{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T23:20:27Z","timestamp":1780615227702,"version":"3.54.1"},"reference-count":121,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T00:00:00Z","timestamp":1756512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gilead Sciences, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The global fight against HIV\/AIDS has been significantly bolstered by the development and implementation of pre-exposure prophylaxis (PrEP), yet innovation in PrEP interventions, improved adherence and greater access are still needed to maximize its benefit. Nonhuman primate (NHP) infection with simian immunodeficiency virus (SIV) has served as an instrumental animal model in advancing HIV PrEP research. This review comprehensively examines the utility of NHP models in evaluating the efficacy, pharmacokinetics, and safety of diverse PrEP strategies, including oral, injectable, implantable, and topical formulations. It discusses the development of diverse challenge models that simulate human transmission routes and the advantages of NHPs in enabling controlled and mechanistically informative studies. It also highlights the successful translation of pivotal NHP studies evaluating tenofovir-based regimens as well the long-acting agents, cabotegravir and lenacapavir, into the clinical settings, emphasizing the consistently high predictive power of the NHP models for the HIV PrEP clinical efficacy. Finally, it underscores the importance of species-specific pharmacologic considerations and the value of NHP data in informing clinical trial design. As the global community strives to end the HIV epidemic as a public health threat in the absence of an efficacious prophylactic vaccine, NHP models make a critical contribution in the development of next-generation HIV prevention tools.<\/jats:p>","DOI":"10.3390\/v17091192","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T08:28:15Z","timestamp":1756715295000},"page":"1192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Use of Nonhuman Primate Models for Advancing HIV PrEP"],"prefix":"10.3390","volume":"17","author":[{"given":"Elena","family":"Bekerman","sequence":"first","affiliation":[{"name":"Gilead Sciences Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Callebaut","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,30]]},"reference":[{"key":"ref_1","unstructured":"Joint United Nations Programme on HIV\/AIDS (2024). 2024 Global AIDS Report\u2014The Urgency of Now: AIDS at a Crossroads, UNAIDS."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e26339","DOI":"10.1002\/jia2.26339","article-title":"The audacious goal to end AIDS by 2030: Aspiration or reality?","volume":"27","author":"Mayer","year":"2024","journal-title":"J. Int. AIDS Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1093\/cid\/ciz1229","article-title":"Evidence of an Association of Increases in Pre-exposure Prophylaxis Coverage with Decreases in Human Immunodeficiency Virus Diagnosis Rates in the United States, 2012\u20132016","volume":"71","author":"Smith","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1017\/S1462399409001343","article-title":"Interactions of host APOBEC3 restriction factors with HIV-1 in vivo: Implications for therapeutics","volume":"12","author":"Albin","year":"2010","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"21136","DOI":"10.1073\/pnas.1316839110","article-title":"Antagonism of SAMHD1 is actively maintained in natural infections of simian immunodeficiency virus","volume":"110","author":"Spragg","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/nature02343","article-title":"The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys","volume":"427","author":"Stremlau","year":"2004","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Wilkins, J., Zheng, Y.M., Yu, J., Liang, C., and Liu, S.L. (2016). Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156739"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"a006841","DOI":"10.1101\/cshperspect.a006841","article-title":"Origins of HIV and the AIDS pandemic","volume":"1","author":"Sharp","year":"2011","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.tim.2008.08.010","article-title":"Relevance of studying T cell responses in SIV-infected rhesus macaques","volume":"16","author":"Valentine","year":"2008","journal-title":"Trends Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/339389a0","article-title":"An African primate lentivirus (SIVsm) closely related to HIV-2","volume":"339","author":"Hirsch","year":"1989","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Chen, S., Lai, C., Wu, X., Lu, Y., Han, D., Guo, W., Fu, L., Andrieu, J.M., and Lu, W. (2011). Variability of bio-clinical parameters in Chinese-origin Rhesus macaques infected with simian immunodeficiency virus: A nonhuman primate AIDS model. