100 N Academy Ave
Danville PA 17822
Medical School: Other - 1989
Accepts Medicare: Yes
Participates In eRX: Yes
Participates In PQRS: Yes
Participates In EHR: No
License #: MD423166
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Cell Surface Downregulation of NK Cell Ligands by Patient-derived HIV-1 Vpu and Nef Alleles. - Journal of acquired immune deficiency syndromes (1999)
HIV-1 Vpu and Nef proteins downregulate cell surface levels of NK cell ligands but functional consequences of individual downregulation events are unclear. We tested how well conserved NK cell ligand downregulation is among Vpu and Nef variants isolated from chronic HIV patients.Proviral vpu and nef sequences were amplified from 27 chronic HIV patients, subcloned, and tested for their ability to downregulate cell surface receptors.Cell surface downregulation of CD4, CD317/tetherin and MHC-I that exert biological functions other than NK cell activation were well conserved among patient derived Vpu and Nef variants. Among NK cell ligands, NTB-A, PVR and ULBP were identified as main targets for Vpu and Nef, the downregulation of which by at least one viral protein was highly conserved. NK cell ligands displayed specific sensitivity to Vpu (NTB-A) or Nef (PVR) and downregulation of cell surface ULBP was identified as a novel and highly conserved activity of HIV-1 Vpu but not Nef.The conservation of downregulation of major NK cell ligands by either HIV-1 Vpu or Nef suggests an important pathophysiological role of this activity, which may impact on the acute but not the chronic phase of HIV infection.
Terminal Differentiation of CD56(dim)CD16(+) Natural Killer Cells Is Associated with Increase in Natural Killer Cell Frequencies After Antiretroviral Treatment in HIV-1 Infection. - AIDS research and human retroviruses
HIV-1 infection results in immunological abnormalities of natural killer (NK) cells such as disturbed distribution of NK cell subsets and downmodulation of activating and upregulation of inhibitory receptors thereby diminishing NK cell killing capacity and cytokine secretion. Antiretroviral treatment (ART) is known to restore phenotype and functions of NK cells. However, the effects of ART on NK cell terminal differentiation, activation, and disturbed distribution have not been studied yet longitudinally. Here, we analyzed the effects of ART on these parameters of peripheral blood NK cells in a longitudinal as well as in a cross-sectional study. We observed that expanded CD56(-)CD16(+) NK cell frequency is inversely correlated with the frequency of CD56(dim)CD16(+) NK cells in treatment-naive HIV-1 patients. Loss of CD56(dim)CD16(+) and expansion of CD56(-)CD16(+) NK cells again restore to the levels of healthy controls after ART. Enhanced immune activation of different NK cell subsets is partially restored after ART. Terminal differentiation of CD56(dim)CD16(+) NK cells is enhanced after ART as measured by CD57 expression. Frequencies of CD57(+)CD56(dim)CD16(+) NK cells are directly correlated with the frequencies of total NK cells suggesting that an increase in the frequencies of CD57(+)CD56(dim)CD16(+) NK cells is reflected by increased frequencies of total NK cells after ART. Taken together these data demonstrate that ART has an effect on the immune restoration of NK cells and is enhanced in the terminal differentiation of CD56(dim)CD16(+) NK cells, which is associated with increased frequencies of total NK cells after ART.
Natural killer cell heterogeneity: cellular dysfunction and significance in HIV-1 immuno-pathogenesis. - Cellular and molecular life sciences : CMLS
Natural killer (NK) cells are innate immune effectors that provide first line of defence against viruses. Human NK cells are heterogeneous in nature, and their functions rely on a dynamic balance between germ-line-encoded activating and inhibitory receptors. HIV-1 infection results in altered NK cell receptor repertoire and impaired effector functions including the ability to lyse virus-infected cells and secretion of antiviral cytokine IFN-Î³. Over the last decade, additional NK cell subset-specific molecules have been identified, leading to emergence of a more complex cellular diversity than previously thought. Herein, we discuss NK cell subset redistribution, altered receptor repertoire and influence of interaction of polymorphic leucocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIR) on HIV-1 disease progression.
High frequencies of polyfunctional CD8+ NK cells in chronic HIV-1 infection are associated with slower disease progression. - Journal of virology
Natural killer (NK) cells are effector and regulatory innate immune cells and play a critical role in the first line of defense against various viral infections. Although previous reports have indicated the vital contributions of NK cells to HIV-1 immune control, nongenetic NK cell parameters directly associated with slower disease progression have not been defined yet. In a longitudinal, retrospective study of 117 untreated HIV-infected subjects, we show that higher frequencies as well as the absolute numbers of CD8(+) CD3(-) lymphocytes are linked to delayed HIV-1 disease progression. We show that the majority of these cells are well-described blood NK cells. In a subsequent cross-sectional study, we demonstrate a significant loss of CD8(+) NK cells in untreated HIV-infected individuals, which correlated with HIV loads and inversely correlated with CD4(+) T cell counts. CD8(+) NK cells had modestly higher frequencies of CD57-expressing cells than CD8(-) cells, but CD8(+) and CD8(-) NK cells showed no differences in the expression of a number of activating and inhibiting NK cell receptors. However, CD8(+) NK cells exhibited a more functional profile, as detected by cytokine production and degranulation.We demonstrate that the frequency of highly functional CD8(+) NK cells is inversely associated with HIV-related disease markers and linked with delayed disease progression. These results thus indicate that CD8(+) NK cells represent a novel NK cell-derived, innate immune correlate with an improved clinical outcome in HIV infection.Copyright Â© 2014, American Society for Microbiology. All Rights Reserved.
