Therapeutic vaccinations aimed at the reconstitution of HIV-1-specific immune responses in infected individuals have been proposed as interventions to enhance immune control following interruption of HAART or to reduce the failure rate of HAART. Here we tested the ability of a subunit vaccine composed of a NefTat fusion protein and envelope glycoprotein gp120 formulated with AS02A
adjuvant to reconstitute HIV-1-specific T cell immunity in infected individuals. In HIV-1 positive individuals taking suppressive combination ART, vaccination caused an increase in HIV-1-specific cytokine production and proliferation by CD4+ T cells. While this vaccine did not induce an increase in cytokine production or degranulation of HIV-1-specific CD8+ T cells, and induced only a transient increase in gp120-specific CD8+ T cell proliferation, the proportion of participants that were dual responders for both gp120-specific IL-2+ CD4+ T cells and CD8+ T cell proliferation increased significantly at week 6 following vaccination. The proliferative and immune responses stimulated by the vaccine may represent de novo
responses or expansion of pre-existing responses that were below the level of detection. Some responses waned over time which can occur in chronic infection with ARV treatment43
. These data demonstrate that gp120-specific CD4+ T cell responses can be elicited or reconstituted in infected individuals and may contribute to enhanced proliferation of gp120-specific CD8+ T cells following stimulation in vitro.
In addition to significant immunogenicity, the gp120/NefTat/AS02A vaccine showed an acceptable safety and reactogenicity profile in the study volunteers. Mild to moderate local reactions were common and resolved within in a few days, and no SAE that occurred during the trial were attributed to the vaccine. One participant in the vaccine arm experienced a worsening of chronic sensory peripheral neuropathy following the second vaccination and elected not to receive a third vaccination.
The ability of HIV-1-specific CD8+ T cells to respond to antigen by proliferation in vitro
has been associated with better control of HIV-1 viremia and slower disease progression in a number of studies41, 44
. Vaccination with the gp120/NefTat/AS02A
vaccine not only reconstituted HIV-1 specific CD4+ T cell help as shown by increasing IL-2 production in response to vaccine-derived peptides, but also caused an transient increase in the proportion of participants who had a positive response for both antigen-specific IL-2+ CD4+ T cells and CD8+ T cell proliferation. Vaccination could have enhanced CD8+ cell proliferation in the setting of increased CD4+ IL2 production by directly modulating intrinsic CD8+ T cell function or by providing IL-2 in the in vitro
proliferation assay. In chronic HIV-1 infection, a prior study demonstrated that loss of HIV-1-specific CD8+ T cell proliferation in progressive infection is in part due to loss of IL-2-secreting HIV-1-specific CD4+ T cells36
. In addition, HIV-1 specific CD8+ T cell proliferative responses were restored in vitro
with the addition of autologous HIV-1-specific CD4+ cells. Therefore, some restoration of CD4+ T cell help with a therapeutic HIV-1 vaccination may help maintain CD8+ T cell function in chronic HIV-1 infection.
Though improvements in both HIV-1-specific CD4+ and CD8+ function were demonstrated following vaccination, no conclusions can be made about the clinical utility of the gp120/NefTat/AS02A
vaccine based on this trial. Several studies indicate that more potent CD8+ T cell functionality is a key difference in long-term non-progressors (LNTP) compared to chronic progressors41, 44–47
, which may account for the improved immunologic control of HIV-1 by LNTPs. Based on these findings a therapeutic vaccine that improves CD8+ T cell functionality may lead to improved control of HIV-1. One way to test this hypothesis would be to administer the therapeutic vaccine to HIV-1-infected participants followed by a treatment interruption and concomitant longitudinal assessment of viral load and CD4+ and CD8+ T cell function. However, treatment interruptions in chronic HIV-1 infection should be undertaken with caution given the results of previous trials of CD4 guided antiretroviral therapy versus continuous therapy in which treatment interruption was associated with an increase in opportunistic infections, death from any cause48
, and morbidity49
In conclusion, we show that therapeutic vaccination with the gp120/NefTat/AS02A vaccine in chronically HIV-1-infected volunteers on suppressive ART was safe, well-tolerated, and resulted in increases in HIV-1-specific CD4+ T cell help and increases in dual responders for both HIV-1-specific IL-2 production by CD4+ T cells and HIV-1-specific CD8+ T cell proliferation. A vaccine strategy of reconstituting CD4+ T cell help in chronic HIV-1 infection and in turn improving virus-specific CD8+ T cell function may augment virologic control resulting in slower disease progression or decreased immune activation. This vaccine is one potential approach to improve HIV-1-specific CD4+ T cell functionality; to assess the clinical implications of this vaccine would require a larger clinical trial and possible treatment interruption.