PT  - JOURNAL ARTICLE
AU  - Elias K. Halvas
AU  - Kevin W. Joseph
AU  - Leah D. Brandt
AU  - Shuang Guo
AU  - Michele D. Sobolewski
AU  - Jana L. Jacobs
AU  - Camille Tumiotto
AU  - John K. Bui
AU  - Joshua C. Cyktor
AU  - Brandon F. Keele
AU  - Gene D. Morse
AU  - Michael J. Bale
AU  - Mary F. Kearney
AU  - John M. Coffin
AU  - Jason W. Rausch
AU  - Xiaolin Wu
AU  - Stephen H. Hughes
AU  - John W. Mellors
TI  - HIV-1 Viremia Not Suppressible By Antiretroviral Therapy Can Originate from Large T-Cell Clones Producing Infectious Virus
AID  - 10.1101/2020.01.30.924159
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.30.924159
4099  - http://biorxiv.org/content/early/2020/01/31/2020.01.30.924159.short
4100  - http://biorxiv.org/content/early/2020/01/31/2020.01.30.924159.full
AB  - BACKGROUND HIV-1 viremia that is not suppressed by combination antiretroviral therapy (ART) is generally attributed to incomplete medication adherence and/or drug resistance. We evaluated individuals referred for non-suppressible viremia (plasma HIV-1 RNA above 40 copies/ml) who reported adherence to ART and did not show drug resistance to their current regimen.METHODS Samples were collected from at least two time points from eight donors who had non-suppressible viremia for more than six months on ART. Single templates of HIV-1 RNA obtained from plasma and viral outgrowth of cultured cells and from proviral DNA were PCR-amplified and sequenced for evidence of clones of cells that produced infectious viruses. Clones were identified by host-proviral integration site analysis.RESULTS HIV-1 genomic RNAs with identical sequences were identified in plasma samples from all eight donors. The identical viral RNA sequences did not change over time and lacked resistance to the ART regimen. In four of the donors, viral RNA sequences obtained from plasma matched those sequences from viral outgrowth cultures, indicating that the viruses were replication-competent. Integration sites for infectious proviruses from those four donors were mapped to introns of the MATR3, ZNF268, ZNF721/ABCA11P, and ABCA11P genes. The sizes of the clones were from 50 million to 350 million cells.CONCLUSION Clones of HIV-1-infected cells producing virus can cause failure of ART to suppress viremia despite medication adherence and absence of drug resistance. The mechanisms involved in clonal expansion and persistence need to be defined to eliminate viremia and the HIV-1 reservoir.