Mirko Paiardini

Publications (56)396.34 Total impact

• Article: Reduced Inflammation and Lymphoid Tissue Immunopathology in Rhesus Macaques Receiving Anti-TNF Treatment During Primary SIV Infection.

  Brian Tabb, David R Morcock, Charles M Trubey, Octavio A Quiñones, Xing Pei Hao, Jeremy Smedley, Rhonda Macallister, Michael Piatak, Levelle D Harris, Mirko Paiardini, Guido Silvestri, Jason M Brenchley, W Gregory Alvord, Jeffrey D Lifson, Jacob D Estes
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  ABSTRACT: Background. HIV/SIV infections induce robust, generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation, fibrotic damage of lymphoid tissues (LTs) and CD4(+) T cell loss, pathogenic processes that contribute to disease progression.Methods. To better understand the contribution of TNF, a key regulator of acute inflammation, to lentiviral pathogenesis, rhesus macaques (RMs) newly infected with SIVmac239 were treated for 12 weeks in a pilot study with adalimumab (Humira), a human anti-TNF mAb.Results. Adalimumab did not affect plasma SIV RNA levels or measures of T-cell immune activation (CD38 or Ki67) in peripheral blood or lymph node T cells. However, compared to untreated RMs, adalimumab-treated RMs showed attenuated expression of pro-inflammatory genes, decreased infiltration of polymorphonuclear cells into the T cell zone (TZ) of LTs and weaker anti-inflammatory regulatory responses to SIV infection (i.e. fewer presumed alternatively activated (CD163(+)) macrophages, IL-10(+) and TGFβ(+) cells), along with reduced LT fibrosis and better preservation of CD4(+) T cells.Conclusions. While HIV/SIV replication drives pathogenesis, these data emphasize the contribution of the inflammatory response to lentiviral infection to overall pathogenesis, and suggest that early modulation of the inflammatory response may help attenuate disease progression.
  The Journal of Infectious Diseases 10/2012; · 6.41 Impact Factor
• Article: Antitumoral Activity of Indole-3-carbinol Cyclic Tri- and Tetrameric Derivatives mixture in Human Breast Cancer Cells: In Vitro and In Vivo Studies.

  Giorgio Brandi, Alessandra Fraternale, Simone Lucarini, Mirko Paiardini, Mauro De Santi, Barbara Cervasi, Maria Filomena Paoletti, Luca Galluzzi, Andrea Duranti, Mauro Magnani
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  ABSTRACT: Indole-3-carbinol (I3C) and its oligomeric derivatives have been widely studied for their chemopreventive and chemotherapeutic properties. We have previously shown that the I3C cyclic tetrameric derivative CTet inhibits breast cancer cell proliferation in vitro and in xenotrasplanted tumor. Here we report the antitumoral activity of a mixture of tri- and tetrameric cyclic I3C derivatives (CTr/CTet) both in vitro (MCF-7 and MDA-MB-231 breast cancer cell lines) and in vivo in a tumor xenograft model. CTr/CTet mixture avoids the low solubility drawbacks of CTet, thus favouring its solubilization, and reducing purification process, time and costs. CTr/CTet mixture has been shown to inhibit breast cancer cell proliferation (IC50 = 1.3 and 1.6 µg/ml in MCF-7 and MDA-MB-231, respectively) inducing the G0/1 cell cycle phase accumulation. The main molecular events related to CTr/CTet activity are the overexpression of p21, p27 and GADD45A, nuclear translocation of FOXO3a, inhibition of Akt activity and downregulation of estrogen receptor. In vivo, the growth of xenotransplanted tumor has been inhibited and the pro-tumoral low molecular weight cyclin E downregulation has been detected. Our data indicate that CTr/CTet is a potential anticancer combination agent for both hormone-responsive and triple-negative breast tumors.
  Anti-cancer agents in medicinal chemistry 10/2012;
• Article: Paucity of interleukin (IL-21)-producing CD4+ T-cells is associated with Th17 cell depletion in SIV-infection of rhesus macaques.