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023177"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1126\/science.284.5415.816","article-title":"Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs","volume":"284","author":"Harouse","year":"1999","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sharma, M., Nag, M., and Del Prete, G.Q. (2024). Minimally Modified HIV-1 Infection of Macaques: Development, Utility, and Limitations of Current Models. Viruses, 16.","DOI":"10.3390\/v16101618"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Swanstrom, A.E., Gorelick, R.J., Welker, J.L., Schmidt, F., Lu, B., Wang, K., Rowe, W., Breed, M.W., Killoran, K.E., and Kramer, J.A. (2023). Long-acting lenacapavir protects macaques against intravenous challenge with simian-tropic HIV. EBioMedicine, 95.","DOI":"10.1016\/j.ebiom.2023.104764"},{"key":"ref_15","unstructured":"Centers for Disease Control and Prevention (CDC) (2025, August 11). How HIV Spreads, Available online: https:\/\/www.cdc.gov\/hiv\/causes\/index.html."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kaur, A., and Vaccari, M. (2024). Exploring HIV Vaccine Progress in the Pre-Clinical and Clinical Setting: From History to Future Prospects. Viruses, 16.","DOI":"10.20944\/preprints202401.0976.v1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1111\/jmp.12188","article-title":"Analysis of putative mucosal SHIV susceptibility factors during repeated DMPA treatments in pigtail macaques","volume":"44","author":"Butler","year":"2015","journal-title":"J. Med. Primatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1097\/QAI.0000000000000975","article-title":"A Depot Medroxyprogesterone Acetate Dose That Models Human Use and Its Effect on Vaginal SHIV Acquisition Risk","volume":"72","author":"Butler","year":"2016","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/nm1096-1084","article-title":"Progesterone implants enhance SIV vaginal transmission and early virus load","volume":"2","author":"Marx","year":"1996","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Garber, D.A., Mitchell, J., Adams, D., Guenthner, P., Deyounks, F., Ellis, S., Kelley, K., Johnson, R., Dobard, C., and Heneine, W. (2018). Development of a repeat-exposure penile SHIV infection model in macaques to evaluate biomedical preventions against HIV. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194837"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1111\/j.1600-0684.2004.00079.x","article-title":"Perinatal transmission of SHIV-SF162P3 in Macaca nemestrina","volume":"33","author":"Jayaraman","year":"2004","journal-title":"J. Med. Primatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1034\/j.1600-0684.2003.00024.x","article-title":"Mother-to-infant transmission of SIV via breast-feeding in rhesus macaques","volume":"32","author":"Amedee","year":"2003","journal-title":"J. Med. Primatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1093\/cid\/ciad537","article-title":"Global HIV Incidence Analysis and Implications for Affordability Using Long-Acting Cabotegravir Versus Continuous and Event-Driven Oral Preexposure Prophylaxis","volume":"78","author":"Sharma","year":"2024","journal-title":"Clin. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1056\/NEJMoa1506273","article-title":"On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection","volume":"373","author":"Molina","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e791","DOI":"10.1016\/S2352-3018(20)30192-2","article-title":"A Bayesian averted infection framework for PrEP trials with low numbers of HIV infections: Application to the results of the DISCOVER trial","volume":"7","author":"Glidden","year":"2020","journal-title":"Lancet HIV"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1128\/AAC.36.11.2381","article-title":"Simian immunodeficiency virus (SIV) infection of infant rhesus macaques as a model to test antiretroviral drug prophylaxis and therapy: Oral 3\u2032-azido-3\u2032-deoxythymidine prevents SIV infection","volume":"36","author":"Marthas","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1056\/NEJM199411033311801","article-title":"Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group","volume":"331","author":"Connor","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cardenas, M.C., Farnan, S., Hamel, B.L., Mejia Plazas, M.C., Sintim-Aboagye, E., Littlefield, D.R., Behl, S., Punia, S., Enninga, E.A.L., and Johnson, E. (2023). Prevention of the Vertical Transmission of HIV; A Recap of the Journey so Far. Viruses, 15.","DOI":"10.3390\/v15040849"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1126\/science.270.5239.1197","article-title":"Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine","volume":"270","author":"Tsai","year":"1995","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1128\/JVI.72.5.4265-4273.1998","article-title":"Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl) adenine