HIV-1 infection is associated with a progressive loss of T cell functional capacity and reduced responsiveness to antigenic stimuli. The mechanisms underlying T cell dysfunction in HIV-1/AIDS are not completely understood. Multiple studies have shown that binding of program death ligand 1 (PD-L1) on the surface of monocytes and dendritic cells to PD-1 on T cells negatively regulates T cell function. Here we show that neutrophils in the blood of HIV-1-infected individuals express high levels of PD-L1. PD-L1 is induced by HIV-1 virions, TLR-7/8 ligand, bacterial lipopolysaccharide (LPS), and IFNα. Neutrophil PD-L1 levels correlate with the expression of PD-1 and CD57 on CD4+ and CD8+ T cells, elevated levels of neutrophil degranulation markers in plasma, and increased frequency of low density neutrophils (LDNs) expressing the phenotype of granulocytic myeloid-derived suppressor cells (G-MDSCs). Neutrophils purified from the blood of HIV-1-infected patients suppress T cell function via several mechanisms including PD-L1/PD-1 interaction and production of reactive oxygen species (ROS). Collectively, the accumulated data suggest that chronic HIV-1 infection results in an induction of immunosuppressive activity of neutrophils characterized by high expression of PD-L1 and an inhibitory effect on T cell function.

The tumor suppressor p53 plays a central role in the DNA damage response. After exposure to genotoxic stress, p53 can both positively and negatively regulate cell fate. Initially, p53 promotes cell survival by inducing cell cycle arrest, DNA repair, and other pro-survival pathways. However, when cells accumulate DNA damage or demonstrate aberrant growth, p53 can direct the elimination of damaged cells. In this review, we will discuss the transcriptional-dependent and -independent roles of p53 in regulating the DNA damage response.

Recent observational studies indicate an association between the use of hormonal contraceptives and acquisition and transmission of HIV-1. The biological and immunological mechanisms underlying the observed association are unknown. Depot medroxyprogesterone acetate (DMPA) is a progestin-only injectable contraceptive that is commonly used in regions with high HIV-1 prevalence. Here we show that medroxyprogesterone acetate (MPA) suppresses the production of key regulators of cellular and humoral immunity involved in orchestrating the immune response to invading pathogens. MPA inhibited the production of interferon (IFN)-γ, IL-2, IL-4, IL-6, IL-12, TNFα, macrophage inflammatory protein-1α (MIP-1α), and other cytokines and chemokines by peripheral blood cells and activated T cells and reduced the production of IFNα and TNFα by plasmacytoid dendritic cells in response to Toll-like receptor-7, -8, and -9 ligands. Women using DMPA displayed lower levels of IFNα in plasma and genital secretions compared with controls with no hormonal contraception. In addition, MPA prevented the down-regulation of HIV-1 coreceptors CXCR4 and CCR5 on the surface of T cells after activation and increased HIV-1 replication in activated peripheral blood mononuclear cell cultures. The presented results suggest that MPA suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens.

p63, a member of the p53 family of transcription factors, is known to be involved in epithelial development. However, its role in tumorigenesis is unclear. Contributing to this uncertainty, the TP63 locus can express multiple gene products from two different promoters. Utilization of the upstream promoter results in expression of the TAp63 variant with an activation domain similar to p53. In contrast, the NH 2 -terminally deleted (⌬N) p63 variant, transcribed from a cryptic promoter in intron 3, lacks such an activation domain. Thus, the TAp63 and ⌬Np63 variants possess a wide ranging ability to up-regulate p53 target genes. Consequentially, the disparity in transactivation potential between p63 variants has given rise to the hypothesis that the ⌬Np63 variant can serve as oncoprotein by opposing the activity of the TAp63 variant and p53. However, recent studies have revealed a transcriptional activity for ⌬Np63. This study was undertaken to address the transcriptional activity of the ⌬Np63 variant. Here, we showed that all NH 2 -terminally deleted p63 isoforms retain a potential in transactivation and growth suppression. Interestingly, ⌬Np63␤ possesses a remarkable ability to suppress cell proliferation and transactivate target genes, which is consistently higher than that seen with ⌬Np63␣. In contrast, ⌬Np63␥ has a weak or undetectable activity dependent upon the cell lines used. We also demonstrate that an intact DNA-binding domain is required for ⌬Np63 function. In addition, we found that the novel activation domain for the ⌬Np63 variant is composed of the 14 unique ⌬N residues along with the adjacent region, including a PXXP motif. Finally, we demonstrated that a PPXY motif shared by ⌬Np63␣ and ⌬Np63␤ is required for optimal transactivation of target gene promoters, suggesting that the PPXY motif is requisite for ⌬Np63 function.p53 functions as a tumor suppressor by transactivating target genes that mediate cell cycle arrest, apoptosis, and other p53-dependent activities. In response to DNA damage, oncogene activation, or other forms of cellular stress, p53 is stabilized by a complex series of post-translational modifications and protein-protein interactions that allow p53 to carry out its tumor suppression activity. Structurally, p53 is organized into several domains, each of which contributes to p53 transcriptional activity. p53 contains two amino-terminal activation domains, AD1 within residues 1-42 and AD2 within residues 43-92, including the proline-rich domain, which enable p53 to form direct associations with transcriptional coactivators. The DNA-binding domain allows for sequence-specific recognition of response elements in p53 target gene promoters. The tetramerization domain directs formation of the p53 tetramer required for DNA binding. Finally, the carboxyl-terminal basic domain has a regulatory function by controlling p53 stability and transcriptional activity (reviewed in Ref. 1).p63, a member of the p53 family of transcription factors, was identified in 1998 (2, 3). Like p53, p63 contains a pr...

G2E3 is a putative ubiquitin ligase (E3) identified in a microarray screen for mitotic regulatory proteins. It shuttles between the cytoplasm and nucleus, concentrating in nucleoli and relocalizing to the nucleoplasm in response to DNA damage. In this study, we demonstrate that G2E3 is an unusual ubiquitin ligase that is essential in early embryonic development to prevent apopotic death. This protein has a catalytically inactive HECT domain and two distinct RING-like ubiquitin ligase domains that catalyze lysine 48-linked polyubiquitination. To address in vivo function, we generated a knock-out mouse model of G2E3 deficiency that incorporates a ␤-galactosidase reporter gene under control of the endogenous promoter. Animals heterozygous for G2E3 inactivation are phenotypically normal with no overt change in development, growth, longevity, or fertility, whereas G2E3 null embryos die prior to implantation. Although normal numbers of G2E3 ؊/؊ blastocysts are present at embryonic day 3.5, these blastocysts involute in culture as a result of massive apoptosis. Using ␤-galactosidase staining as a marker for protein expression, we demonstrate that G2E3 is predominantly expressed within the central nervous system and the early stages of limb bud formation of the developing embryo. In adult animals, the most intense staining is found in Purkinje cell bodies and cells lining the ductus deferens. In summary, G2E3 is a dual function ubiquitin ligase essential for prevention of apoptosis in early embryogenesis.