  Luca Micci, Barbara Cervasi, Zachary S Ende, Robin I Iriele, Elane Reyes-Aviles, Carol Vinton, James Else, Guido Silvestri, Aftab A Ansari, Francois Villinger, Savita Pahwa, Jacob D Estes, Jason M Brenchley, Mirko Paiardini
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  ABSTRACT: Interleukin (IL)-21 regulates Th17 cell homeostasis, enhances the differentiation of memory B cells and antibody-secreting plasma cells, and promotes the maintenance of CD8(+) T-cell responses. In this study, we investigated the phenotype, function, and frequency of blood and intestinal IL-21-producing cells in nonhuman primates that are hosts of progressive (rhesus macaques; RMs) and nonprogressive (sooty mangabeys; SMs) SIV infection. We found that, in both species, memory CD4(+)CD95(+)CCR6(-) T-cells are the main IL-21 producers, and that only a small fraction of CD4(+)IL-21(+) T-cells produce IL-17. During chronic SIV infection of RMs, CD4(+)IL-21(+) T-cells were significantly depleted in both blood and rectal mucosa, with the extent of this depletion correlating with the loss of Th17 cells. Furthermore, treatment with IL-21 increased the in vivo levels of Th17 cells in SIV-infected RMs. In contrast, normal levels of CD4(+)IL-21(+) T-cells were found in SIV-infected SMs. Collectively, these data indicate that depletion of IL-21-producing CD4(+) T-cells distinguishes progressive from nonprogressive SIV infection of RMs and SMs, and suggest that depletion of CD4(+)IL-21(+) T-cells is involved in the preferential loss of Th17 cells that is associated with SIV disease progression. Further pre-clinical studies of IL-21 as a potential immunotherapeutic agent for HIV infection may be warranted.
  Blood 09/2012; · 9.90 Impact Factor
• Article: Differential infection patterns of CD4+ T cells and lymphoid tissue viral burden distinguish progressive and nonprogressive lentiviral infections.

  Jason M Brenchley, Carol Vinton, Brian Tabb, Xing Pei Hao, Elizabeth Connick, Mirko Paiardini, Jeffrey D Lifson, Guido Silvestri, Jacob D Estes
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  ABSTRACT: Nonhuman primate natural hosts for simian immunodeficiency viruses (SIV) develop a non-resolving chronic infection, but do not develop AIDS. Mechanisms to explain the nonprogressive nature of SIV infection in natural hosts that underlie maintained high levels of plasma viremia without apparent loss of target cells remain unclear. Here, we used comprehensive approaches (i.e. FACS sorting, qRT-PCR, immunohistochemistry, and in situ hybridization) to study viral infection within subsets of peripheral blood and lymphoid tissue (LT) CD4(+) T cells in cohorts of chronically SIV-infected rhesus macaques (RM), HIV-infected humans and SIVsmm-infected sooty mangabeys (SM). We find: (1) infection frequencies among CD4(+) T cells in chronically SIV-infected RM are significantly higher than those in SIVsmm-infected SM; (2) infected cells are found in distinct anatomical LT niches and different CD4(+) T cell subsets in SIV-infected RM and SM, with infection patterns of RM reflecting HIV infection in humans; (3) T(FH) cells are infected at higher frequencies in RM and humans than in SM and; (4) LT viral burden, including follicular dendritic cell deposition of virus, is increased in RM and humans compared to SM. These data provide insights into how natural hosts are able to maintain high levels of plasma viremia while avoiding development of immunodeficiency.
  Blood 09/2012; · 9.90 Impact Factor
• Article: Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution.

