Marta Bull1,2, Caroline Mitchell3, Jaime Soria4, Sheila Styrchak1, Corey Williams1, Joan Dragavon5, Kevin J Ryan6, Edward Acosta6, Frankline Onchiri7, Robert W Coombs5,8, Alberto La Rosa9,10, Eduardo Ticona4, Lisa M Frenkel1,2. 1. Seattle Children's Research Institute, Seattle, Washington, USA. 2. Department of Pediatrics, University of Washington, Seattle, Washington, USA. 3. Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA. 4. Infectious Diseases Department, Hospital Nacional Dos de Mayo, Universidad Nacional Mayor de San Marcos, Lima, Peru. 5. Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA. 6. School of Medicine, University of Alabama, Birmingham, Alabama, USA. 7. Core for Biomedical Statistics, Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, Washington, USA. 8. Department of Medicine, University of Washington, Seattle, Washington, USA. 9. Asociaciòn Civil Impacta Salud y Educación, Lima, Peru, and. 10. Merck Sharp & Dohme, Lima, Peru.
Abstract
BACKGROUND: During antiretroviral treatment (ART) with plasma HIV RNA below the limit of quantification, HIV RNA can be detected in genital or rectal secretions, termed discordant shedding (DS). We hypothesized that proliferating cells produce virions without HIV replication. METHODS: ART-naive Peruvians initiating ART were observed for DS over 2 years. HIV env and pol genomes were amplified from DS. Antiretrovirals and cytokines/chemokines concentrations were compared at DS and control time points. RESULTS: Eighty-two participants had ART suppression. DS was detected in 24/82 (29%) participants: 13/253 (5%) cervicovaginal lavages, 20/322 (6%) seminal plasmas, and 6/85 (7%) rectal secretions. HIV RNA in DS specimens was near the limit of quantification and not reproducible. HIV DNA was detected in 6/13 (46%) DS cervicovaginal lavages at low levels. Following DNase treatment, 5/39 DS specimens yielded HIV sequences, all without increased genetic distances. Women with and without DS had similar plasma antiretroviral levels and DS in 1 woman was associated with inflammation. CONCLUSIONS: HIV RNA and DNA sequences and therapeutic antiretroviral plasma levels did not support HIV replication as the cause of DS from the genital tract. Rather, our findings infer that HIV RNA is shed due to proliferation of infected cells with virion production.
BACKGROUND: During antiretroviral treatment (ART) with plasma HIV RNA below the limit of quantification, HIV RNA can be detected in genital or rectal secretions, termed discordant shedding (DS). We hypothesized that proliferating cells produce virions without HIV replication. METHODS: ART-naive Peruvians initiating ART were observed for DS over 2 years. HIV env and pol genomes were amplified from DS. Antiretrovirals and cytokines/chemokines concentrations were compared at DS and control time points. RESULTS: Eighty-two participants had ART suppression. DS was detected in 24/82 (29%) participants: 13/253 (5%) cervicovaginal lavages, 20/322 (6%) seminal plasmas, and 6/85 (7%) rectal secretions. HIV RNA in DS specimens was near the limit of quantification and not reproducible. HIV DNA was detected in 6/13 (46%) DS cervicovaginal lavages at low levels. Following DNase treatment, 5/39 DS specimens yielded HIV sequences, all without increased genetic distances. Women with and without DS had similar plasma antiretroviral levels and DS in 1 woman was associated with inflammation. CONCLUSIONS:HIV RNA and DNA sequences and therapeutic antiretroviral plasma levels did not support HIV replication as the cause of DS from the genital tract. Rather, our findings infer that HIV RNA is shed due to proliferation of infected cells with virion production.
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