Acquired Immunodeficiency Syndrome: Schacker T

Berrey MM, Schacker T, Collier AC, Shea T, Brodie SJ, Mayers D, Coombs R, Krieger J, Chun TW, Fauci A, Self SG, Corey L. · Department of Medicine, University of Washington, Seattle, WA, USA. · J Infect Dis. · Pubmed #11319682 No free full text.

Abstract: Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.

Li Q, Estes JD, Duan L, Jessurun J, Pambuccian S, Forster C, Wietgrefe S, Zupancic M, Schacker T, Reilly C, Carlis JV, Haase AT. · Department of Microbiology, University of Minnesota, Minneapolis, MN 55455, USA. · J Infect Dis. · Pubmed #18199035 No free full text.

Abstract: The enteropathic manifestations of the human immunodeficiency virus (HIV) and the simian immunodeficiency virus (SIV) in late infection are usually due to infection by other microbes, but in early infection the viruses themselves cause an enteropathy by heretofore undetermined mechanisms. Here we report that SIV induces massive apoptosis of intestinal epithelial cells lining the small and large bowel, thus identifying apoptosis as the driving force behind the regenerative pathology of early infection. We found that apoptosis of gut epithelium paralleled the previously documented apoptosis and massive depletion of CD4 T cells in gut lamina propria, triggered by established mechanisms of gut epithelial cell apoptosis and, at peak, possibly by virus interactions with GPR15/Bob, an intestinal epithelial cell-associated alternative coreceptor for SIV and HIV-1. Apoptosis in early SIV infection is thus the common theme of the pathological processes that quickly afflict the innate as well as adaptive arms of the gut immune system.

Estes JD, Wietgrefe S, Schacker T, Southern P, Beilman G, Reilly C, Milush JM, Lifson JD, Sodora DL, Carlis JV, Haase AT. · Department of Microbiology, University of Minnesota, Minneapolis, MN 55455, USA. · J Infect Dis. · Pubmed #17230415 No free full text.

Abstract: In human immunodeficiency virus (HIV) infection, collagen deposition and fibrosis within the T cell zone disrupt the lymphatic tissue architecture, contributing to depletion of CD4(+) T cells and limiting immune reconstitution. We used relevant animal and in vitro models to investigate the kinetics and possible underlying mechanism(s) of this process. In the lymphatic tissue of simian immunodeficiency virus (SIV)-infected rhesus macaques, we observed parallel increases in immune activation, transforming growth factor (TGF) beta 1-positive regulatory T (T(reg)) cells, and collagen type I deposition by 7 days after inoculation, consistent with the hypothesis that early immune activation elicits a countering T(reg) cell response associated with TGF beta 1 expression and collagen deposition. In support of this hypothesis and the possible role of fibrosis in viral pathogenesis, we show (1) spatial colocalization and temporal concordance in levels of TGF beta 1(+) T(reg) cells and collagen deposition; (2) TGF beta 1(+) inducible T(reg) cell stimulation of primary lymphatic tissue fibroblasts to produce collagen type I in vitro; and (3) high levels of immune activation, TGF beta 1(+) T(reg) cells, and collagen deposition in pathogenic SIV infection of macaques, in contrast to apathogenic SIV infection in sooty mangabeys in which levels of immune activation, TGF beta 1(+) T(reg) cells, and collagen deposition were low. We thus conclude that the response of TGF beta 1(+) T(reg) cells to immune activation in early SIV/HIV infection is a double-edged sword: TGF beta 1(+) T(reg) cells normally have a positive effect by limiting immunopathological and autoreactive immune responses, but they also have a negative effect by dampening the antiviral immune response and, as we show here, causing deleterious effects on CD4(+) T cell homeostasis by inducing collagen deposition in lymphatic tissues.

Estes JD, Li Q, Reynolds MR, Wietgrefe S, Duan L, Schacker T, Picker LJ, Watkins DI, Lifson JD, Reilly C, Carlis J, Haase AT. · Department of Microbiology, Medical School, University of Minnesota, Minneapolis 55455, USA. · J Infect Dis. · Pubmed #16453267 No free full text.

Abstract: Here we report the results of an investigation into the possibility that one mechanism responsible for the establishment of persistent human immunodeficiency virus infection is an early regulatory T (Treg) cell response that blunts virus-specific responses. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model, we show that, indeed, viral replication and immune activation in lymphatic tissue drive a premature immunosuppressive response, with dramatic increases in the frequencies of CD4+CD25+FOXP3+ Treg cells, transforming growth factor- beta 1+ cells, interleukin-10+ cells, and indoleamine 2,3-dioxygenase+CD3+ cells. When we compared SIV infection with rhesus cytomegalovirus (RhCMV) infection, we found that the frequency of Treg cells paralleled the magnitude of immune activation during both infections but that the magnitude of immune activation and of the Treg cell response were lower and peaked much later during RhCMV infection. Importantly, the frequency of Treg cells inversely correlated with the magnitude of the SIV-specific cytotoxic T lymphocyte response. We conclude that an early Treg cell response during acute SIV infection may contribute to viral persistence by prematurely limiting the antiviral immune response before infection is cleared.

Li Q, Schacker T, Carlis J, Beilman G, Nguyen P, Haase AT. · Department of Microbiology, Department of Medicine, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA. · J Infect Dis. · Pubmed #14767808 No free full text.

Abstract: Highly active antiretroviral therapy (HAART) curtails human immunodeficiency virus type 1 (HIV-1) replication in lymphatic tissues and partially reverses the pathological damage associated with infection, but the genes that mediate these pathological and reparative processes remain largely unknown. To identify these genes, we used microarrays to profile gene expression in serial lymph node biopsy specimens obtained before and after treatment. We discovered approximately 200 treatment-responsive genes, many of them known mediators and moderators of immune activation and defenses, particularly innate defense genes, which, surprisingly, were expressed at all stages of HIV-1 infection. Most of the rest of the treatment-responsive genes we categorized as mediators of trafficking, reformation of active follicles, and tissue repair. We propose a model in which nearly counterbalanced functions of mediators and moderators of immune activation and defenses account for the slow dynamics of HIV-1 infection before treatment. This model suggests that there could be a role for anti-inflammatory agents, alone or in combination with HAART, in treating HIV-1 infection by tipping this balance to mitigate pathology.