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More than 35% and 40% of the mpox cases suffer from co-infection with HIV and sexually transmitted infections (STIs) (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum, and herpes simplex virus), respectively. Bacterial superinfection can also occur. Co-infection of MPXV and other infectious agents may enhance disease severity, deteriorate outcomes, elongate the recovery process, and potentially contribute to the morbidity and mortality of the ensuing diseases. However, the interplays between MPXV and HIV, bacteria, other STI pathogens and host cells are poorly studied. There are many open questions regarding the impact of co-infections with HIV, STIs, or bacterial superinfections on the diagnosis and treatment of MPXV infections, including clinical and laboratory-confirmed mpox diagnosis, suboptimal treatment effectiveness, and induction of antiviral drug resistance. In this review article, we will discuss the progress and knowledge gaps in MPXV biology, antiviral therapy, pathogenesis of human MPXV and its co-infection with HIV, STIs, or bacterial superinfections, and the impact of the co-infections on the diagnosis and treatment of mpox disease. This review not only sheds light on the MPXV infection and co-infection of other etiologies but also calls for more research on MPXV life cycles and the molecular mechanisms of pathogenesis of co-infection of MPXV and other infectious agents, as well as research and development of a novel multiplex molecular testing panel for the detection of MPXV and other STI co-infections.<\/jats:p>","DOI":"10.3390\/v16050784","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T03:35:55Z","timestamp":1715744155000},"page":"784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Mpox (Monkeypox) Virus and Its Co-Infection with HIV, Sexually Transmitted Infections, or Bacterial Superinfections: Double Whammy or a New Prime Culprit?"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1225-9936","authenticated-orcid":false,"given":"Benjamin M.","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Pathology and Laboratory Medicine, Children\u2019s National Hospital, Washington, DC 20010, USA"},{"name":"Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA"},{"name":"Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA"},{"name":"Department of Microbiology, Immunology & Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA"},{"name":"Children\u2019s National Research Institute, Washington, DC 20012, USA"},{"name":"The District of Columbia Center for AIDS Research, Washington, DC 20052, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2246-4581","authenticated-orcid":false,"given":"Natella Y.","family":"Rakhmanina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA"},{"name":"The District of Columbia Center for AIDS Research, Washington, DC 20052, USA"},{"name":"Division of Infectious Diseases, Children\u2019s National Hospital, Washington, DC 20010, USA"},{"name":"Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC 20005, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, School of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8593-0770","authenticated-orcid":false,"given":"Michael I.","family":"Bukrinsky","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA"},{"name":"The District of Columbia Center for AIDS Research, Washington, DC 20052, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2220415120","DOI":"10.1073\/pnas.2220415120","article-title":"Virulence differences of mpox (monkeypox) virus clades I, IIa, and IIb.1 in a small animal model","volume":"120","author":"Americo","year":"2023","journal-title":"Proc. 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