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HIV-infected macrophages are more resistant than CD4+ T cells to both virus- and immune-mediated death pathways including apoptosis, facilitating their persistence in tissue sanctuary sites and potential to contribute to viral rebound upon therapy cessation. This resistance is driven by HIV-induced modulation of both intrinsic and extrinsic apoptotic pathways, alongside survival mechanisms including autophagy. In this review, we examine the biological mechanisms promoting macrophage survival and explore novel translational strategies aimed at subverting this resistance. Crucially, we highlight the methodological limitations hindering progress, including the scarcity of robust in vitro macrophage models, the influence of culture conditions, and physiological relevance to macrophages in vivo. We emphasise that a macrophage-inclusive approach, incorporating improved pre-clinical models and developing clinical measurements to quantify the reservoir in human tissue, is essential to successfully eliminate this distinct reservoir and advance toward sustained ART-free remission.<\/jats:p>","DOI":"10.3390\/v18030347","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T13:12:24Z","timestamp":1773321144000},"page":"347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["To Kill a Macrophage: Targeted Strategies to Eliminate Macrophage Reservoirs of HIV"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7023-6061","authenticated-orcid":false,"given":"Laura","family":"Rikard-Bell","sequence":"first","affiliation":[{"name":"Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"},{"name":"School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgane","family":"Brunton-O\u2019Sullivan","sequence":"additional","affiliation":[{"name":"Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4086-5212","authenticated-orcid":false,"given":"Sushama","family":"Telwatte","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Jaworowski","sequence":"additional","affiliation":[{"name":"Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"},{"name":"Department of Infectious Diseases, Monash University, Melbourne, VIC 3004, Australia"},{"name":"School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna C.","family":"Hearps","sequence":"additional","affiliation":[{"name":"Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia"},{"name":"Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia"},{"name":"Department of Infectious Diseases, Monash University, Melbourne, VIC 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1126\/science.278.5341.1295","article-title":"Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy","volume":"278","author":"Finzi","year":"1997","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.immuni.2018.04.030","article-title":"Targeting the Latent Reservoir for HIV-1","volume":"48","author":"Sengupta","year":"2018","journal-title":"Immunity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1146\/annurev-pathol-050520-112001","article-title":"In Vivo Dynamics of the Latent Reservoir for HIV-1: New Insights and Implications for Cure","volume":"17","author":"Siliciano","year":"2022","journal-title":"Annu. 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