Cristian Apetrei

Publications (69)500.45 Total impact

• Article: SIVagm Infection in Wild African Green Monkeys from South Africa: Epidemiology, Natural History, and Evolutionary Considerations.

  Dongzhu Ma, Anna Jasinska, Jan Kristoff, J Paul Grobler, Trudy Turner, Yoon Jung, Christopher Schmitt, Kevin Raehtz, Felix Feyertag, Natalie Martinez Sosa, Viskam Wijewardana, Donald S Burke, David L Robertson, Russell Tracy, Ivona Pandrea, Nelson Freimer, Cristian Apetrei
  [show abstract] [hide abstract]
  ABSTRACT: Pathogenesis studies of SIV infection have not been performed to date in wild monkeys due to difficulty in collecting and storing samples on site and the lack of analytical reagents covering the extensive SIV diversity. We performed a large scale study of molecular epidemiology and natural history of SIVagm infection in 225 free-ranging AGMs from multiple locations in South Africa. SIV prevalence (established by sequencing pol, env, and gag) varied dramatically between infant/juvenile (7%) and adult animals (68%) (p<0.0001), and between adult females (78%) and males (57%). Phylogenetic analyses revealed an extensive genetic diversity, including frequent recombination events. Some AGMs harbored epidemiologically linked viruses. Viruses infecting AGMs in the Free State, which are separated from those on the coastal side by the Drakensberg Mountains, formed a separate cluster in the phylogenetic trees; this observation supports a long standing presence of SIV in AGMs, at least from the time of their speciation to their Plio-Pleistocene migration. Specific primers/probes were synthesized based on the pol sequence data and viral loads (VLs) were quantified. VLs were of 10(4)-10(6) RNA copies/ml, in the range of those observed in experimentally-infected monkeys, validating the experimental approaches in natural hosts. VLs were significantly higher (10(7)-10(8) RNA copies/ml) in 10 AGMs diagnosed as acutely infected based on SIV seronegativity (Fiebig II), which suggests a very active transmission of SIVagm in the wild. Neither cytokine levels (as biomarkers of immune activation) nor sCD14 levels (a biomarker of microbial translocation) were different between SIV-infected and SIV-uninfected monkeys. This complex algorithm combining sequencing and phylogeny, VL quantification, serology, and testing of surrogate markers of microbial translocation and immune activation permits a systematic investigation of the epidemiology, viral diversity and natural history of SIV infection in wild African natural hosts.
  PLoS Pathogens 01/2013; 9(1):e1003011. · 9.13 Impact Factor
• Source

  Available from: Will Fischer

  Article: Distinct Evolutionary Pressures Underlie Diversity in Simian and Human Immunodeficiency Virus Lineages.

  Will Fischer, Cristian Apetrei, Mario L Santiago, Yingying Li, Rajeev Gautam, Ivona Pandrea, George M Shaw, Beatrice H Hahn, Norman L Letvin, Gary J Nabel, Bette T Korber
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  ABSTRACT: Simian immunodeficiency virus infection of rhesus macaques causes immune depletion and disease closely resembling human AIDS, and is well-recognized as the most relevant animal model for the human disease. Experimental investigations of viral pathogenesis and vaccine protection primarily involve a limited set of related viruses originating in sooty mangabeys (SIVsmm). The diversity of HIV-1 has evolved in humans in about a century; in contrast, SIV isolates used in the macaque model evolved in sooty mangabeys over millennia. To investigate the possible consequences of such different evolutionary histories on selection pressures and observed diversity in SIVsmm and HIV-1, we isolated, sequenced, and analyzed 20 independent isolates of SIV sooty mangabey (SIVsmm), including representatives of 7 distinct clades of viruses isolated from natural infection. We found SIVsmm diversity to be lower overall than HIV-1 M group diversity. Compared to HIV-1, reduced positive selection (i.e., less diversifying evolution) was evident in extended regions of SIVsmm proteins, most notably in Gag p27 and Env gp120. In addition, the relative diversity of proteins in the two lineages was distinct: SIVsmm Env and Gag were much less diverse than their HIV-1 counterparts; this may be explained by lower SIV-directed immune activity in mangabeys relative to HIV-1-directed immunity in humans. These findings add an additional layer of complexity to the interpretation, and potentially, to the predictive utility of the SIV/macaque model, and highlight the unique features of human and simian lentiviral evolution that inform studies of pathogenesis and strategies for AIDS vaccine design.
  Journal of Virology 10/2012; · 5.40 Impact Factor
• Article: Nonhuman Primate Models for HIV Cure Research.

  Cristian Apetrei, Ivona Pandrea, John W Mellors
  PLoS Pathogens 08/2012; 8(8):e1002892. · 9.13 Impact Factor
• Article: Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates.