  Ming Zeng, Mirko Paiardini, Jessica C Engram, Greg J Beilman, Jeffrey G Chipman, Timothy W Schacker, Guido Silvestri, Ashley T Haase
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  ABSTRACT: Loss of the fibroblastic reticular cell (FRC) network in lymphoid tissues during HIV-1 infection has been shown to impair the survival of naive T cells and limit immune reconstitution after antiretroviral therapy. What causes this FRC loss is unknown. Because FRC loss correlates with loss of both naive CD4 and CD8 T-cell subsets and decreased lymphotoxin-β, a key factor for maintenance of FRC network, we hypothesized that loss of naive T cells is responsible for loss of the FRC network. To test this hypothesis, we assessed the consequences of antibody-mediated depletion of CD4 and CD8 T cells in rhesus macaques and sooty mangabeys. We found that only CD4 T-cell depletion resulted in FRC loss in both species and that this loss was caused by decreased lymphotoxin-β mainly produced by the CD4 T cells. We further found the same dependence of the FRC network on CD4 T cells in HIV-1-infected patients before and after antiretroviral therapy and in other immunodeficiency conditions, such as CD4 depletion in cancer patients induced by chemotherapy and irradiation. CD4 T cells thus play a central role in the maintenance of lymphoid tissue structure necessary for their own homeostasis and reconstitution.
  Blood 05/2012; 120(9):1856-67. · 9.90 Impact Factor
• Article: Natural SIV hosts: showing AIDS the door.

  Ann Chahroudi, Steven E Bosinger, Thomas H Vanderford, Mirko Paiardini, Guido Silvestri
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  ABSTRACT: Many species of African nonhuman primates are naturally infected with simian immunodeficiency viruses (SIVs) in the wild and in captivity. In contrast to HIV-infected humans, these natural SIV hosts typically do not develop AIDS, despite chronic infection with a highly replicating virus. In this Review, we discuss the most recent advances on the mechanisms of protection from disease progression in natural SIV hosts, with emphasis on how they differ from pathogenic HIV/SIV infections of humans and rhesus macaques. These mechanisms include: (i) resolution of immune activation after acute infection, (ii) restricted pattern of target cell infection, and (iii) protection from mother-to-infant transmission. We highlight the areas that should be pursued in future studies, focusing on potential applications for the treatment and prevention of HIV infection.
  Science 03/2012; 335(6073):1188-93. · 31.20 Impact Factor
• Source

  Available from: Giancarlo Ceccarelli

  Article: Microbial translocation and infectious diseases: what is the link?

  Gabriella D'Ettorre, Daniel Douek, Mirko Paiardini, Giancarlo Ceccarelli, Vincenzo Vullo
  International Journal of Microbiology 01/2012; 2012:356981.
• Article: Cloning and analysis of sooty mangabey alternative coreceptors that support simian immunodeficiency virus SIVsmm entry independently of CCR5.

  Sarah T C Elliott, Nadeene E Riddick, Nicholas Francella, Mirko Paiardini, Thomas H Vanderford, Bing Li, Cristian Apetrei, Donald L Sodora, Cynthia A Derdeyn, Guido Silvestri, Ronald G Collman
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  ABSTRACT: Natural host sooty mangabeys (SM) infected with simian immunodeficiency virus SIVsmm do not develop AIDS despite high viremia. SM and other natural hosts express very low levels of CCR5 on CD4(+) T cells, and we recently showed that SIVsmm infection and robust replication occur in vivo in SM genetically lacking CCR5, indicating the use of additional entry pathways. SIVsmm uses several alternative coreceptors of human origin in vitro, but which molecules of SM origin support entry is unknown. We cloned a panel of putative coreceptors from SM and tested their ability to mediate infection, in conjunction with smCD4, by pseudotypes carrying Envs from multiple SIVsmm subtypes. smCXCR6 supported efficient infection by all SIVsmm isolates with entry levels comparable to those for smCCR5, and smGPR15 enabled entry by all isolates at modest levels. smGPR1 and smAPJ supported low and variable entry, whereas smCCR2b, smCCR3, smCCR4, smCCR8, and smCXCR4 were not used by most isolates. In contrast, SIVsmm from rare infected SM with profound CD4(+) T cell loss, previously reported to have expanded use of human coreceptors, including CXCR4, used smCXCR4, smCXCR6, and smCCR5 efficiently and also exhibited robust entry through smCCR3, smCCR8, smGPR1, smGPR15, and smAPJ. Entry was similar with both known alleles of smCD4. These alternative coreceptors, particularly smCXCR6 and smGPR15, may support virus replication in SM that have restricted CCR5 expression as well as SM genetically lacking CCR5. Defining expression of these molecules on SM CD4(+) subsets may delineate distinct natural host target cell populations capable of supporting SIVsmm replication without CD4(+) T cell loss.
  Journal of Virology 11/2011; 86(2):898-908. · 5.40 Impact Factor
• Article: CCR5 blockade is well tolerated and induces changes in the tissue distribution of CCR5+ and CD25+ T cells in healthy, SIV-uninfected rhesus macaques.

