Current HIV Research - Volume 8, Issue 4, 2010

The “mini hot topic” issue on Novel Vaccines and Adjuvants aims to present the most updated information on newly developed concepts in vaccines and adjuvants targeted to cancers as well as infectious diseases. Safety problems related to traditional attenuated or inactivated vaccines, together with broadening the vaccine concept to human diseases other than infectious (i.e. cancer), have considerably fuelled the vaccinology field in the search for the optimal safe and immunogenic vaccine model. In particular, the lack of an effective vaccine for HIV/AIDS is strongly pushing the entire vaccinology field to generate and validate new concepts, including novel strategies for antigen delivery and presentation, novel priming and boost protocols. Each of these strategies has a specific immunogenic property which can be used in standalone or combinatorial approaches, broadening the possibility of inducing specific or both arms of the immune response. Compared to the traditional vaccines, however, most of these novel approaches show a significantly low immunogenicity. This drawback, coupled to the need of inducing both arms of the adaptive immune response (humoral and cellular), is intensely driving the identification and design of novel adjuvants (including novel adjuvant's concepts) to significantly increase the number of available options besides the standard alum in human vaccines. In particular, the development of a completely novel class of adjuvants hitting the mucosal sites is of high relevance for the whole field. The recent acquisitions on the key role of innate immunity, and in particular of dendritic cells and their pathogen recognition receptors (including Toll-Like Receptors) in triggering and amplifying the adaptive immune response, have a multiplication effect on the number of “arrows” in the armamentarium of modern vaccinology. Dendritic cells can be specifically targeted, ex vivo or in vivo, to improve the antigen delivery and presentation to effector lymphocytes. Ligands of Toll-Like Receptors appears to be efficient adjuvants for significantly improving not only the immunogenicity of delivered antigens but also the specificity of the elicited immune response. All these different perspectives are greatly contributing to fill the pieces of our knowledge on mechanisms underlying the effective elicitation of protective immune responses by vaccines. This will enable the switch from the “empirical” to the “knowledge-based” age of the vaccinology which should lead to the development of even more successful vaccines for preventive as well as therapeutic intervention strategies. The papers included in the present Mini Hot Topic Issue on “Novel Vaccines and Adjuvants” will significantly contribute in describing some of the most significant aspects of this exciting and evolving field.

Genetic immunization with lentiviral vectors is under evaluation as a means for induction of sustained immune response. Lentiviral vectors showed reduced antivector immune responses and efficiently transduced post-mitotic cells in vivo, including antigen presenting cells, such as dendritic cells and macrophages, thus providing a significant benefit over other vector-based antigen delivery platforms. Several evidences indicate that a single immunization with lentiviral vectors induces strong and sustained effector and memory T-cell immune responses, as well as antibody production. New generation of lentiviral vectors with improved biosafety profile are also under development. In particular, integration defective lentiviral vectors have been generated and used as an efficient and safe delivery system for both gene therapy and immunization purposes. Taken together, these evidences support the ongoing development of lentiviral vector-based genetic immunization strategies for safe applications in the clinic.

HIV-1 has resulted in a devastating AIDS pandemic. An effective HIV/AIDS vaccine that can be used to either, prevent HIV infection, control infection or prevent progression of the disease to AIDS is needed. In this review we discuss the use of Mycobacterium bovis BCG, the tuberculosis vaccine, as a vaccine vector for an HIV vaccine. Numerous features make BCG an attractive vehicle to deliver HIV antigens. It has a good safety profile, elicits long-lasting cellular immune responses and in addition manufacturing costs are affordable, a necessary consideration for developing countries. In this review we discuss the numerous factors that influence generation of a genetically stable recombinant BCG vaccine for HIV.

Particulate structures hold great promise for the development of effective and affordable recombinant prophylactic as well as therapeutic vaccines. Different types of particulate structures, including virus-like particles (VLPs) and virosomes, have been developed depending on the nature of the viral pathogen to be targeted and the type of immune response (humoral vs cellular) to be elicited. Particulate structures allow the insertion or fusion of foreign antigenic sequences, resulting in chimeric particles delivering foreign antigens on their surface. Similarly, they are used as carriers for foreign antigens, including non-protein antigens, via chemical conjugation. Particulate structures, indeed, represent a very efficient system for delivering antigens to antigen presenting cells (APC) which, in turn, trigger and amplify the adaptive immune response. The present review will address the biological and immunological properties of particulate structures, in particular VLPs, as platform for vaccine development.

HIV remains one of the most important deadly infections today, due to the lack of a preventive vaccine and limited access to medical care in developing countries. In developed countries, antiretroviral therapy is available, but it can not eliminate the virus, implying that life-long therapy is necessary. Therefore, it is important that other strategies such as therapeutic vaccination will be developed to control virus replication or even eliminate the virus. The major obstacles towards such a strategy are the huge variability of the virus and the profound HIV-induced immune dysfunction. In this review we focus on dendritic cell based immunotherapies against HIV. To develop an efficient immunotherapy, several elements should be taken into account such as which antigen and loading strategy to use, how to deliver the immunogen, how to optimize the interaction between antigenic peptide and T cells and avoid tolerance. Clearly, to develop an immunotherapy to complement the effect of HAART, it is not sufficient to enhance T cell responses against a consensus sequence or against the prevailing plasma virus. Broad and potent immune responses are needed to suppress the entire quasispecies, including the latent reservoir, and to prevent any escape.