treatment for prevention of persistent simian immunodeficiency virus SIVmne infection depends critically on timing of initiation and duration of treatment","volume":"72","author":"Tsai","year":"1998","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1086\/507306","article-title":"Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges","volume":"194","author":"Subbarao","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1056\/NEJMoa1108524","article-title":"Antiretroviral prophylaxis for HIV prevention in heterosexual men and women","volume":"367","author":"Baeten","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Garcia-Lerma, J.G., Otten, R.A., Qari, S.H., Jackson, E., Cong, M.E., Masciotra, S., Luo, W., Kim, C., Adams, D.R., and Monsour, M. (2008). Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med., 5.","DOI":"10.1371\/journal.pmed.0050028"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1056\/NEJMoa2407001","article-title":"Twice-Yearly Lenacapavir or Daily F\/TAF for HIV Prevention in Cisgender Women","volume":"391","author":"Bekker","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1056\/NEJMoa1011205","article-title":"Preexposure chemoprophylaxis for HIV prevention in men who have sex with men","volume":"363","author":"Grant","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1056\/NEJMoa1110711","article-title":"Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana","volume":"367","author":"Thigpen","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1056\/NEJMoa1202614","article-title":"Preexposure prophylaxis for HIV infection among African women","volume":"367","author":"Corneli","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1056\/NEJMoa1402269","article-title":"Tenofovir-based preexposure prophylaxis for HIV infection among African women","volume":"372","author":"Marrazzo","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e25407","DOI":"10.1002\/jia2.25407","article-title":"Daily and event-driven pre-exposure prophylaxis for men who have sex with men in Belgium: Results of a prospective cohort measuring adherence, sexual behaviour and STI incidence","volume":"22","author":"Vuylsteke","year":"2019","journal-title":"J. Int. AIDS Soc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0140-6736(20)31065-5","article-title":"Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): Primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial","volume":"396","author":"Mayer","year":"2020","journal-title":"Lancet"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1093\/infdis\/jiz383","article-title":"Efficacy of Oral Tenofovir Alafenamide\/Emtricitabine Combination or Single-Agent Tenofovir Alafenamide Against Vaginal Simian Human Immunodeficiency Virus Infection in Macaques","volume":"220","author":"Massud","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_42","first-page":"14","article-title":"Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection","volume":"2","author":"Cong","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Radzio, J., Aung, W., Holder, A., Martin, A., Sweeney, E., Mitchell, J., Bachman, S., Pau, C.P., Heneine, W., and Garcia-Lerma, J.G. (2012). Prevention of vaginal SHIV transmission in macaques by a coitally-dependent Truvada regimen. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050632"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1093\/jac\/dku162","article-title":"Tenofovir diphosphate concentrations and prophylactic effect in a macaque model of rectal simian HIV transmission","volume":"69","author":"Anderson","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1093\/infdis\/jiw312","article-title":"Chemoprophylaxis with Oral Emtricitabine and Tenofovir Alafenamide Combination Protects Macaques from Rectal Simian\/Human Immunodeficiency Virus Infection","volume":"214","author":"Massud","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Mutua, G., Sanders, E., Mugo, P., Anzala, O., Haberer, J.E., Bangsberg, D., Barin, B., Rooney, J.F., Mark, D., and Chetty, P. (2012). Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033103"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kibengo, F.M., Ruzagira, E., Katende, D., Bwanika, A.N., Bahemuka, U., Haberer, J.E., Bangsberg, D.R., Barin, B., Rooney, J.F., and Mark, D. (2013). Safety, adherence and acceptability of intermittent tenofovir\/emtricitabine as HIV pre-exposure prophylaxis (PrEP) among HIV-uninfected Ugandan volunteers living in HIV-serodiscordant relationships: A randomized, clinical trial. