A phase I, randomized study of combined IL-2 and therapeutic immunisation with antiretroviral therapy

Gareth AD Hardy^*¹ , Nesrina Imami^*¹ , Mark R Nelson² , Ann K Sullivan² , Ron Moss³ , Marlén MI Aasa-Chapman⁴ , Brian Gazzard² and Frances M Gotch¹

¹Department of Immunology, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK

²Department of HIV/GU Medicine, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK

³Immune Response Corporation, Carlsbad, CA, USA

⁴Wohl Virion Centre, Windeyer Institute of Medical Sciences, UCL, London, W1T 4JF, UK

author email corresponding author email* Contributed equally

Journal of Immune Based Therapies and Vaccines 2007, 5:6doi:10.1186/1476-8518-5-6


Published:	11 April 2007

Abstract

Background

Fully functional HIV-1-specific CD8 and CD4 effector T-cell responses are vital to the containment of viral activity and disease progression. These responses are lacking in HIV-1-infected patients with progressive disease. We attempted to augment fully functional HIV-1-specific CD8 and CD4 effector T-cell responses in patients with advanced chronic HIV-1 infection.

Design

Chronically infected patients with low CD4 counts T-cell counts who commenced antiretroviral therapy (ART) were subsequently treated with combined interleukin-2 and therapeutic vaccination.

Methods

Thirty six anti-retroviral naive patients were recruited and initiated on combination ART for 17 weeks before randomization to: A) ongoing ART alone; B) ART with IL-2 twice daily for 5 days every four weeks starting at week 17 for 3 cycles; C) ART with IL-2 as in group B and Remune HIV-1 vaccine administered once every 3 months, starting at week 17; and D) ART with Remune vaccine as in group C. Patients were studied for 65 weeks following commencement of ART, with an additional prior 6 week lead-in observation period. CD4 and CD8 T-cell counts, evaluations of HIV-1 RNA levels and proliferative responses to recall and HIV-1 antigens were complemented with assessment of IL-4-secretion alongside quantification of anti-HIV-1 CD8 T-cell responses and neutralizing antibody titres.

Results

Neither IL-2 nor Remune™ vaccination induced sustained HIV-1-specific T-cell responses. However, we report an inverse relationship between HIV-1-specific proliferative responses and IL-4 production which continuously increased in patients receiving immunotherapy, but not patients receiving ART alone.

Conclusion

Induction of HIV-1-specific cell-mediated responses is a major challenge in chronically HIV-1-infected patients even when combining immunisation with IL-2 therapy. An antigen-specific IL-4-associated suppressive response may play a role in attenuating HIV-specific responses.