HIV-1 infection of astrocytes also damages the blood brain barrier (BBB) which can lead to recruitment of natural killer (NK) cells to the CNS . NK cells are granular lymphocytes that play a vital role in defense against viral infections and cancer. (NCRs) play a critical role in the cytolytic function of NK cells. Among the NCRs, NKp44 is unique in expression and signal transduction. NKp44 is usually expressed only upon activation of NK cells and it can mediate both activating and inhibitory signals to NK cells. Here, we have studied the expression and function of natural cytotoxicity receptor NKp44 upon NK-astrocytes interactions in the presence or absence of an HIV peptide (HIV-3S peptide) shown to induce NK cell killing of CD4+ T cells during HIVCinfection. Using a fusion protein consisting of the extracellular domain name of NKp44 fused to Fc portion of human IgG, we decided the expression of a novel ligand for NKp44 (NKp44L) on astrocytes. Incubation of astrocytes with HIV-3S peptide downregulated NKp44L expression on astrocytes implicating protection from NK mediated killing. Thus, our study showed that NKp44 have a protective effect on astrocytes from NK cell mediated killing during HIV contamination and impact astrocyte role in HAND. Dynorphin A (1-13) Acetate Introduction The human immunodeficiency virus (HIV-1) can invade the central nervous system (CNS) after primary contamination and infect CNS resident cells, such as astrocytes. HIV-1 infected CNS cells results in inflammatory responses generated in the CNS, leading to long-term neuroinflammation and neuronal damage . This neuronal damage can cause neuropsychological deficits, collectively referred to as HIV-associated neurological disorders (HAND) . Since, both HIV-1 binding EHNA hydrochloride and contamination can affect astrocyte function, astrocytes have a strong pathogenic potential for being intimately involved in HAND . HIV-1 contamination of astrocytes also damages the blood brain barrier (BBB) which can lead to recruitment of natural killer (NK) cells to the CNS . NK cells are granular lymphocytes that play a vital role in defense against viral infections and cancer. NK EHNA hydrochloride cells survey host tissues and kill abnormal cells or virally infected cells [5, 6]. The majority of NK cells are localized in peripheral blood, lymph nodes, spleen and bone marrow but can be induced to migrate toward inflammation site by different chemoattractants . NK cell function is usually regulated by a balance between activating and inhibitory signals transmitted through NK cell surface receptors upon conversation with their ligands. Their functions include: release of cytotoxic granules, antibody-dependent cell-mediated cytotoxicity (ADCC), and cytokine production [8, 9]. NK cells work to control viral infections by secreting IFN- and TNF- [5, 10, 11]. NK cells undoubtedly play a EHNA hydrochloride role in the immune response against HIV-1. NK cells can limit HIV replication through direct killing of infected cells as well as the secretion of anti-viral cytokines and chemokines that suppress HIV-1 replication [12, 13]. NK cells from HIV patients show a functional impairment to kill tumor cells, a possible explanation for the increase in opportunistic tumors in HIV patients . Studies have also shown that HIV-1 uncovered but not infected individuals showed an increase in NK cell function suggesting a protective effect [14, 15]. Conversely, HIV decreases the expression of natural cytotoxicity receptors (NCRs), overall decreasing NK cell activation [13, 16]. Expression of NK activating receptor KIR3DS1 in combination with HLA-B allele is usually associated with delayed progression to AIDS and KIR3DS1 in the absence of HLA-B allele is usually associated with more rapid progression to AIDS . EHNA hydrochloride Not only is usually NK cell receptor expression altered during HIV-1, their ligand expression can also be altered. HIV induces the NKG2D ligands and downregulates CD48 ligand . The cell-cell interactions of NK cells and HIV-1 infected astrocytes especially in the context of HAND are understudied. Natural cytotoxicity receptor NKp44 (CD336) is only expressed on activated NK cells. IL-2 induces the expression of NKp44 on NK cells . NKp44 can be activating or inhibitory depending on the ligand it binds [20, 21]. Strikingly, NKp44L has not yet been detected on circulating cells isolated from healthy individuals, but EHNA hydrochloride it is usually expressed on a large panel of the tumor and transformed cells [22, 23]. The known cellular activating ligand of NKp44 (NKp44L) is an isoform of the mixed-lineage leukemia-5 protein (MLL5) [22, 23]. Its activating ligand is usually expressed in numerous tumor and transformed cell lines rendering them more sensitive for NK cytotoxicity. Previous studies in.