J Virol. 2014 Oct;88(20):11648-57.

Effect of vaginal immunization with HIVgp140 and HSP70 on HIV-1 replication and innate and T cell adaptive immunity in women.

Lewis DJ1, Wang Y2, Huo Z1, Giemza R3, Babaahmady K4, Rahman D2, Shattock RJ4, Singh M5, Lehner T6.
  • 1Surrey Clinical Research Centre, University of Surrey, Guildford, United Kingdom.
  • 2King’s College London at Guy’s Hospital, London, United Kingdom.
  • 3King’s College London at Denmark Hill Campus, London, United Kingdom.
  • 4Mucosal Infection and Immunity Group, Medicine, Imperial College London, London, United Kingdom.
  • 5Lionex GmbH, Braunschweig, Germany.
  • 6King’s College London at Guy’s Hospital, London, United Kingdom thomas.lehner@kcl.ac.uk.

 

Abstract

The international effort to prevent HIV-1 infection by vaccination has failed to develop an effective vaccine. The aim of this vaccine trial in women was to administer by the vaginal mucosal route a vaccine consisting of HIV-1 gp140 linked to the chaperone 70-kDa heat shock protein (HSP70). The primary objective was to determine the safety of the vaccine. The secondary objective was to examine HIV-1 infectivity ex vivo and innate and adaptive immunity to HIV-1. Protocol-defined female volunteers were recruited. HIV-1 CN54gp140 linked to HSP70 was administered by the vaginal route. Significant adverse reactions were not detected. HIV-1 was significantly inhibited ex vivo in postimmunization CD4(+) T cells compared with preimmunization CD4(+) T cells. The innate antiviral restrictive factor APOBEC3G was significantly upregulated, as were CC chemokines which induce downregulation of CCR5 in CD4(+) T cells. Indeed, a significant inverse correlation between the proportion of CCR5(+) T cells and the concentration of CCL-3 or CCL-5 was found. Importantly, the upregulation of APOBEC3G showed a significant inverse correlation, whereas CCR5 exhibited a trend to correlate with inhibition of HIV-1 infection (r = 0.51). Furthermore, specific CD4(+) and CD8(+) T cell proliferative responses were significantly increased and CD4(+) T cells showed a trend to have an inverse correlation with the viral load (r = -0.60). However, HIVgp140-specific IgG or IgA antibodies were not detected. The results provide proof of concept that an innate mechanism consisting of CC chemokines, APOBEC3G, and adaptive immunity by CD4 and CD8 T cells might be involved in controlling HIV-1 infectivity following vaginal mucosal immunization in women. (This study has been registered at ClinicalTrials.gov under registration no. NCT01285141.) Importance: Vaginal immunization of women with a vaccine consisting of HIVgp140 linked to the 70-kDa heat shock protein (HSP70) elicited ex vivo significant inhibition of HIV-1 replication in postimmunization CD4(+) T cells compared with that in preimmunization peripheral blood mononuclear cells. There were no significant adverse events. The vaccine induced the significant upregulation of CC chemokines and the downmodulation of CCR5 expression in CD4(+) T cells, as well as an inverse correlation between them. Furthermore, the level of CCR5 expression was directly correlated with the viral load, consistent with the protective mechanism in which a decrease in CCR5 molecules on CD4(+) T cells decreases HIV-1 envelope binding. Expression of the antiviral restriction factor APOBEC3G was inversely correlated with the viral load, suggesting that it may inhibit intracellular HIV-1 replication. Both CD4(+) and CD8(+) T cells showed HIVgp140- and HSP70-specific proliferation. A strong inverse correlation between the proportion of CC chemokine-modulated CCR5-expressing CD4(+) T cells and the stimulation of CD4(+) or CD8(+) T cell proliferation by HIVgp140 was found, demonstrating a significant interaction between innate and adaptive immunity. This is the first clinical trial of vaginal immunization in women using only HIVgp140 and HSP70 administered by the mucosal route (3 times) in which a dual innate protective mechanism was induced and enhanced by significant adaptive CD4(+) and CD8(+) T cell proliferative responses.

PMID: 25008917

 

Supplement

Limited attention has been paid to innate immunity, which had been reported in the two natural protective mechanisms; homozygous chemokine receptor CCR5-delta32 deletion (1,2) and alloimmunity (3,4). Both natural immune responses can be induced by immunization and had been demonstrated in humans and NHP, eliciting a dual innate pre- and post-entry HIV immune mechanism. The viral restriction factor, such as APOBEC3G may inhibit post-entry any HIV which had escaped pre-entry inhibition by CC chemokines or anti-CCR5 antibodies, as a significant proportion of CCR5+ coreceptors on CD4+ T cells are still available for HIV-1 infection   (5,6,7 ). In addition to alloimmunization, long term non-progressors (LTNP) and HIV-1 exposed uninfected people are likely to share this mechanism (8,9).

The paper by Lewis et al (10) was highlighted by an extensive ‘Commentary’ in the J. of Virology (Heydenburg Fuller et al, 11). “ Innate responses induced by these new approaches are largely intended to   augment adaptive immune effector mechanisms of protection but are generally thought to contribute little or no direct role in protection because innate immunity is transient and believed to induce no memory…..A paper by Lewis and his colleagues published in this issue (10) provides the first proof-of-concept trial in humans for   an alternative concept whereby an HIV vaccine could induce specific innate factors that not only enhance the development of virus-specific adaptive immunity, but could also contribute directly to protection by increasing the host’s resistance to HIV infection”.

 

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  10. Lewis DJ, Wang Y, Huo Z, Giemza R, Babaahmady K, Rahman D, Shattock RJ, Singh M, Lehner T. Effect of vaginal immunization with HIVgp140 and HSP70 on HIV-1 replication and innate and T cell adaptive immunity in women. J Virol. 2014 Oct;88(20):11648-57.
  11. Heydenburg Fuller D, Richert-Spuhler L E, Klatt N R. HIV Vaccine trial exploits a dual and central role for the innate immunity. J of Virol. (2014)88 11640-11643.

 

 

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