Efficient vaccines combined with adjuvants potentiate and enhance antibody avidity and increase T cell longevity, particularly in individuals with compromised immunity. The efficacy of a novel vaccine can be improved by specifically targeting its immunogenic subunits and expressing it in live probiotic vector (i.e. Lactobacillus acidophilus) that protects vaccine bioavailability and to induces not only mucosal but also systemic immunity against microbes. Accordingly, our data clearly show that specific Lactobacillus species (L. gasseri) not only optimally activate DCs but also deliver targeted antigens to mucosal DCs via 12-mer peptides derived from a phage display library resulting in robust humoral and T cell immunity against microbial challenge. This effort is accomplished via novel tools that provide “targeting” of the vaccine, evaluation of innovative vaccine effectiveness against a wide array of microbes, and controlling gene expression/presentation technologies in probiotic lactobacilli that can be orally consumed at high levels resulting in natural delivery of a “targeted” antigen to mucosal DCs. In this review I will discuss the potential benefits and efficacy of the employed vaccine strategy that may be feasible for various studies in the field.

The vast majority of pathogens invade the body through or establish infections in the mucosal tissues. Development of vaccines to combat mucosal infections represents a top priority. Mucosal immunization has recently attracted much interest as a means of generating protective immunity against mucosal pathogens. Conversely, only very few mucosal vaccines are presently approved for human use. The development of a broad range of mucosal vaccines will necessitate the development of safe and effective mucosal adjuvants and delivery systems. Over the past decade, a number of immunomodulatory agents, including toxin based adjuvants, Toll like receptor (TLR) mimetics and non TLR-targeting immunostimulators as well as delivery systems have shown promise for mucosal administration in experimental animals. However, their possible use in humans remains to be established. This paper attempts to provide a brief overview of the mucosal immunization and adjuvants with an emphasis on mucosal adjuvants in or close to clinic.

HIV-1 infection is associated with hematologic abnormalities including defective myelopoiesis. Most studies of myelopoiesis during HIV-1 infection were performed using unfractionated bone marrow-derived mononuclear cells, thus resulting in significant inter-individual variability in the numbers of cultured precursors. Here we evaluated the myelopoietic potential of circulating CD34+ progenitors by conducting a longitudinal analysis of antiretroviral therapy (ART)-induced changes of colony forming units-granulocyte and monocyte (CFU-GM) growth. Twelve HIV-infected individuals were studied longitudinally before and after initiation of ART (i.e. at a time when plasma HIV-RNA levels had become undetectable); thirty-one HIV-uninfected healthy individuals were enrolled as controls. Peripheral bloodderived CD34+ progenitors were purified by immunomagnetic sorting, and cultured in methylcellulose-based medium containing stem cell factor, granulocyte-monocyte colony-stimulating factor and interleukin-3. ART-induced changes in the proportion of CD8+ T cells expressing surface HLA-DR were also evaluated. We found that CFU-GM levels were increased in untreated HIV-infected individuals when compared to uninfected controls but declined significantly following ART, in parallel with the decline of HIV-RNA levels in plasma and with the down-regulation of HLA-DR expression on CD8+ T cells. These findings suggest that, in untreated HIV-infected individuals, chronic inflammation and/or immune activation is associated with defective myelopoiesis and accumulation of myeloid precursors. ART-induced suppression of HIV-1 replication is associated with normalization of CFU-GM levels.

Recently, a mechanism of negative regulation of immune responses by a specialized population of so-called regulatory T cells (Tregs) has become a focus of intense investigation. Through the discovery of transcription factor Foxp3 as a central molecular determinant of Tregs differentiation and function, the complex biology of these cells, including maintenance of immunological tolerance to “self” and regulation of immune responses to pathogens, commensals, and tumors, has become the focus of intense investigation. The ability to control the infection and to delay the progression of the infection to AIDS and/or death is probably regulated by a balance between host factors, such as immunologic response and viral factors. Different rates of disease progression among HIV-1 infected individuals have been observed. In this context, Tregs may play an important role in the immunopathology of HIV-1 infection due to their potent suppressive activity of both T cell activation and effector function. In this review, we present the molecular and immunological aspects of Tregs in the HIV system and the association between Tregs and highly active antiretroviral therapy (HAART).

Objectives: The primary objective was to assess HIV-1 susceptibility to the protease inhibitor (PI) tipranavir and other antiretroviral (ARV) agents among treatment-experienced patients (TEP). Secondarily, clinicians' use of resistance testing was examined. Methods: UTILIZE was an observational study conducted at 40 sites in the United States. Patients currently failing a PI-based regimen were randomized to receive either a genotype (GT) or combined phenotype-genotype test (PGT) and a treatment decision was made at the second study visit. Results: 246 patients enrolled, 236 had resistance test results, and 139 (59%) had evidence of HIV-1 resistance to ≥1 PI. Among these 139 patients, more than 50% had viruses that remained sensitive to tipranavir and darunavir, whereas susceptibility to other PIs was markedly lower (<22%). Increasing prior PI exposure was associated with reduced susceptibility to most ARV agents. After obtaining resistance test results, 83% of patients changed therapy. Newly available or investigational ARVs were used frequently. The reason investigators most often cited for changing therapy was the patient resistance test results (82%) and the most common reason for not changing therapy was the inability to construct an active regimen. The majority of patients who exhibited PI resistance received two or more active agents in the new regimen. Conclusions: Overall, 59% of TEPs failing a PI-based regimen had HIV-1 with PI resistance. The majority of these patients' viruses remained sensitive to either tipranavir or darunavir. Investigators used results from resistance assays to construct a new regimen, frequently with newer agents. In PI-experienced patients, tipranavir and darunavir remain the most likely available active PIs.