FcÎ³RIII (CD16)-mediated ADCC by NKÂ cells is regulated by monocytes and FcÎ³RII (CD32). - European journal of immunology
Monocytes are known to engage in reciprocal crosstalk with NKÂ cells but their influence on NK-cell-associated antibody-dependent cellular cytotoxicity (ADCC) is not well understood. We demonstrate that in humans FcÎ³RIII (CD16)-dependent ADCC by NKÂ cells is considerably enhanced by monocytes, and that this effect is regulated by FcÎ³RII (CD32) crosslinking in healthy individuals. It is known that during HIV-1 infection, NKÂ cells are known to express low levels of CD16 and exhibit reduced ADCC. We show that immune regulation of CD16-mediated NK-cell cytotoxicity by monocytes through CD32 engagement is substantially disturbed in chronic progressive HIV-1 infection. Expression of activating isoform of CD32 represented a compensatory mechanism for reduced expression of CD16 on NKÂ cells during HIV-1 infection. As a result, the regulation of NK-cell-associated ADCC by monocytes is skewed and eventually constitutes a novel factor that contributes to HIV-1-associated immune deficiency, dysregulation and pathogenesis. Our data therefore provide evidence, for the first time, that in humans monocytes act as a rheostat for FcÎ³RIII-mediated NK-cell functions maintaining a well-balanced immune response.Â© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Optimal gating strategy for determining CD4+ recent thymic emigrants in human immunodeficiency virus-1 infected patients. - Viral immunology
Alterations of the frequencies of recent thymic emigrants (RTEs) in blood have been demonstrated to be associated with human immunodeficiency virus-1 (HIV-1) disease progression and immune reconstitution following antiretroviral therapy. Flow cytometry is a technology that offers many advantages over T-cell receptor excision circles (TRECs) quantification to determine the RTE subset in blood. However, the gating strategies for identifying RTEs by flow cytometry have not been evaluated and compared in much detail. In the present study, we compared the frequencies and the senescence levels of RTEs in 54 HIV-1 seronegative controls (HC) and 70 HIV-1 seropositive (HIV-1+) subjects using two different gating strategies by flow cytometry. Our analysis indicated that the CD4+ RTE population determined by the expressing pattern CD45RO-CD31+ contained the terminal effector memory T-cell population after HIV-1 infection, which could significantly affect the further phenotypic and functional studies. Our data demonstrate the necessity of including an additional marker such as CCR7 to distinguish better CD4+RTE subset in HIV-1+ subjects.
Loss of CCR7 expression on CD56(bright) NK cells is associated with a CD56(dim)CD16âº NK cell-like phenotype and correlates with HIV viral load. - PloS one
NK cells are pivotal sentinels of the innate immune system and distinct subpopulations in peripheral blood have been described. A number of studies addressed HIV-induced alterations of NK cell phenotype and functionality mainly focusing on CD56(dim)CD16âº and CD56â»CD16âº NK cells. However, the impact of HIV-infection on CD56(bright) NK cells is less well understood. Here we report a rise of CD56(bright) NK cells in HIV-infected individuals, which lack CCR7-expression and strongly correlate with HIV viral load. CCR7â»CD56(bright) NK cells were characterized by increased cytolytic potential, higher activation states and a more differentiated phenotype. These cells thus acquired a number of features of CD56(dim)CD16âº NK cells. Furthermore, CD56(bright) NK cells from HIV patients exhibited higher degranulation levels compared to uninfected individuals. Thus, chronic HIV-infection is associated with a phenotypic and functional shift of CD56(bright) NK cells, which provides a novel aspect of HIV-associated pathogenesis within the NK cell compartment.
Phenotypically and functionally distinct subsets contribute to the expansion of CD56-/CD16+ natural killer cells in HIV infection. - AIDS (London, England)
Chronic HIV infection has been associated with activation and increased turnover of natural killer (NK) cells as well as with disturbed homeostasis of the NK cell compartment, including loss of CD56(+) NK cells and accumulation of dysfunctional CD56(-)/CD16(+) NK cells. We performed a comprehensive phenotypical and functional characterization of this population.A cross-sectional study was performed to analyze CD56(-)/CD16(+) NK cells from 34 untreated HIV-infected and 15 seronegative individuals.NK cells were analyzed by flow cytometry. Degranulation was assessed by measuring their expression of CD107a after stimulation with K562 cells, interleukin-12 and interleukin-15.CD56(-)/CD16(+) NK cells are heterogeneous and composed of two populations, namely CD122(-)/CCR7(+) cells and CD122(-)/CCR7(+) cells. We show that expanded CD122(+) but not CCR7(+) cells in HIV-seropositive individuals are characterized by expression of senescence marker CD57 similarly to CD56(dim)/CD16(+) NK cells along with expression of KIRs, CD8, perforin and granzyme B. Despite expression of perforin and granzyme B, CD57 expressing cells exhibited less numbers of degranulating cells as measured by CD107a, indicating their functional impairment. However, there was no correlation between expansion of total CD56(-)/CD16(+) NK cells or the distinct subpopulations and viral load or CD4 cell count.These data indicate that expansion of CD56(-)/CD16(+) cells in HIV infection is driven by a distinct subset within this population with high expression of terminal differentiation marker with a phenotype resembling CD56(-)/CD16(+) NK cells.
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100 N Academy Ave Danville, PA 17822
100 N Academy Ave
100 N Academy Ave (Mail Code) 27-70
100 N Academy Ave
Geisinger Medical Ctr 100 North Academy Avenue