Vinflunine, a novel microtubule inhibitor, suppresses calmodulin interaction with the microtubule-associated protein STOP.

Vinca alkaloids vinblastine and vincristine and some of their derivatives such as vinorelbine are widely used in therapy of leukemia and several solid tumors. Their action is associated with alterations of the mitotic spindle functions that prevent the cell cycle progression and lead to mitotic block. A number of studies show that some Vinca alkaloids inhibit CaM-target interaction.

Tat mutations in an African cohort that do not prevent transactivation but change its immunogenic properties.

Humoral responses against extra-cellular HIV-1 Tat may be beneficial as Tat has been implicated in the viral pathogenesis associated with HIV-1 disease progression. We determined the levels of anti-Tat IgG in sera of HIV-1 seropositive individuals from the Rural Clinical Cohort in Uganda using nine different Tat proteins representative of the major subtypes presently accounting for 97% of infections worldwide. We observed the presence of anti-Tat IgG able to react against the various subtypes tested, although none cross-reacted against all nine variants.

Reservoir cells no longer detectable after a heterologous SHIV challenge with the synthetic HIV-1 Tat Oyi vaccine.

Background: Extra-cellular roles of Tat might be the main cause of maintenance of HIV-1 infected CD4 T cells or reservoir cells. We developed a synthetic vaccine based on a Tat variant of 101 residues called Tat Oyi, which was identified in HIV infected patients in Africa who did not progress to AIDS. We compared, using rabbits, different adjuvants authorized for human use to test on ELISA the recognition of Tat variants from the five main HIV-1 subtypes.

The C terminus of HIV-1 Tat modulates the extent of CD178-mediated apoptosis of T cells.

HIV infection and the progression to AIDS are characterized by the depletion of CD4(+) T cells through apoptosis of the uninfected bystander cells and the direct killing of HIV-infected cells. This is mediated in part by the human immunodeficiency virus, type 1 Tat protein, which is secreted by virally infected cells and taken up by uninfected cells and CD178 gene expression, which is critically involved in T cell apoptosis. The differing ability of HIV strains to induce death of infected and uninfected cells may play a role in the clinical and biological differences displayed by HIV strains.

HIV-1 Tat protein enhances microtubule polymerization.

Background: HIV infection and progression to AIDS is characterized by the depletion of T cells, which could be due, in part, to apoptosis mediated by the extra-cellular HIV-encoded Tat protein as a consequence of Tat binding to tubulin. Microtubules are tubulin polymers that are essential for cell structure and division. Molecules that target microtubules induce apoptosis and are potent anti-cancer drugs.

The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis.

Human immunodeficiency virus (HIV) infection and the progression to AIDS are characterized by the depletion of CD4(+) T-cells. HIV-1 infection leads to apoptosis of uninfected bystander cells and the direct killing of HIV-infected cells. This is mediated, in part, by the HIV-1 Tat protein, which is secreted by virally infected cells and taken up by uninfected cells.

Full-length HIV-1 Tat protein necessary for a vaccine.

AIDS vaccines now use a truncated version of 86 residues of the Tat protein related to the HIV-1 HXB2 strain predominant in Europe and North America. We compared antibodies raised in rabbits using a B subtype short Tat HXB2(86) and a full-length Tat HXB2(100). Serum against HXB2(86) recognizes only B and D subtypes while serum against HXB2(100) recognizes B, D, and C subtype variants.

A possible improvement for structure-based drug design illustrated by the discovery of a Tat HIV-1 inhibitor.

The HIV-1 Tat protein is a promising target for AIDS therapy, due to its extra-cellular roles against the immune system. From the 2D-NMR structure of Tat, we have designed molecules, called TDS, able to bind to Tat and inhibit HIV-1 replication in vitro. This new family of antivirals is composed of a triphenylene aromatic ring substituted with at least one carbon chain bearing a succinimide group.

Tat HIV-1 primary and tertiary structures critical to immune response against non-homologous variants.

Clinical studies show that in the absence of anti-retroviral therapy an immune response against the human immunodeficiency virus type 1 (HIV-1), transacting transcriptional activator (Tat) protein correlates with long term non-progression. The purpose of this study is to try to understand what can trigger an effective immune response against Tat. We used five Tat variants from HIV strains identified in different parts of the world and showed that mutations of as much as 38% exist without any change in activity.