Early correction of cell cycle perturbations predicts the immunological response to therapy in HIV-infected patients

Abstract

These observations suggest that correction of cell cycle dysregulation predicts a good immunological response to HAART and that sequential analysis of cell cycle dysregulation might help to identify patients that could benefit from alternative, immune-based interventions in addition to standard HAART.

Perturbations of Cell Cycle Control in T Cells Contribute to the Different Outcomes of Simian Immunodeficiency Virus Infection in Rhesus Macaques and Sooty Mangabeys

“…As shown in Fig. 2C, and similar to what has been described in HIV-infected individuals (34), no correlation was found between the fraction of cyclin B "high" CD3 ϩ T cells and the fraction of CD3 ϩ T cells expressing Ki67 in SIV-infected RMs. This latter finding confirms that expression of high levels of cyclin B does not simply reflect the fraction of circulating proliferating T cells (34).…”

Apoptosis in SIV infection

“…Cytokines, in contrast, prevented both the apoptotic phenotype and the cell death by preserving mitochondrial membrane potential staining for the argyrophilic Nucleolar Organizing Regions (AgNOR) and the subcellular localization of nucleolin in confocal microscopy. [122][123][124][125][126][127] Importantly, the HIV-associated cell cycle dysregulation is exacerbated by in vitro treatment with mitogens and appears to be correlated with induction of T-cell apoptosis; 122,123,126 however, these cell cycle perturbations and apoptosis are reduced after exogenous administration of IL-2 in vitro. 122 In mitogen-activated lymphocytes from HIV-infected patients, the inappropriate activation of the cyclin B1/p34 cdc2 kinase complex is temporally associated with increased threonine phosphorylation, augmented fragmentation, and prominent extranuclear and cell surface localization of nucleolin.…”

Turnover of lymphocytes and conceptual paradigms in HIV infection

“…On the one hand, HAART reduces the numbers of CD4 + T cells that are infected and directly killed by the virus, while on the other hand, HAART facilitates the re-establishment of normal T cell dynamics by decreasing the level of antigenic load and thereby indirectly reducing the level of T cell activation and AICD. That HAART more likely acts to increase CD4 + T cell levels through this indirect mechanism is supported by the observation that an increase in CD4 + T cell counts that follows initiation of HAART is more strictly correlated, in certain clinical situations, with its salutary effect on immune activation and apoptosis than with direct effects to decrease levels of HIV replication (16,22). These particularly illuminating clinical situations include HIV-infected individuals with persistent suppression of viremia but no significant CD4 + T cell increase after initiation of HAART (so-called immunological nonresponders) and who exhibit evidence of persistent immune activation (22); and individuals with drug-resistant HIV variants who manifest sustained CD4 + T cell increases despite only partial suppression of viremia in the presence of HAART, in association with decreased levels of immune activation while continuing on therapy (23).…”