oa Editorial [Hot Topic: Update on HIV Vaccines: Which way now? (Guest Editor: Liljana Stevceva)]

Three years ago, halting of the Merck & Co Inc clinical trial (STEP trial) and subsequent discovery that this HIV vaccine candidate MRK Ad5 HIV-1 gag/pol/nef had no positive impact but actually caused harm in some of the participants generated lots of pessimism in the research community. After the initial shock, it became apparent, however that valuable lessons were learned from this negative experience. For one, it became clear that vaccine designed to only elicit T cells responses at systemic sites and including a single HIV gene insert, will not be sufficient to reduce transmission or lower viremia in people. It also became apparent that future use of adenovirus-based vectored vaccines needs to be carefully planned with respect to vector type, gene inserts, route of immunization and risk factors among subject volunteers. The inability to come up with a potentially successful HIV vaccine after more than 26 years of efforts and often in a situation where preclinical data was very promising almost completely halted research in this field. The step back however, also generated many questions and influenced research efforts subsequently refocusing considerable amount of research efforts on reliable correlates of protection to vaccines. Of course, ability to develop successful HIV vaccine is tightly related to the development of reliable and clearly defined immune correlates of HIV control. While a substantial number of immune markers were associated with HIV control in the past, this was rarely accompanied with a clear evidence of cause and effect hampering the assessment as to how useful these could potentially be in designing a vaccine or even in predicting the outcome of an HIV infection. New fields of research have also been opened that look into innate immune responses and the ways innate immune responses influence generating acquired immunity. This led to development of Systems Biology approach that among other things looks into novel correlates of protection for vaccines. Recent results from the world's largest HIV/AIDS vaccine trial of more than 16,000 volunteers in which infection has been prevented in 31% of cases generated new excitement among HIV researchers. The trial was sponsored by the US army and the National Institute of Allergy and Infectious Diseases of NIH. Although the level of protection is very low it offered hope that vaccine can be improved and that protective HIV vaccine is possible. Novel molecules such as toll-like receptor agonists and PD-1 receptor ligands antagonists might prove to be powerful in enhancing immune responses as adjuvants to HIV vaccines. Programmed death-1 (PD-1) is a negative immunoregulatory cell surface receptor molecule whose interaction with its ligands PD-L1 and PD-L2 down modulates T-cell immune responses. PD-1 is up regulated on T cells of HIVinfected individuals and high levels of PD-1 on HIV-infected T cells correlate with viral load and with a state of cellular anergy, or ‘ exhaustion’ that results in decreased cellular proliferation, cytotoxic function and cytokine secretion. Interruption of PD-1 with its ligand PD-L1 rescues HIV-infected cells from this state of anergy or ‘ exhaustion’ and presents promising adjuvant to be used for therapeutic or preventative vaccine.....