Integration site patterns, clonal expansion, and co-infection effects in HIV reservoirs: a systematic review of studies in people on antiretroviral therapy
Bright Forkuo-Forkuo 1, 2 
, John Atanniba-Atanniba 2 , Evelyn Y. Bonney-Bonney 2 , Richard Donkor-Donkor 3 , Reuben Adjei-Adjei 4 , Mary Amoakoh-Coleman-Amoakoh-Coleman 2 , Kwamena W. C. Sagoe-Sagoe 3 , George B. Kyei-Kyei 2, 5, 6
1 University of Ghana Medical School, Accra, Ghana; 2 Department of Virology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana; 3 Department of Microbiology, University of Ghana Medical School, Accra, Ghana; 4 College of Health Sciences, University of Ghana, Accra, Ghana; 5 Medical and Scientific Research Centre, University of Ghana Medical Centre, Accra, Ghana; 6 Department of Medicine and Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, USA
*Correspondence: George B. Kyei-Kyei. Email: g.kyei@wustl.edu
Abstract
HIV integrated into specific loci of the host’s genome plays a significant role in clonal expansion and the persistence of the HIV reservoir. Certain factors, such as the HIV subtype, co-infections, inflammatory, and immune activation signaling, have been found to influence the integration sites (ISs). This systematic review examines IS patterns, clonal expansion, and the effects of co-infection on HIV reservoirs. A comprehensive search was conducted across four databases. We identified 18 articles published between 2016 and 2025 that met our criteria. We described the methods used for the IS analysis studies, features of the ISs, and their impact on clonal expansion. We also described the effects of cytomegalovirus (CMV), Mycobacterium tuberculosis (MTB), and influenza virus on the ISs and clonal dynamics. Eleven (61.1%) of the studies were conducted in the USA. Subtypes were mainly HIV-1 B. Ligand-mediated polymerase chain reaction or its variants were the most reported methods. Most HIV integration events occurred within genic regions, with reported proportions ranging from 77.0% to 100.0% of all sites. Most of the ISs were within introns, were in opposite orientation, occurred in cancer-associated genes, and influenced clonal expansion. CMV, MTB, and influenza did not significantly affect IS features but were associated with increased clonality. Expanded HIV-infected cell clones are integrated into genes regulating proliferation and immune signaling. Viral and immune co-factors may influence clonal persistence through other mechanisms. Understanding these will be critical for reservoir-targeted cure strategies.
