lunzen Jan, Walter Hauke, Prevalence of key resistance mutations K65R, K103N, and M184V as minority HIV-1 variants in chronically HIV-1 infected, treatment-naïve patients., in Journal of clinical virology : the official publication of the Pan American Society for Clinical Vir, 50(2), 156-61.
Reappearance of minority K103N HIV-1 variants after interruption of ART initiated during primary HIV-1 infection.
Metzner Karin J, Leemann Christine, Di Giallonardo Francesca, Grube Christina, Scherrer Alexandra U, Braun Dominique, Kuster Herbert, Weber Rainer, Guenthard Huldrych F, Reappearance of minority K103N HIV-1 variants after interruption of ART initiated during primary HIV-1 infection., in PloS one, 6(7), 7-7.

Associated projects

Number Title Start Funding scheme
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large
130865 HIV-1 Transmission in Switzerland: Long term-molecular epidemiology and biological properties of transmitted viruses 01.11.2010 Project funding (special)
116035 Factors associated with viral control after primary HIV-1 infection and viral determinants associated with HIV-1 transmission 01.04.2007 Project funding (special)
134277 Swiss HIV Cohort Study (SHCS) 01.01.2011 Cohort Studies Large

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