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BackgroundAntiretroviral preexposure prophylaxis (PrEP), using daily oral combination tenofovir disoproxil fumarate plus emtricitabine, is an effective human immunodeficiency virus (HIV) prevention strategy for populations at high risk of HIV acquisition. Although the primary mode of action for the protective effect of PrEP is probably direct antiviral activity, nonhuman primate studies suggest that PrEP may also allow for development of HIV-specific immune responses, hypothesized to result from aborted HIV infections providing a source of immunologic priming. We sought to evaluate whether PrEP affects the development of HIV-specific immune response in humans.Methods and resultsWithin a PrEP clinical trial among high-risk heterosexual African men and women, we detected HIV-specific CD4(+) and CD8(+) peripheral blood T-cell responses in 10%-20% of 247 subjects evaluated. The response rate and magnitude of T-cell responses did not vary significantly between those assigned PrEP versus placebo, and no significant difference between those assigned PrEP and placebo was observed in measures of innate immune function.ConclusionsWe found no evidence to support the hypothesis that PrEP alters either the frequency or magnitude of HIV-specific immune responses in HIV-1-exposed seronegative individuals. These results suggest that PrEP is unlikely to serve as an immunologic prime to aid protection by a putative HIV vaccine.

STI571 is the most innovative drug for the cure of Chronic Myeloid Leukemia. It inhibits, in fact, the disease causative event, the p210 bcr-abl tyrosine kinase, and addresses clonal myeloid progenitors to apoptotic death. Here, we demonstrated that STI571 also induces growth arrest by activating the Chk2-Cdc25A-Cdk2 axis, a pathway complementary to p53 in the activation of G1/S cell cycle checkpoint. In vitro exposure to STI571 of 32D murine myeloid progenitor cell clones transducing a temperature-sensitive p210 bcr-abl construct was associated with Chk2 phosphorylation and activation, Cdc25A degradation and persistent Cdk2 inhibitory phosphorylation, preventing, in turn, cell transition to and progression throughout the S phase of cell cycle. Chk2 and Cdc25A are both components of a complex network that integrates signals involved in regulated cell cycle progression, DNA repair and cell decision between life or death. Chk2 gene mutations or decreased expression, leading to its protein loss of function on Cdc25A target, and Cdc25A overexpression have been linked to poor prognosis of human cancers. In CML, they might further enhance the proliferative advantage and genomic instability of clonal myeloid progenitors featuring a class of poor prognosis patients eventually resistant to STI571.The Hematology Journal (2004) 5, 168-177. doi:10.1038/sj.thj.6200365 [ABSTRACT FROM AUTHOR]

An abstract of the article "Pre-exposure Prophylaxis Does Not Enhance HIV-specific T-cell Responses" by Laura Pattacini and colleagues is presented.

Objective: Two distinct hypotheses have been proposed for T-cell involvement in protection from HIV-1 acquisition. First, HIV-1-specific memory T-cell responses generated on HIV-1 exposure could mount an efficient response to HIV-1 and inhibit the establishment of an infection. Second, a lower level of immune activation could reduce the numbers of activated, HIV-1-susceptible CD4 T cells, thereby diminishing the likelihood of infection., Methods: To test these hypotheses, we conducted a prospective study among high-risk heterosexual men and women, and tested peripheral blood samples from individuals who subsequently acquired HIV-1 during follow-up (cases) and from a subset of those who remained HIV-1 uninfected (controls)., Results: We found no difference in HIV-1-specific immune responses between cases and controls, but Treg frequency was higher in controls as compared with cases and was negatively associated with frequency of effector memory CD4 T cells., Conclusions: Our findings support the hypothesis that low immune activation assists in protection from HIV-1 infection.

Objective: Novel drugs targeting TNF-alpha are available for treatment of RA. Fibroblast-like synoviocytes (FLSs) play a fundamental role in RA progression, through their expansion caused in part by resistance to cell death induction. The aim of our study was to determine the effects of different anti-TNF-alpha agents on FLS apoptosis., Methods: FLS from patients with either RA or OA were co-cultured with peripheral blood mononuclear cells (PBMCs), and incubated with various drugs for 6 days. Subsequently, apoptosis induction was detected by Nucleosome ELISA and terminal deoxynucleotidyl transferase dUTP nick end labeling. Western blot was used to determine the activation of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-focal adhesion kinase (FAK) pathway as well as Bax and Bcl-2 levels. Immunoprecipitation was used for studying phosphorylation of transmembrane TNF-alpha (tmTNF-alpha)., Results: All the tested drugs induced apoptosis of FLSs in the presence of PBMCs obtained from the same patient only when the two cell populations were in direct contact by activating the PTEN-FAK pathway and increasing Bax levels. This effect was not due to antibody-dependent cell-mediated cytotoxicity. Only the two antibodies infliximab and adalimumab were able to up-regulate Bcl-2., Conclusions: Etanercept is more effective in inducing FLS apoptosis compared with the other drugs tested. This induction is dependent on the presence of PBMCs, and involves the activation of PTEN-FAK pathway. Bcl-2 increase induced by the monoclonal antibodies infliximab and adalimumab may play a protective role and thus counteract their pro-apoptotic effect on FLSs.

Background and Objectives: The p210 bcr-abl fusion protein has a key role in the pathogenesis of chronic myeloid leukemia (CML). However, its influence on disease progression to blast crisis is marginal and mostly due to its effect of impairing the genomic stability of clonal myeloid progenitors through pathways still largely unknown., Design and Methods: To elucidate the role of p53 in CML progression we generated, from the 32D murine myeloid cell line, several clones co-expressing the E6 product gene of human papilloma virus (HPV) 16, which abrogates p53 function, and a temperature-sensitive bcr-abl construct encoding a fully active p210 protein only at the permissive temperature of 33 degrees C., Results: Co-expression of the two proteins resulted in a significant enlargement of the G(2)/M phase of cell cycle and in the appearance of a poly-aneuploid cell population. Furthermore, with continuous in vitro passages the p210 tyrosine kinase became dispensable for growth. Increased levels of cyclin B(1) and enhanced activity of its associated cyclin-dependent kinase (cdc2) became apparent during the clonal evolution of p210 bcr-abl-transduced 32D cell clones lacking p53., Interpretation and Conclusions: The acceleration of clonal evolution of p210 bcr-abl-transduced 32D myeloid progenitors associated with p53 functional abrogation is consistent with oncosuppressor loss having a key role in CML progression. This would allow emergence of additional genomic aberrations which would lead to the fully transformed phenotype of blast crisis. Deregulated activity of the cyclin B1-cdc2 complex may be involved in the loss of temporal co-ordination of mitotic events and further free the barrier to genomic instability of CML clonal myeloid progenitors lacking p53.