Anti-apoptotic effects of Interleukin 7 in Human Immunodeficiency Virus Type 1 infection: Mechanism and implications for immune reconstitution strategies

Vassena, Lia (2012). Anti-apoptotic effects of Interleukin 7 in Human Immunodeficiency Virus Type 1 infection: Mechanism and implications for immune reconstitution strategies. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000ee9e

Abstract

Although HAART has introduced great improvements in the clinical outcome of HIV-1- infected individuals, the current protocols often fail in completely restoring the CD4⁺T-cell lymphopenia. Therefore, innovative approaches based on the use of immune adjuvants to HAART, including cytokines like IL-2, IL-15 and IL-7, are being explored. The present thesis aims at investigating the immunomodulatory effects of IL- 7 in HIV /SIV infection, focusing on its pro-survival properties.

The first part of this work describes the results of a study in vitro to evaluate the effects of IL-7 on T cells from HIV -l-infected individuals, and shows that this cytokine strongly protects both CD4⁺ and CD8⁺T cells from spontaneous apoptosis. IL-7-mediated apoptosis reduction ex vivo inversely correlated with the CD4⁺T-cell count of the patient in vivo, suggesting that IL-7 treatment could be useful also for patients at with advanced disease. Moreover, the protective effect of IL-7 was not associated with the induction of cellular proliferation or viral replication.

The second part of this work describes the results of a study in vivo of IL-7 administration during the acute phase of SIV infection in rhesus macaques, the pathogenic animal model for AIDS. IL-7 treatment prevented the depletion of circulating naive and memory CD4⁺T cells that typically occurs within the very first weeks of infection, primarily by reducing the levels of apoptosis. Moreover, IL-7 treatment also induced sustained increases in all subsets of circulating CD8⁺T cells. Of note, treatment with IL-7 did not have any effect on SIV plasma viral load nor on the content of SIV DNA provirus. Finally, IL-7-treated animals developed earlier and stronger CD8⁺ and CD4⁺T-cell responses as compared to untreated animals, although overall no protective effects on disease progression were observed. Taken together, these data further support the use of IL-7 as an immunomodulatory adjuvant to HAART in HIV-I-infected individuals, and suggest that this cytokine may be a useful tool to preserve or restore the CD4⁺T-cell pool during both the acute and chronic phases of the infection.