  Jessica E Taaffe, Steven E Bosinger, Gregory Q Del Prete, James G Else, Sarah Ratcliffe, Christopher D Ward, Thi Migone, Mirko Paiardini, Guido Silvestri
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  ABSTRACT: CCR5 is a main co-receptor for HIV, but also homes lymphocytes to sites of inflammation. We hypothesized that inhibition of CCR5 signaling would reduce HIV-associated chronic immune activation. To test this hypothesis, we administered an antagonistic anti-CCR5 monoclonal antibody (HGS101) to five uninfected rhesus macaques (RMs) and monitored lymphocyte dynamics in blood and tissue. CCR5 blockade resulted in decreased levels of CCR5+ T cells in blood and, at later timepoints, in lymph nodes. Additionally, the levels of CD25+ T cells increased in lymph nodes, but decreased in blood, bone marrow, and rectal mucosa. Finally, a profile of gene expression from HGS101-treated RMs revealed a subtle, but consistent, in vivo signature of CCR5 blockade that suggests a mild immune-modulatory effect. Treatment with anti-CCR5 antibody induces changes in the tissue distribution of CCR5+ and CD25+ T cells that may impact on the overall levels of immune activation during HIV and SIV infection.
  Journal of Medical Primatology 11/2011; 41(1):24-42. · 1.30 Impact Factor
• Article: Depletion of CD4⁺ T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques.

  Alexandra M Ortiz, Nichole R Klatt, Bing Li, Yanjie Yi, Brian Tabb, Xing Pei Hao, Lawrence Sternberg, Benton Lawson, Paul M Carnathan, Elizabeth M Cramer, [......], Francisco Gonzalez-Scarano, Mirko Paiardini, Aftab A Ansari, Sarah Ratcliffe, James G Else, Jason M Brenchley, Ronald G Collman, Jacob D Estes, Cynthia A Derdeyn, Guido Silvestri
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  ABSTRACT: CD4+ T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of CD4+ T cells as mediators of antiviral immune responses and targets for virus replication is still unclear. Here, we have generated data in SIV-infected rhesus macaques (RMs) that suggest that CD4+ T cells are essential in establishing control of virus replication during acute infection. To directly assess the role of CD4+ T cells during primary SIV infection, we in vivo depleted these cells from RMs prior to infecting the primates with a pathogenic strain of SIV. Compared with undepleted animals, CD4+ lymphocyte-depleted RMs showed a similar peak of viremia, but did not manifest any post-peak decline of virus replication despite CD8+ T cell- and B cell-mediated SIV-specific immune responses comparable to those observed in control animals. Interestingly, depleted animals displayed rapid disease progression, which was associated with increased virus replication in non-T cells as well as the emergence of CD4-independent SIV-envelopes. Our results suggest that the antiviral CD4+ T cell response may play an important role in limiting SIV replication, which has implications for the design of HIV vaccines.
  The Journal of clinical investigation 11/2011; 121(11):4433-45. · 15.39 Impact Factor
• Source

  Available from: PubMed Central

  Article: Low levels of SIV infection in sooty mangabey central memory CD⁴⁺ T cells are associated with limited CCR5 expression.

