SHIV Remission in Macaques with Early Treatment Initiation and Ultra Long-lasting Antiviral Activity

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Dec 5

PMID 39632836

Authors

Michele B Daly

Chuong Dinh

Angela Holder

Donna Rudolph

Susan Ruone

Alison Swaims-Kohlmeier

George Khalil

Sunita Sharma

James Mitchell

Jillian Condrey

Daniel Kim

Yi Pan

Kelly Curtis

Peter Williams

William Spreen

Walid Heneine

J Gerardo Garcia-Lerma

Affiliations

Soon will be listed here.

Abstract

Studies in SIV-infected macaques show that the virus reservoir is particularly refractory to conventional suppressive antiretroviral therapy (ART). We posit that optimized ART regimens designed to have robust penetration in tissue reservoirs and long-lasting antiviral activity may be advantageous for HIV or SIV remission. Here we treat macaques infected with RT-SHIV with oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine without (n = 4) or with (n = 4) the immune activator vesatolimod after the initial onset of viremia. We document full suppression in all animals during treatment (4-12 months) and no virus rebound after treatment discontinuation (1.5-2 years of follow up) despite CD8 + T cell depletion. We show efficient multidrug penetration in virus reservoirs and persisting rilpivirine in plasma for 2 years after the last dose. Our results document a type of virus remission that is achieved through early treatment initiation and provision of ultra long-lasting antiviral activity that persists after treatment cessation.

References

Lee W, He G, Eisenberg E, Cihlar T, Swaminathan S, Mulato A . Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005; 49(5):1898-906. PMC: 1087627. DOI: 10.1128/AAC.49.5.1898-1906.2005. View

Cranston R, Dezzutti C, Siegel A, Engstrom J, Shetler C, Richardson-Harman N . A Multiple Dose Phase 1 Assessment of Rilpivirine Long Acting in a Model of Preexposure Prophylaxis Against HIV. AIDS Res Hum Retroviruses. 2019; 35(9):794-804. DOI: 10.1089/AID.2018.0265. View

Waterboer T, Sehr P, Pawlita M . Suppression of non-specific binding in serological Luminex assays. J Immunol Methods. 2006; 309(1-2):200-4. DOI: 10.1016/j.jim.2005.11.008. View

Garcia-Lerma J, Aung W, Cong M, Zheng Q, Youngpairoj A, Mitchell J . Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. J Virol. 2011; 85(13):6610-7. PMC: 3126530. DOI: 10.1128/JVI.00311-11. View

Curtis K, Kennedy M, Charurat M, Nasidi A, Delaney K, Spira T . Development and characterization of a bead-based, multiplex assay for estimation of recent HIV type 1 infection. AIDS Res Hum Retroviruses. 2011; 28(2):188-97. DOI: 10.1089/aid.2011.0037. View

Ndungu T, McCune J, Deeks S . Why and where an HIV cure is needed and how it might be achieved. Nature. 2019; 576(7787):397-405. PMC: 8052635. DOI: 10.1038/s41586-019-1841-8. View

Tsai A, Irrinki A, Kaur J, Cihlar T, Kukolj G, Sloan D . Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy. J Virol. 2017; 91(8). PMC: 5375698. DOI: 10.1128/JVI.02166-16. View

Melody K, McBeth S, Kline C, Kashuba A, Mellors J, Ambrose Z . Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase. Antimicrob Agents Chemother. 2015; 59(12):7762-70. PMC: 4649225. DOI: 10.1128/AAC.01937-15. View

Andrews C, Spreen W, Mohri H, Moss L, Ford S, Gettie A . Long-acting integrase inhibitor protects macaques from intrarectal simian/human immunodeficiency virus. Science. 2014; 343(6175):1151-4. PMC: 4308974. DOI: 10.1126/science.1248707. View

10.

Fletcher C, Podany A, Thorkelson A, Winchester L, Mykris T, Anderson J . The Lymphoid Tissue Pharmacokinetics of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide in HIV-Infected Persons. Clin Pharmacol Ther. 2020; 108(5):971-975. PMC: 7935460. DOI: 10.1002/cpt.1883. View

11.

Busman-Sahay K, Starke C, Nekorchuk M, Estes J . Eliminating HIV reservoirs for a cure: the issue is in the tissue. Curr Opin HIV AIDS. 2021; 16(4):200-208. PMC: 8171814. DOI: 10.1097/COH.0000000000000688. View

12.

Borducchi E, Liu J, Nkolola J, Cadena A, Yu W, Fischinger S . Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature. 2018; 563(7731):360-364. PMC: 6237629. DOI: 10.1038/s41586-018-0600-6. View

13.

Gupta S, Berhe M, Crofoot G, Benson P, Ramgopal M, Sims J . Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial. Lancet HIV. 2022; 10(1):e15-e23. DOI: 10.1016/S2352-3018(22)00291-0. View

14.

Passaes C, Desjardins D, Chapel A, Monceaux V, Lemaitre J, Melard A . Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8 T-cells. Nat Commun. 2024; 15(1):178. PMC: 10784587. DOI: 10.1038/s41467-023-44389-3. View

15.

Crowell T, Ritz J, Zheng L, Naqvi A, Cyktor J, Puleo J . Impact of antiretroviral therapy during acute or early HIV infection on virologic and immunologic outcomes: results from a multinational clinical trial. AIDS. 2024; 38(8):1141-1152. PMC: 11323228. DOI: 10.1097/QAD.0000000000003881. View

16.

Chavez L, Calvanese V, Verdin E . HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T Cells. PLoS Pathog. 2015; 11(6):e1004955. PMC: 4466167. DOI: 10.1371/journal.ppat.1004955. View

17.

Garcia-Lerma J, Otten R, Qari S, Jackson E, Cong M, Masciotra S . Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med. 2008; 5(2):e28. PMC: 2225435. DOI: 10.1371/journal.pmed.0050028. View

18.

Balzarini J, Weeger M, Camarasa M, De Clercq E, Uberla K . Sensitivity/resistance profile of a simian immunodeficiency virus containing the reverse transcriptase gene of human immunodeficiency virus type 1 (HIV-1) toward the HIV-1-specific non-nucleoside reverse transcriptase inhibitors. Biochem Biophys Res Commun. 1995; 211(3):850-6. DOI: 10.1006/bbrc.1995.1890. View

19.

Lim S, Osuna C, Hraber P, Hesselgesser J, Gerold J, Barnes T . TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. Sci Transl Med. 2018; 10(439). PMC: 5973480. DOI: 10.1126/scitranslmed.aao4521. View

20.

Namazi G, Fajnzylber J, Aga E, Bosch R, Acosta E, Sharaf R . The Control of HIV After Antiretroviral Medication Pause (CHAMP) Study: Posttreatment Controllers Identified From 14 Clinical Studies. J Infect Dis. 2018; 218(12):1954-1963. PMC: 6217727. DOI: 10.1093/infdis/jiy479. View