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074314"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e68","DOI":"10.1016\/S2352-3018(17)30156-X","article-title":"Daily and non-daily pre-exposure prophylaxis in African women (HPTN 067\/ADAPT Cape Town Trial): A randomised, open-label, phase 2 trial","volume":"5","author":"Bekker","year":"2018","journal-title":"Lancet HIV"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1093\/jac\/dkaa476","article-title":"Two-dose emtricitabine\/tenofovir alafenamide plus bictegravir prophylaxis protects macaques against SHIV infection","volume":"76","author":"Bekerman","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Massud, I., Ruone, S., Zlotorzynska, M., Haaland, R., Mills, P., Cong, M.E., Kelley, K., Johnson, R., Holder, A., and Dinh, C. (2020). Single oral dose for HIV pre or post-exposure prophylaxis: User desirability and biological efficacy in macaques. EBioMedicine, 58.","DOI":"10.1016\/j.ebiom.2020.102894"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1086\/426452","article-title":"Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: Strategy to study HIV preclinical interventions in nonhuman primates","volume":"191","author":"Otten","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3140","DOI":"10.1128\/JVI.78.6.3140-3144.2004","article-title":"Repeated low-dose mucosal simian immunodeficiency virus SIVmac239 challenge results in the same viral and immunological kinetics as high-dose challenge: A model for the evaluation of vaccine efficacy in nonhuman primates","volume":"78","author":"McDermott","year":"2004","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1097\/COH.0b013e3283582d30","article-title":"Oral antiretroviral chemoprophylaxis: Current status","volume":"7","author":"Baeten","year":"2012","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.antiviral.2015.11.009","article-title":"Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human Immunodeficiency Virus","volume":"125","author":"Ray","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_55","unstructured":"Kiweewa, F.M. (2025, January 9\u201312). Adherence to F\/TAF in cisgender women prevents HIV with low risk of resistance or diagnostic delay. Proceedings of the Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, USA."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1126\/science.1248707","article-title":"Long-acting integrase inhibitor protects macaques from intrarectal simian\/human immunodeficiency virus","volume":"343","author":"Andrews","year":"2014","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1093\/infdis\/jiaa095","article-title":"Long-Acting Cabotegravir Protects Macaques Against Repeated Penile Simian-Human Immunodeficiency Virus Exposures","volume":"222","author":"Dobard","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1097\/QAD.0000000000001343","article-title":"Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251","volume":"31","author":"Andrews","year":"2017","journal-title":"AIDS"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1126\/scitranslmed.3010297","article-title":"The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge","volume":"7","author":"Radzio","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1016\/S0140-6736(22)00538-4","article-title":"Cabotegravir for the prevention of HIV-1 in women: Results from HPTN 084, a phase 3, randomised clinical trial","volume":"399","author":"Hughes","year":"2022","journal-title":"Lancet"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1056\/NEJMoa2101016","article-title":"Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women","volume":"385","author":"Landovitz","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/s41586-021-04279-4","article-title":"Long-acting capsid inhibitor protects macaques from repeat SHIV challenges","volume":"601","author":"Vidal","year":"2022","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e167818","DOI":"10.1172\/JCI167818","article-title":"Long-acting lenacapavir acts as an effective preexposure prophylaxis in a rectal SHIV challenge macaque model","volume":"133","author":"Bekerman","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1056\/NEJMoa2411858","article-title":"Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons","volume":"392","author":"Kelley","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1097\/QAD.0000000000002934","article-title":"Broadly neutralizing antibody-mediated protection of macaques against repeated intravenous exposures to simian-human immunodeficiency virus","volume":"35","author":"Garber","year":"2021","journal-title":"AIDS"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1128\/JVI.73.5.4009-4018.1999","article-title":"Protection of Macaques against pathogenic simian\/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies","volume":"73","author":"Mascola","year":"1999","journal-title":"J. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/72309","article-title":"Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection","volume":"6","author":"Baba","year":"2000","journal-title":"Nat. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/72318","article-title":"Protection of macaques against vaginal transmission of a pathogenic HIV-1\/SIV chimeric virus by passive infusion of neutralizing antibodies","volume":"6","author":"Mascola","year":"2000","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"18921","DOI":"10.1073\/pnas.1214785109","article-title":"Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo","volume":"109","author":"Moldt","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1126\/scitranslmed.3008992","article-title":"Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor","volume":"6","author":"Pegu","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nature17677","article-title":"A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges","volume":"533","author":"Gautam","year":"2016","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1126\/science.aag0491","article-title":"Antibody-mediated protection against SHIV challenge includes systemic clearance of distal virus","volume":"353","author":"Liu","year":"2016","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/imr.12511","article-title":"Use of broadly neutralizing antibodies for HIV-1 prevention","volume":"275","author":"Pegu","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e653","DOI":"10.1016\/S2352-3018(23)00140-6","article-title":"Safety, tolerability, pharmacokinetics, and immunological activity of dual-combinations and triple-combinations of anti-HIV monoclonal antibodies PGT121, PGDM1400, 10-1074, and VRC07-523LS administered intravenously to HIV-uninfected adults: A phase 1 randomised trial","volume":"10","author":"Sobieszczyk","year":"2023","journal-title":"Lancet HIV"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1056\/NEJMoa2031738","article-title":"Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition","volume":"384","author":"Corey","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1093\/infdis\/jiz271","article-title":"Once-Weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques from Intrarectal Challenge with SHIV109CP3","volume":"221","author":"Markowitz","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_77","unstructured":"Markowitz, M. (2020, January 8\u201311). Weekly oral islatravir provides effective PEP against IV challenge with SIVMAC251. Proceedings of the Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA."},{"key":"ref_78","unstructured":"Landovitz, R.J. (2024, January 6\u201310). Safety and tolerability of oral Islatravir (ISL) once-monthly (QM) as pre-exposure prophylaxis (PrEP) in cisgender men and transgender women at elevated risk for acquiring HIV-1. Proceedings of the HIV Research for Prevention Conference, Lima, Peru."},{"key":"ref_79","unstructured":"Delany-Moretlwe, S. (2024, January 6\u201310). Safety and tolerability of oral Islatravir (ISL) once-monthly (QM) as pre-exposure prophylaxis (PrEP) in cisgender women at elevated risk for acquiring HIV-1. Proceedings of the HIV Research for Prevention Conference, Lima, Peru."},{"key":"ref_80","unstructured":"Diamond, T.L. (2024, January 6\u201310). Weekly oral prophylaxis with MK-8527 protects rhesus macaques from rectal challenge with simian-human immunodeficiency virus. Proceedings of the Conference on HIV Research for Prevention, Lima, Peru."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2000163","DOI":"10.1002\/adtp.202000163","article-title":"Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates","volume":"4","author":"Sizovs","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e01893-19","DOI":"10.1128\/AAC.01893-19","article-title":"A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques","volume":"64","author":"Su","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"eadg2887","DOI":"10.1126\/scitranslmed.adg2887","article-title":"Long-acting refillable nanofluidic implant confers protection against SHIV infection in nonhuman primates","volume":"15","author":"Capuani","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.1093\/jac\/dkac252","article-title":"Safety and efficacy of a biodegradable implant releasing tenofovir alafenamide for vaginal protection in a macaque model","volume":"77","author":"Massud","year":"2022","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jconrel.2023.12.031","article-title":"Antiviral potency of long-acting islatravir subdermal implant in SHIV-infected macaques","volume":"366","author":"Capuani","year":"2024","journal-title":"J. Control Release"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e26426","DOI":"10.1002\/jia2.26426","article-title":"Acceptability of an annual tenofovir alafenamide implant for HIV prevention in South African women: Findings from the CAPRISA 018 Phase I clinical trial","volume":"28","author":"Gengiah","year":"2025","journal-title":"J. Int. AIDS Soc."