  Mirko Paiardini, Barbara Cervasi, Elane Reyes-Aviles, Luca Micci, Alexandra M Ortiz, Ann Chahroudi, Carol Vinton, Shari N Gordon, Steven E Bosinger, Nicholas Francella, [......], Nadeene E Riddick, Ronald G Collman, Cristian Apetrei, Ivona Pandrea, James Else, Jan Munch, Frank Kirchhoff, Miles P Davenport, Jason M Brenchley, Guido Silvestri
  [show abstract] [hide abstract]
  ABSTRACT: Naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys do not progress to AIDS despite high-level virus replication. We previously showed that the fraction of CD4(+)CCR5(+) T cells is lower in sooty mangabeys compared to humans and macaques. Here we found that, after in vitro stimulation, sooty mangabey CD4(+) T cells fail to upregulate CCR5 and that this phenomenon is more pronounced in CD4(+) central memory T cells (T(CM) cells). CD4(+) T cell activation was similarly uncoupled from CCR5 expression in sooty mangabeys in vivo during acute SIV infection and the homeostatic proliferation that follows antibody-mediated CD4(+) T cell depletion. Sooty mangabey CD4(+) T(CM) cells that express low amounts of CCR5 showed reduced susceptibility to SIV infection both in vivo and in vitro when compared to CD4(+) T(CM) cells of rhesus macaques. These data suggest that low CCR5 expression on sooty mangabey CD4(+) T cells favors the preservation of CD4(+) T cell homeostasis and promotes an AIDS-free status by protecting CD4(+) T(CM) cells from direct virus infection.
  Nature medicine 06/2011; 17(7):830-6. · 27.14 Impact Factor
• Article: Immunodeficiency lentiviral infections in natural and non-natural hosts.

  Jason M Brenchley, Mirko Paiardini
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  ABSTRACT: The host immune system is profoundly affected during the acute phase of progressive immunodeficiency lentiviral infections. Studies of these alterations have been quite restricted in humans because of the limited availability of samples from acutely HIV-infected persons. Therefore, numerous studies have turned attention to nonhuman primate models. Specifically, SIV-infected rhesus macaques (RMs) have been informative for understanding the pathogenesis of HIV infection in humans. Indeed, advantages of the nonhuman primate model include the ability to study the very early events after infection and the ability to retrieve copious amounts of tissues. In addition, nonhuman primates allow for comparative studies between non-natural and natural hosts for SIV, in which SIV infection results in progression, or not, to AIDS, respectively. Although SIV infection of RM is the best model for HIV infection, the immunologic and/or virologic phenomena in SIV-infected RM do not always reflect those seen in HIV-infected humans. Here virologic and immunologic aspects of acute HIV infection of humans and SIV infection of Asian and African nonhuman primates are discussed and compared in relation to how these aspects relate to disease progression.
  Blood 04/2011; 118(4):847-54. · 9.90 Impact Factor
• Article: Editorial: Hijacking the IL-7/IL-7R system in HIV infection.

  Mirko Paiardini
  Journal of leukocyte biology 04/2011; 89(4):491-3. · 4.99 Impact Factor
• Article: HIV persistence in the gut mucosa of HIV-infected subjects undergoing antiretroviral therapy correlates with immune activation and increased levels of LPS.

  Gabriella d'Ettorre, Mirko Paiardini, Lorenzo Zaffiri, Mauro Andreotti, Giancarlo Ceccarelli, Cecilia Rizza, Marileda Indinnimeo, Stefano Vella, Claudio M Mastroianni, Guido Silvestri, Vincenzo Vullo
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  ABSTRACT: We investigated the relationship between viral persistence in the gut, microbial translocation, and T cell activation during chronic HIV infection. Plasma levels of LPS, fraction of circulating CD8+CD38+ T cells, and levels of HIV-DNA in rectosigmoid biopsies and peripheral blood mononuclear cells were determined in 22 HIV-infected individuals and 10 healthy controls. We found that in untreated HIV-infected individuals, HIV-DNA load was higher in the gut mucosa than in the blood. Also, ART-treated patients exhibited lower levels of LPS and CD8+CD38+ T cells than untreated patients, but higher levels than controls. In ART-treated individuals, the level of HIV-DNA in the gut correlated with levels of LPS and fraction of CD8+CD38+ T cells. We concluded that in ART-treated individuals, higher levels of gut-associated HIV-DNA are associated with persistent immune activation and microbial translocation.
  Current HIV research 04/2011; 9(3):148-53. · 1.98 Impact Factor
• Article: HIV Persistence in the Gut Mucosa of HIV-Infected Subjects Undergoing Antiretroviral Therapy Correlates with Immune Activation and Increased Levels of LPS

