Article

Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1.

Department of Immunology, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2009; 106(47):19940-5. DOI: 10.1073/pnas.0907898106
Source: PubMed

ABSTRACT In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing alpha(4)beta(7) integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-gamma production in response to Ad stimulation correlated with Ad5 antibody titers. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with preexisting immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.

0 Followers
 · 
344 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Adenoviruses (Ads) have attracted researchers from across the disciplines for several reasons. Their ability to recombine with and express the heterologous genes encouraged their development as gene/vaccine delivery vectors. Preclinical and clinical trials using these vectors have shown significant promise for their future development while highlighting certain limitations. Areas covered: Ad vector development, clinical application of these vectors in gene therapy and vaccine development, and promises that these vectors offered for future development are discussed. Also, various factors affecting their in vivo efficacy as well as the strategies being pursued to overcome these obstacles are described. Expert opinion: Decades of efforts have resulted in understanding various aspects of human Ad 5 biology as well as the in vivo behavior of vectors derived from this serotype. While this vector has shown great potential, some of the limitations highlighted in recent studies have reinforced the quest for an ideal vector derived from novel Ads. Combinatorial approaches to address the various limitations of the existing vectors must be pursued to develop novel vectors with enhanced clinical potential.
    Expert Opinion on Biological Therapy 12/2014; 15(3):1-15. DOI:10.1517/14712598.2015.993374 · 3.65 Impact Factor
  • AIDS (London, England) 02/2015; 29(4):395-400. DOI:10.1097/QAD.0000000000000548 · 6.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibody-mediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4(+) T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Env-based AIDS vaccines regardless of the mechanism of antibody-mediated protection.
    Proceedings of the National Academy of Sciences 10/2014; 111(44). DOI:10.1073/pnas.1413550111 · 9.81 Impact Factor

Full-text

Download
53 Downloads
Available from
May 21, 2014