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Open Access 16-01-2024 | Human Immunodeficiency Virus

More than the Infinite Monkey Theorem: NHP Models in the Development of a Pediatric HIV Cure

Authors: Jairo A. Fonseca, Alexis C. King, Ann Chahroudi

Published in: Current HIV/AIDS Reports | Issue 1/2024

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Abstract

Purpose of Review

An HIV cure that eliminates the viral reservoir or provides viral control without antiretroviral therapy (ART) is an urgent need in children as they face unique challenges, including lifelong ART adherence and the deleterious effects of chronic immune activation. This review highlights the importance of nonhuman primate (NHP) models in developing an HIV cure for children as these models recapitulate the viral pathogenesis and persistence.

Recent Findings

Several cure approaches have been explored in infant NHPs, although knowledge gaps remain. Broadly neutralizing antibodies (bNAbs) show promise for controlling viremia and delaying viral rebound after ART interruption but face administration challenges. Adeno-associated virus (AAV) vectors hold the potential for sustained bNAb expression. Therapeutic vaccination induces immune responses against simian retroviruses but has yet to impact the viral reservoir. Combining immunotherapies with latency reversal agents (LRAs) that enhance viral antigen expression should be explored.

Summary

Current and future cure approaches will require adaptation for the pediatric immune system and unique features of virus persistence, for which NHP models are fundamental to assess their efficacy.
Literature
1.
go back to reference UNAIDS. UNAIDS Global AIDS Update 2023. United Nations; 2023. UNAIDS. UNAIDS Global AIDS Update 2023. United Nations; 2023.
5.
go back to reference Patel K, Hernan MA, Williams PL, Seeger JD, McIntosh K, Van Dyke RB, et al. Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study. Clin Infect Dis. 2008;46(4):507–15. https://doi.org/10.1086/526524.CrossRefPubMed Patel K, Hernan MA, Williams PL, Seeger JD, McIntosh K, Van Dyke RB, et al. Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study. Clin Infect Dis. 2008;46(4):507–15. https://​doi.​org/​10.​1086/​526524.CrossRefPubMed
13.
go back to reference Jaafoura S, de Goer de Herve MG, Hernandez-Vargas EA, Hendel-Chavez H, Abdoh M, Mateo MC, et al. Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4(+) memory T Cells. Nat Commun. 2014;5:5407. https://doi.org/10.1038/ncomms6407. Jaafoura S, de Goer de Herve MG, Hernandez-Vargas EA, Hendel-Chavez H, Abdoh M, Mateo MC, et al. Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4(+) memory T Cells. Nat Commun. 2014;5:5407. https://​doi.​org/​10.​1038/​ncomms6407.
15.
go back to reference Mavigner M, Habib J, Deleage C, Rosen E, Mattingly C, Bricker K, et al. Simian immunodeficiency virus persistence in cellular and anatomic reservoirs in antiretroviral therapy-suppressed infant rhesus macaques. J Virol. 2018;92(18). https://doi.org/10.1128/JVI.00562-18. Mavigner M, Habib J, Deleage C, Rosen E, Mattingly C, Bricker K, et al. Simian immunodeficiency virus persistence in cellular and anatomic reservoirs in antiretroviral therapy-suppressed infant rhesus macaques. J Virol. 2018;92(18). https://​doi.​org/​10.​1128/​JVI.​00562-18.
16.
go back to reference Obregon-Perko V, Bricker KM, Mensah G, Uddin F, Kumar MR, Fray EJ, et al. Simian-human immunodeficiency virus SHIV.C.CH505 persistence in ART-suppressed infant macaques is characterized by elevated SHIV RNA in the gut and a high abundance of intact SHIV DNA in naive CD4(+) T cells. J Virol. 2020;95(2). https://doi.org/10.1128/JVI.01669-20. Obregon-Perko V, Bricker KM, Mensah G, Uddin F, Kumar MR, Fray EJ, et al. Simian-human immunodeficiency virus SHIV.C.CH505 persistence in ART-suppressed infant macaques is characterized by elevated SHIV RNA in the gut and a high abundance of intact SHIV DNA in naive CD4(+) T cells. J Virol. 2020;95(2). https://​doi.​org/​10.​1128/​JVI.​01669-20.
17.