  Gabriella d'Ettorre, Mirko Paiardini, Lorenzo Zaffiri, Mauro Andreotti, Giancarlo Ceccarelli, Cecilia Rizza, Marileda Indinnimeo, Stefano Vella, Claudio M. Mastroianni, Guido Silvestri, Vincenzo Vullo
  [show abstract] [hide abstract]
  ABSTRACT: We investigated the relationship between viral persistence in the gut, microbial translocation, and T cell activation during chronic HIV infection. Plasma levels of LPS, fraction of circulating CD8+CD38+ T cells, and levels of HIV-DNA in rectosigmoid biopsies and peripheral blood mononuclear cells were determined in 22 HIV-infected individuals and 10 healthy controls. We found that in untreated HIV-infected individuals, HIV-DNA load was higher in the gut mucosa than in the blood. Also, ART-treated patients exhibited lower levels of LPS and CD8+CD38+ T cells than untreated patients, but higher levels than controls. In ART-treated individuals, the level of HIV-DNA in the gut correlated with levels of LPS and fraction of CD8+CD38+ T cells. We concluded that in ART-treated individuals, higher levels of gut-associated HIV-DNA are associated with persistent immune activation and microbial translocation.
  Current HIV Research 03/2011; 9(3):148-153. · 1.75 Impact Factor
• Article: HIV-associated immune activation: from bench to bedside.

  Gabriella d'Ettorre, Mirko Paiardini, Giancarlo Ceccarelli, Guido Silvestri, Vincenzo Vullo
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  ABSTRACT: HIV infection is associated with a state of chronic, generalized immune activation that has been shown in many studies to be a key predictor of progression to AIDS. Consistent with this model, nonpathogenic SIV infections of natural hosts, such as the sooty mangabeys, are characterized by low levels of immune activation during the chronic phase of infection. The molecular, cellular, and pathophysiological mechanisms underlying the HIV-associated immune activation are complex and still poorly understood. There is, however, growing consensus that both viral and host factors contribute to this phenotype, with emphasis on the role played by the mucosal immune dysfunction (and consequent microbial translocation) as well as the pattern of in vivo-infected CD4(+) T cells. The observation that antiretroviral therapy (ART)-induced suppression of HIV replication does not fully resolve immune activation provided the rationale for a number of exploratory studies of potential immune modulatory treatments to be used in HIV-infected individuals in addition to standard ART. This review provides an update on the causes and consequences of the HIV-associated immune activation, and a summary of the immune modulatory approaches that are currently under clinical investigation.
  AIDS research and human retroviruses 02/2011; 27(4):355-64. · 2.18 Impact Factor
• Article: Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys.

  Ming Liang Chan, Janka Petravic, Alexandra M Ortiz, Jessica Engram, Mirko Paiardini, Deborah Cromer, Guido Silvestri, Miles P Davenport
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  ABSTRACT: Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, 'natural hosts' of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to 'fuel the fire' of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.
  Proceedings of the Royal Society B: Biological Sciences 12/2010; 277(1701):3773-81. · 5.41 Impact Factor
• Article: Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals.