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1126\/scitranslmed.3010298","article-title":"A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge","volume":"7","author":"Andrews","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(25)00405-2","article-title":"Pharmacokinetics and safety of once-yearly lenacapavir: A phase 1, open-label study","volume":"405","author":"Jogiraju","year":"2025","journal-title":"Lancet"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/s41586-020-2443-1","article-title":"Clinical targeting of HIV capsid protein with a long-acting small molecule","volume":"584","author":"Link","year":"2020","journal-title":"Nature"},{"key":"ref_90","unstructured":"Bekerman, E., Hansen, D., Lu, B., Wang, K., Rowe, W., Campigotto, F., Zheng, J., Das, M., Callebaut, C., and Yant, S.R. (2021, January 18\u201321). Long-acting Capsid Inhibitor Effective as PrEP Against Vaginal SHIV Transmission in Macaques. Proceedings of the 11th IAS Conference on HIV Science, Virtual."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Baeten, J.M. (2025). Lenacapavir for Human Immunodeficiency Virus (HIV) Prevention: A Commitment to Equitable Access and Partnership by Gilead Sciences. Clin. Infect. Dis., ciaf116.","DOI":"10.1093\/cid\/ciaf116"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1080\/22221751.2020.1713707","article-title":"Broadly neutralizing antibodies for HIV-1: Efficacies, challenges and opportunities","volume":"9","author":"Liu","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1038\/s41591-022-01953-6","article-title":"Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition","volume":"28","author":"Gilbert","year":"2022","journal-title":"Nat. Med."},{"key":"ref_94","unstructured":"Raheem, I.T. (2024, January 3\u20136). Discovery of MK-8527, a long-acting HIV nucleoside reverse transcriptase translocation inhibitor. Proceedings of the Conference on Retroviruses and Opportunistic Infections, Denver, CO, USA."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1128\/JVI.05842-11","article-title":"Durable protection from vaginal simian-human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue","volume":"86","author":"Dobard","year":"2012","journal-title":"J. Virol."},{"key":"ref_96","unstructured":"Miller, C., Rosenberg, Z., and Bischofberger, N. (1996, January 19\u201324). Use of topical PMPA to prevent vaginal transmission of SIV. Proceedings of the 9th International Conference on Antiviral Research, Fukushima, Japan."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Cranage, M., Sharpe, S., Herrera, C., Cope, A., Dennis, M., Berry, N., Ham, C., Heeney, J., Rezk, N., and Kashuba, A. (2008). Prevention of SIV rectal transmission and priming of T cell responses in macaques after local pre-exposure application of tenofovir gel. PLoS Med., 5, discussion e157.","DOI":"10.1371\/journal.pmed.0050157"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1128\/AAC.00330-07","article-title":"Concentrations of dapivirine in the rhesus macaque and rabbit following once daily intravaginal administration of a gel formulation of [14C]dapivirine for 7 days","volume":"52","author":"Nuttall","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"10358","DOI":"10.1128\/JVI.01073-09","article-title":"Complete protection from repeated vaginal simian-human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine","volume":"83","author":"Parikh","year":"2009","journal-title":"J. Virol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1126\/science.1193748","article-title":"Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women","volume":"329","author":"Frohlich","year":"2010","journal-title":"Science"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1056\/NEJMoa1506110","article-title":"Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women","volume":"375","author":"Baeten","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1056\/NEJMoa1602046","article-title":"Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women","volume":"375","author":"Nel","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/S1473-3099(18)30428-6","article-title":"Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): A phase 3, randomised, double-blind, placebo-controlled trial","volume":"18","author":"Lombard","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e87","DOI":"10.1016\/S2352-3018(20)30304-0","article-title":"Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): An open-label, extension study","volume":"8","author":"Baeten","year":"2021","journal-title":"Lancet HIV"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1016\/S2352-3018(20)30300-3","article-title":"Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): An open-label, extension study","volume":"8","author":"Nel","year":"2021","journal-title":"Lancet HIV"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Makarova, N., Singletary, T., Peet, M.M., Mitchell, J., Holder, A., Dinh, C., Agrahari, V., Mendoza, M., Pan, Y., and Heneine, W. (2022). Pharmacokinetics and efficacy of topical inserts containing tenofovir alafenamide fumarate and elvitegravir administered rectally in macaques. EBioMedicine, 86.","DOI":"10.1016\/j.ebiom.2022.104338"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Dobard, C.W., Peet, M.M., Nishiura, K., Holder, A., Dinh, C., Mitchell, J., Khalil, G., Pan, Y., Singh, O.N., and McCormick, T.J. (2022). Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques. EBioMedicine, 86.","DOI":"10.1016\/j.ebiom.2022.104361"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1093\/infdis\/jiad599","article-title":"Extended Postexposure Protection Against Vaginal Simian\/Human Immunodeficiency Virus Infection with Tenofovir Alafenamide Fumarate\/Elvitegravir Inserts in Macaques","volume":"229","author":"Makarova","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1093\/infdis\/jiae211","article-title":"A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide\/Elvitegravir Insert Administered Rectally for HIV Prevention","volume":"230","author":"Riddler","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1093\/infdis\/jiv334","article-title":"Protection Against Rectal Chimeric Simian\/Human Immunodeficiency Virus Transmission in Macaques by Rectal-Specific Gel Formulations of Maraviroc and Tenofovir","volume":"212","author":"Dobard","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1093\/jac\/dks422","article-title":"Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques","volume":"68","author":"Malcolm","year":"2013","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_112","first-page":"238","article-title":"Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex with Men (HPTN 069\/ACTG A5305)","volume":"215","author":"Gulick","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"384","DOI":"10.7326\/M17-0520","article-title":"Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women: A Phase 2 Randomized Trial","volume":"167","author":"Gulick","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Obiero, J., Mwethera, P.G., Hussey, G.D., and Wiysonge, C.S. (2012). Vaginal microbicides for reducing the risk of sexual acquisition of HIV infection in women: Systematic review and meta-analysis. BMC Infect. Dis., 12.","DOI":"10.1186\/1471-2334-12-289"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Tan, S., Lu, L., Li, L., Liu, J., Oksov, Y., Lu, H., Jiang, S., and Liu, S. (2013). Polyanionic candidate microbicides accelerate the formation of semen-derived amyloid fibrils to enhance HIV-1 infection. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059777"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1517\/13543784.2012.667072","article-title":"A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection","volume":"21","author":"Gengiah","year":"2012","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Bauermeister, J.A., Dominguez Islas, C., Jiao, Y., Tingler, R., Brown, E., Zemanek, J., Giguere, R., Balan, I., Johnson, S., and Macagna, N. (2023). A randomized trial of safety, acceptability and adherence of three rectal microbicide placebo formulations among young sexual and gender minorities who engage in receptive anal intercourse (MTN-035). PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0284339"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"8952","DOI":"10.1128\/JVI.01204-13","article-title":"Lack of prophylactic efficacy of oral maraviroc in macaques despite high drug concentrations in rectal tissues","volume":"87","author":"Massud","year":"2013","journal-title":"J. Virol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1128\/AAC.00984-06","article-title":"Preclinical safety assessments of UC781 anti-human immunodeficiency virus topical microbicide formulations","volume":"51","author":"Patton","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1097\/QAI.0b013e3182575914","article-title":"The safety, persistence, and acceptability of an antiretroviral microbicide candidate UC781","volume":"60","author":"Bunge","year":"2012","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1023\/A:1016169202830","article-title":"Comparison of oral absorption and bioavailablity of drugs between monkey and human","volume":"19","author":"Chiou","year":"2002","journal-title":"Pharm. Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/9\/1192\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:36:16Z","timestamp":1760034976000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/9\/1192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,30]]},"references-count":121,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["v17091192"],"URL":"https:\/\/doi.org\/10.3390\/v17091192","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,30]]}}}