Small steps forward for HIV vaccine development

Mothe, Beatriz; Brander, Christian

doi:10.1038/s41591-020-0837-0

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Small steps forward for HIV vaccine development

brief-report

Author(s): Beatriz Mothe ¹ ^, ² ^, ³ ^, , Christian Brander ² ^, ³ ^, ⁴ ^, ⁵

Publication date (Electronic): 2 April 2020

Journal: Nature Medicine

Publisher: Nature Publishing Group US

Keywords: Translational research, Vaccines

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Abstract

A trial of a therapeutic vaccine against HIV induces cellular immunity and, although it provides hope, it highlights the hurdles for the development of such strategies.

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Most cited references 11

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HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells.

Michael Betts, Martha Nason, Sadie West … (2006)

Establishing a CD8(+) T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8(+) T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8(+) T-cell response by measuring 5 CD8(+) T-cell functions (degranulation, IFN-gamma, MIP-1beta, TNF-alpha, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8(+) T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8(+) T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8(+) T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8(+) T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy.

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Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.

R Koup, J. T. Safrit, Y Cao … (1994)

Virologic and immunologic studies were performed on five patients presenting with primary human immunodeficiency virus type 1 (HIV-1) infection. CD8+ cytotoxic T lymphocyte (CTL) precursors specific for cells expressing antigens of HIV-1 Gag, Pol, and Env were detected at or within 3 weeks of presentation in four of the five patients and were detected in all five patients by 3 to 6 months after presentation. The one patient with an absent initial CTL response had prolonged symptoms, persistent viremia, and low CD4+ T-cell count. Neutralizing antibody activity was absent at the time of presentation in all five patients. These findings suggest that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and indicate a role for CTL in protective immunity to HIV-1 in vivo.

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Early antibody therapy can induce long-lasting immunity to SHIV

Yoshiaki Nishimura, Rajeev Gautam, Tae-Wook Chun … (2017)

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56–177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.

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Author and article information

Contributors

Beatriz Mothe:

ORCID: http://orcid.org/0000-0001-9975-407X

bmothe@irsicaixa.es

Journal

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med

Title: Nature Medicine

Publisher: Nature Publishing Group US (New York )

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date (Electronic): 2 April 2020

Publication date (Print): 2020

Volume: 26

Issue: 4

Pages: 466-467

Affiliations

[1 ]ISNI 0000 0004 1767 6330, GRID grid.411438.b, Infectious Diseases Department, , Hospital Universitari Germans Trias i Pujol, ; Badalona, Spain

[2 ]IrsiCaixa AIDS Research Institute, Badalona, Spain

[3 ]GRID grid.440820.a, Universitat de Vic-Central of Catalonia, ; Vic, Spain

[4 ]AELIX Therapeutics, Barcelona, Spain

[5 ]ISNI 0000 0000 9601 989X, GRID grid.425902.8, ICREA, ; Barcelona, Spain

Author information

Beatriz Mothe http://orcid.org/0000-0001-9975-407X

Article

Publisher ID: 837

DOI: 10.1038/s41591-020-0837-0

PMC ID: 7224125

PubMed ID: 32242125

SO-VID: 5c396e9b-d5cb-42f8-b2e8-8d4d94f4ac6d

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.