  Shari N Gordon, Barbara Cervasi, Pamela Odorizzi, Randee Silverman, Faten Aberra, Gregory Ginsberg, Jacob D Estes, Mirko Paiardini, Ian Frank, Guido Silvestri
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  ABSTRACT: HIV infection is associated with depletion of intestinal CD4(+) T cells, resulting in mucosal immune dysfunction, microbial translocation, chronic immune activation, and progressive immunodeficiency. In this study, we examined HIV-infected individuals with active virus replication (n = 15), treated with antiretroviral therapy (n = 13), and healthy controls (n = 11) and conducted a comparative analysis of T cells derived from blood and four gastrointestinal (GI) sites (terminal ileum, right colon, left colon, and sigmoid colon). As expected, we found that HIV infection is associated with depletion of total CD4(+) T cells as well as CD4(+)CCR5(+) T cells in all GI sites, with higher levels of these cells found in ART-treated individuals than in those with active virus replication. While the levels of both CD4(+) and CD8(+) T cell proliferation were higher in the blood of untreated HIV-infected individuals, only CD4(+) T cell proliferation was significantly increased in the gut of the same patients. We also noted that the levels of CD4(+) T cells and the percentages of CD4(+)Ki67(+) proliferating T cells are inversely correlated in both blood and intestinal tissues, thus suggesting that CD4(+) T cell homeostasis is similarly affected by HIV infection in these distinct anatomic compartments. Importantly, the level of intestinal CD4(+) T cells (both total and Th17 cells) was inversely correlated with the percentage of circulating CD4(+)Ki67(+) T cells. Collectively, these data confirm that the GI tract is a key player in the immunopathogenesis of HIV infection, and they reveal a strong association between the destruction of intestinal CD4(+) T cell homeostasis in the gut and the level of systemic CD4(+) T cell activation.
  The Journal of Immunology 10/2010; 185(9):5169-79. · 5.79 Impact Factor
• Article: Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ lymphocyte depletion in nonhuman primates.

  Jessica C Engram, Barbara Cervasi, Jose A M Borghans, Nichole R Klatt, Shari N Gordon, Ann Chahroudi, James G Else, Robert S Mittler, Donald L Sodora, Rob J de Boer, Jason M Brenchley, Guido Silvestri, Mirko Paiardini
  [show abstract] [hide abstract]
  ABSTRACT: Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4(+) or CD8(+) lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4(+) or CD8(+) T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4(+) and CD8(+) lymphocyte depletions were followed by a largely lineage-specific CD4(+) and CD8(+) T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4(+) T cells than RMs. In addition, in both species CD8(+) T-cell repopulation was faster than that of CD4(+) T cells, with CD8(+) T cells reconstituting a normal pool within 60 days and CD4(+) T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4(+) T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4(+) T-cell destruction is chronic.
  Blood 08/2010; 116(5):748-58. · 9.90 Impact Factor
• Article: Downregulation of robust acute type I interferon responses distinguishes nonpathogenic simian immunodeficiency virus (SIV) infection of natural hosts from pathogenic SIV infection of rhesus macaques.

  Levelle D Harris, Brian Tabb, Donald L Sodora, Mirko Paiardini, Nichole R Klatt, Daniel C Douek, Guido Silvestri, Michaela Müller-Trutwin, Ivona Vasile-Pandrea, Cristian Apetrei, Vanessa Hirsch, Jeffrey Lifson, Jason M Brenchley, Jacob D Estes
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  ABSTRACT: The mechanisms underlying the AIDS resistance of natural hosts for simian immunodeficiency virus (SIV) remain unknown. Recently, it was proposed that natural SIV hosts avoid disease because their plasmacytoid dendritic cells (pDCs) are intrinsically unable to produce alpha interferon (IFN-alpha) in response to SIV RNA stimulation. However, here we show that (i) acute SIV infections of natural hosts are associated with a rapid and robust type I IFN response in vivo, (ii) pDCs are the principal in vivo producers of IFN-alpha/beta at peak acute infection in lymphatic tissues, and (iii) natural SIV hosts downregulate these responses in early chronic infection. In contrast, persistently high type I IFN responses are observed during pathogenic SIV infection of rhesus macaques.
  Journal of Virology 08/2010; 84(15):7886-91. · 5.40 Impact Factor