go back to reference Katusiime MG, Guo S, Neer V, Patro SC, Wu X, Horner A, et al. Infected naive CD4+ T cells in children with HIV can proliferate and persist on ART. CROI-Conference on Retroviruses and Opportunistic Infections Seattle, WA, United States. 2023. Katusiime MG, Guo S, Neer V, Patro SC, Wu X, Horner A, et al. Infected naive CD4+ T cells in children with HIV can proliferate and persist on ART. CROI-Conference on Retroviruses and Opportunistic Infections Seattle, WA, United States. 2023.
19.
39.
go back to reference Ballan WM, Vu BA, Long BR, Loo CP, Michaelsson J, Barbour JD, et al. Natural killer cells in perinatally HIV-1-infected children exhibit less degranulation compared to HIV-1-exposed uninfected children and their expression of KIR2DL3, NKG2C, and NKp46 correlates with disease severity. J Immunol. 2007;179(5):3362–70. https://doi.org/10.4049/jimmunol.179.5.3362.CrossRefPubMed Ballan WM, Vu BA, Long BR, Loo CP, Michaelsson J, Barbour JD, et al. Natural killer cells in perinatally HIV-1-infected children exhibit less degranulation compared to HIV-1-exposed uninfected children and their expression of KIR2DL3, NKG2C, and NKp46 correlates with disease severity. J Immunol. 2007;179(5):3362–70. https://​doi.​org/​10.​4049/​jimmunol.​179.​5.​3362.CrossRefPubMed
51.
go back to reference Muenchhoff M, Chung AW, Roider J, Dugast AS, Richardson S, Kloverpris H, et al. Distinct immunoglobulin Fc glycosylation patterns are associated with disease nonprogression and broadly neutralizing antibody responses in children with HIV infection. mSphere. 2020;5(6). https://doi.org/10.1128/mSphere.00880-20. Muenchhoff M, Chung AW, Roider J, Dugast AS, Richardson S, Kloverpris H, et al. Distinct immunoglobulin Fc glycosylation patterns are associated with disease nonprogression and broadly neutralizing antibody responses in children with HIV infection. mSphere. 2020;5(6). https://​doi.​org/​10.​1128/​mSphere.​00880-20.
68.
go back to reference Cromhout. G., Bengu. N., Adland. E., Herbert. N., Lim. N., Govender. K., et al. Sustained aviraemia in the absence of anti-retroviral therapy in male children following in utero vertical HIV transmission. IAS 2023 - International AIDS Society Conference on HIV Science. Brisbane, Australia. 2023. Cromhout. G., Bengu. N., Adland. E., Herbert. N., Lim. N., Govender. K., et al. Sustained aviraemia in the absence of anti-retroviral therapy in male children following in utero vertical HIV transmission. IAS 2023 - International AIDS Society Conference on HIV Science. Brisbane, Australia. 2023.
69.
go back to reference Volmink J, Marais B. HIV: mother-to-child transmission. BMJ Clin Evid. 2008;2008(0909). Volmink J, Marais B. HIV: mother-to-child transmission. BMJ Clin Evid. 2008;2008(0909).
70.
go back to reference Milush JM, Kosub D, Marthas M, Schmidt K, Scott F, Wozniakowski A, et al. Rapid dissemination of SIV following oral inoculation. AIDS. 2004;18(18):2371–80.PubMed Milush JM, Kosub D, Marthas M, Schmidt K, Scott F, Wozniakowski A, et al. Rapid dissemination of SIV following oral inoculation. AIDS. 2004;18(18):2371–80.PubMed
104.
go back to reference Frange P, Faye A, Avettand-Fenoel V, Bellaton E, Descamps D, Angin M, et al. HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. Lancet HIV. 2016;3(1):e49-54. https://doi.org/10.1016/S2352-3018(15)00232-5.CrossRefPubMed Frange P, Faye A, Avettand-Fenoel V, Bellaton E, Descamps D, Angin M, et al. HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. Lancet HIV. 2016;3(1):e49-54. https://​doi.​org/​10.​1016/​S2352-3018(15)00232-5.CrossRefPubMed
107.
go back to reference Goswami R, Nelson AN, Tu JJ, Dennis M, Feng L, Kumar A, et al. Analytical treatment interruption after short-term antiretroviral therapy in a postnatally simian-human immunodeficiency virus-infected infant rhesus macaque model. mBio. 2019;10(5). https://doi.org/10.1128/mBio.01971-19. Goswami R, Nelson AN, Tu JJ, Dennis M, Feng L, Kumar A, et al. Analytical treatment interruption after short-term antiretroviral therapy in a postnatally simian-human immunodeficiency virus-infected infant rhesus macaque model. mBio. 2019;10(5). https://​doi.​org/​10.​1128/​mBio.​01971-19.
109.
