Douglas Nixon

Publications (7)9.33 Total impact

• Article: Immune escape mutations detected within HIV-1 epitopes associated with viral control during treatment interruption.

  Becky Schweighardt, Terri Wrin, Duncan A Meiklejohn, Gerald Spotts, Christos J Petropoulos, Douglas F Nixon, Frederick M Hecht
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  ABSTRACT: We analyzed immune responses in chronically HIV-infected individuals who took part in a treatment interruption (TI) trial designed for patients who initiated antiretroviral therapy within 6 months of seroconversion. In the 2 subjects who exhibited the best viral control, we detected CD8(+) T-cell responses against 1-2 Gag epitopes during the early weeks of TI and a subsequent increase in the number of epitopes recognized by the later time points. Each of these subjects developed mutations within the epitopes targeted by the highest magnitude responses. In the subject with the worst viral control, we detected responses against 2 Gag epitopes throughout the entire TI and no Gag mutations. The magnitude of these responses increased dramatically with time, greatly exceeding those detected in the virologic controllers. The highest levels of contemporaneous autologous neutralizing antibody activity were detected in the virologic controllers, and a subsequent escape mutation developed within the envelope gene of one controller that abrogated the response. These data suggest that immune escape mutations are a sign of viral control during TI, and that the absence of immune escape mutations in the presence of high levels of viral replication indicates the lack of an effective host immune response.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 11/2009; 53(1):36-46. · 4.43 Impact Factor
• Article: Lower cytokine secretion ex vivo by natural killer T cells in HIV-infected individuals is associated with higher CD161 expression.

  Jennifer E Snyder-Cappione, Christopher P Loo, Karina I Carvalho, Carlotta Kuylenstierna, Steven G Deeks, Frederick M Hecht, Michael G Rosenberg, Johan K Sandberg, Esper G Kallas, Douglas F Nixon
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  ABSTRACT: Natural killer T (NKT) cells are efficiently targeted by HIV and severely reduced in numbers in the circulation of infected individuals. The functional capacity of the remaining NKT cells in HIV-infected individuals is poorly characterized. This study measured NKT cell cytokine production directly ex vivo and compared these responses with both the disease status and NKT subset distribution of individual patients. NKT cell frequencies, subsets, and ex-vivo effector functions were measured in the peripheral blood mononuclear cells of HIV-infected patients and healthy controls by flow cytometry. We measured cytokines from NKT cells after stimulation with either alpha-galactosyl ceramide-loaded CD1d dimers (DimerX-alphaGalCer) or phorbol myristate acetate and ionomycin. The frequencies of NKT cells secreting interferon-gamma and tumor necrosis factor-alpha were significantly lower in HIV-infected patients than healthy controls after DimerX-alphaGalCer treatment, but responses were similar after treatment with phorbol myristate acetate and ionomycin. The magnitude of the interferon-gamma response to DimerX-alphaGalCer correlated inversely with the number of years of infection. Both interferon-gamma and tumor necrosis factor-alpha production in response to DimerX-alphaGalCer correlated inversely with CD161 expression. The ex-vivo Th1 responses of circulating NKT cells to CD1d-glycolipid complexes are impaired in HIV-infected patients. NKT cell functions may be progressively lost over time in HIV infection, and CD161 is implicated in the regulation of NKT cell responsiveness.
  AIDS (London, England) 08/2009; 23(15):1965-70. · 4.91 Impact Factor
• Article: HIV-1 infection induces retrotransposition of LINE-1 elements

  Jones R Brad, Keith Garrison, Haihan Song, Anton Buzdin, Naveed Anwar, Duncan Meiklejohn, Lishomwa Ndhlovu, Douglas Nixon, Mario Ostrowski
  Retrovirology. 01/2009;
• Article: Paleovirology of human endogenous retroviruses

  Robert Gifford, Aris Katzourakis, Robert Belshaw, Douglas Nixon
  Retrovirology. 01/2009;
• Article: The frequency of CD127^lowexpressing CD4⁺CD25^highT regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis

  Jakob Michaëlsson, Hugo Barbosa, Kimberley Jordan, Joan Chapman, Milena Brunialti, Walter Neto, Youko Nukui, Ester Sabino, Marco Chieia, Acary Oliveira, Douglas Nixon, Esper Kallas
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  ABSTRACT: Abstract Background CD4⁺CD25^highregulatory T (T_Reg) cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of T_Regcell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of T_Regcells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP) patients, and to correlate with measures of T cell activation. Results We were able to confirm that HTLV-I drives activation, spontaneous IFNγ production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4⁺T_Regcells (CD4⁺CD25^highT cells) in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4⁺T_Regcells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127^lowT_Regcells in healthy control subjects. Finally, the proportion of CD127^lowT_Regcells correlated inversely with HTLV-1 proviral load. Conclusion Taken together, the results suggest that T_Regcells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4⁺T cells, in particular those expressing the CD25^highCD127^lowphenotype. T_Regcells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.
  BMC Immunology. 01/2008;
• Article: IL-2 production correlates with effector cell differentiation in HIV-specific CD8+ T cells

  Laurel Nomura, Brinda Emu, Rebecca Hoh, Perry Haaland, Steven Deeks, Jeffrey Martin, Joseph McCune, Douglas Nixon, Holden Maecker
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  ABSTRACT: Abstract Background Diminished IL-2 production and lack of effector differentiation have been reported for HIV-specific T cells. In this study, we examined the prevalence of these phenomena using 8-color cytokine flow cytometry, and tested the hypothesis that these two findings were causally related. We analyzed cytokine profiles and memory/effector phenotypes of HIV-specific and CMV-specific T cells using short-term in vitro stimulation with HIV or CMV peptide pools. Nineteen HIV-positive subjects with progressive disease and twenty healthy, HIV-negative subjects were examined. Results Among HIV-infected subjects, there were significantly fewer CD8+ IL-2+ T cells responding to HIV compared to CMV, with no significant difference in CD4+ IL-2+ T cells. The majority of CMV-specific T cells in both HIV-negative and HIV-positive subjects appeared to be terminally differentiated effector cells (CD8+ CD27- CD28- CD45RA+ or CD8+ CD27- CD28- CD45RA-). In HIV-positive subjects, the most common phenotype of HIV-specific T cells was intermediate in differentiation (CD8+ CD27+ CD28- CD45RA-). These differences were statistically significant, both as absolute cell frequencies and as percentages. There was a significant correlation between the absolute number of HIV-specific CD8+ IL-2+ T cells and HIV-specific CD8+ CD27- CD28- CD45RA+ terminal effector cells. Conclusion IL-2 production from antigen-specific CD8+ T cells correlates with effector cell differentiation of those cells.
  AIDS Research and Therapy. 01/2006;
• Article: CD4+CD25high Regulatory T Cells in the Developing Human Immune System: Implications for Pediatric HIV Infection

  Jakob Michaëlsson, Jeff Mold, Joseph McCune, Douglas Nixon
  Retrovirology. 01/2005;