go back to reference Sugimoto C, Merino KM, Hasegawa A, Wang X, Alvarez XA, Wakao H, et al. Critical role for monocytes/macrophages in rapid progression to AIDS in pediatric simian immunodeficiency virus-infected rhesus macaques. J Virol. 2017;91(17). https://doi.org/10.1128/JVI.00379-17. Sugimoto C, Merino KM, Hasegawa A, Wang X, Alvarez XA, Wakao H, et al. Critical role for monocytes/macrophages in rapid progression to AIDS in pediatric simian immunodeficiency virus-infected rhesus macaques. J Virol. 2017;91(17). https://​doi.​org/​10.​1128/​JVI.​00379-17.
113.
119.
go back to reference Nelson AN, Goswami R, Dennis M, Tu J, Mangan RJ, Saha PT, et al. Simian-human immunodeficiency virus SHIV.CH505-infected infant and adult rhesus macaques exhibit similar env-specific antibody kinetics, despite distinct T-follicular helper and germinal center B cell landscapes. J Virol. 2019;93(15). https://doi.org/10.1128/JVI.00168-19. Nelson AN, Goswami R, Dennis M, Tu J, Mangan RJ, Saha PT, et al. Simian-human immunodeficiency virus SHIV.CH505-infected infant and adult rhesus macaques exhibit similar env-specific antibody kinetics, despite distinct T-follicular helper and germinal center B cell landscapes. J Virol. 2019;93(15). https://​doi.​org/​10.​1128/​JVI.​00168-19.
125.
go back to reference Obregon-Perko V, Awasthi A, Barfield R, Berendam S, Yagnik B, Styles T, et al. Viral rebound dynamics in SHIV-infected infant macaques are predicted by distinct immunovirologic features measured before and after one year of antiretroviral therapy. IAS 2023 - International AIDS Society Conference on HIV Science. Brisbane, Australia. 2023. Obregon-Perko V, Awasthi A, Barfield R, Berendam S, Yagnik B, Styles T, et al. Viral rebound dynamics in SHIV-infected infant macaques are predicted by distinct immunovirologic features measured before and after one year of antiretroviral therapy. IAS 2023 - International AIDS Society Conference on HIV Science. Brisbane, Australia. 2023.
133.
go back to reference Berendam SJ, Styles TM, Morgan-Asiedu PK, Tenney D, Kumar A, Obregon-Perko V, et al. Systematic assessment of antiviral potency, breadth, and synergy of triple broadly neutralizing antibody combinations against simian-human immunodeficiency viruses. J Virol. 2021;95(3). https://doi.org/10.1128/JVI.01667-20. Berendam SJ, Styles TM, Morgan-Asiedu PK, Tenney D, Kumar A, Obregon-Perko V, et al. Systematic assessment of antiviral potency, breadth, and synergy of triple broadly neutralizing antibody combinations against simian-human immunodeficiency viruses. J Virol. 2021;95(3). https://​doi.​org/​10.​1128/​JVI.​01667-20.
144.
go back to reference Chahroudi A. Nonhuman primate studies of pediatric cure interventions. CROI-Conference on Retroviruses and Opportunistic Infections. Seattle, WA, United States. 2023. Chahroudi A. Nonhuman primate studies of pediatric cure interventions. CROI-Conference on Retroviruses and Opportunistic Infections. Seattle, WA, United States. 2023.
156.
go back to reference Yagnik B, Styles T, Berendam SJ, Phan C, Goswami R, Dankwa S, et al. Therapeutic vaccination of SHIV-infected, ART-suppressed infant rhesus macaques. CROI-Conference on Retroviruses and Opportunistic Infections. Seattle, WA, United States. 2023. Yagnik B, Styles T, Berendam SJ, Phan C, Goswami R, Dankwa S, et al. Therapeutic vaccination of SHIV-infected, ART-suppressed infant rhesus macaques. CROI-Conference on Retroviruses and Opportunistic Infections. Seattle, WA, United States. 2023.
162.
go back to reference Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood. 2000;96(3):785–93.CrossRefPubMed Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood. 2000;96(3):785–93.CrossRefPubMed
163.
go back to reference Walker RE, Bechtel CM, Natarajan V, Baseler M, Hege KM, Metcalf JA, et al. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood. 2000;96(2):467–74.PubMed Walker RE, Bechtel CM, Natarajan V, Baseler M, Hege KM, Metcalf JA, et al. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood. 2000;96(2):467–74.PubMed
Metadata
Title
More than the Infinite Monkey Theorem: NHP Models in the Development of a Pediatric HIV Cure
Authors
Jairo A. Fonseca
Alexis C. King
Ann Chahroudi
Publication date
16-01-2024
Publisher
Springer US
Published in
Current HIV/AIDS Reports / Issue 1/2024
Print ISSN: 1548-3568
Electronic ISSN: 1548-3576
DOI
https://doi.org/10.1007/s11904-023-00686-6
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