  Ivona Pandrea, Elaine Cornell, Cara Wilson, Ruy M Ribeiro, Dongzhu Ma, Jan Kristoff, Cuiling Xu, George S Haret-Richter, Anita Trichel, Cristian Apetrei, Alan Landay, Russell Tracy
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  ABSTRACT: HIV infection is associated with increased risk of cardiovascular complications, the underlying mechanism of which remains unclear. Plasma levels of the coagulation biomarker D-dimer (DD) correlate with increased mortality and cardiovascular events in HIV-infected patients. We compared the incidence of cardiovascular lesions and the levels of the coagulation markers DD and thrombin antithrombin in pathogenic SIV infections of rhesus and pigtailed macaques (PTMs) and in nonpathogenic SIV infection of African green monkeys (AGMs) and sooty mangabeys. Hypercoagulability and cardiovascular pathology were only observed in pathogenic SIV infections. In PTMs infected with SIV from AGMs (SIVagm), DD levels were highly indicative of AIDS progression and increased mortality and were associated with cardiovascular lesions, pointing to SIVagm-infected PTMs as an ideal animal model for the study of HIV-associated cardiovascular disease. In pathogenic SIV infection, DD increased early after infection, was strongly correlated with markers of immune activation/inflammation and microbial translocation (MT), and was only peripherally associated with viral loads. Endotoxin administration to SIVagm-infected AGMs (which lack chronic SIV-induced MT and immune activation) resulted in significant increases of DD. Our results demonstrate that hypercoagulation and cardiovascular pathology are at least in part a consequence of excessive immune activation and MT in SIV infection.
  Blood 05/2012; 120(7):1357-66. · 9.90 Impact Factor
• Article: Mucosal simian immunodeficiency virus transmission in African green monkeys: susceptibility to infection is proportional to target cell availability at mucosal sites.

  Ivona Pandrea, Nicholas F Parrish, Kevin Raehtz, Thaidra Gaufin, Hannah J Barbian, Dongzhu Ma, Jan Kristoff, Rajeev Gautam, Fang Zhong, George S Haret-Richter, Anita Trichel, George M Shaw, Beatrice H Hahn, Cristian Apetrei
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  ABSTRACT: African green monkeys (AGMs) are naturally infected with a simian immunodeficiency virus (SIVagm) that is nonpathogenic in its host. Although SIVagm is common and widespread, little is known about the mechanisms that govern its transmission. Since the earliest virus-host interactions may provide key insights into the nonpathogenic phenotype of SIVagm, we developed a mucosal transmission model for this virus. Using plasma from an acutely infected AGM as the virus inoculum, we exposed adult and juvenile AGMs, as well as pigtailed macaques (PTMs) as a nonnatural host control, by mucosal routes to increasing titers of virus and compared the doses needed to establish a productive infection. Four juvenile and four adult AGMs as well as two PTMs were intrarectally (IR) exposed, while two additional adult female AGMs were intravaginally (IVAG) exposed. No animal became infected following exposure to 10(5) RNA copies. Both PTMs but none of the AGMs became infected following exposure to 10(6) RNA copies. Finally, all adult AGMs and two of the four juvenile AGMs became infected following exposure to 10(7) RNA copies, acquiring either one (2 IR infected juveniles, 1 IR infected adult, 2 IVAG infected adults) or two (3 IR infected adults) transmitted founder viruses. These results were consistent with immunophenotypic data, which revealed a significant correlation between the percentage of CD4(+) T cells expressing CCR5 in the mucosa and the susceptibility to infection, in terms of both the viral dose and the numbers of transmitted founder viruses. Moreover, studies of uninfected AGMs showed that the fraction of CCR5-expressing CD4(+) T cells increased significantly with age. These results indicate that (i) AGMs are readily infected with SIVagm by both intrarectal and intravaginal routes, (ii) susceptibility to infection is proportional to the number of available CCR5(+) CD4(+) target cells in the mucosa, and (iii) the paucity of CCR5(+) CD4(+) target cells in infant and juvenile AGMs may explain the near absence of vertical transmission.
  Journal of Virology 02/2012; 86(8):4158-68. · 5.40 Impact Factor
• 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: Immunovirological analyses of chronically simian immunodeficiency virus SIVmnd-1- and SIVmnd-2-infected mandrills (Mandrillus sphinx).

  Cristian Apetrei, Beth Sumpter, Sandrine Souquiere, Ann Chahroudi, Maria Makuwa, Patricia Reed, Ruy M Ribeiro, Ivona Pandrea, Pierre Roques, Guido Silvestri
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  ABSTRACT: Simian immunodeficiency virus (SIV) infection in African nonhuman primate (NHP) natural hosts is usually nonpathogenic, despite high levels of virus replication. We have previously shown that chronic SIV infection in sooty mangabeys (SMs) and African green monkeys (AGMs) is associated with low levels of immune activation and bystander T cell apoptosis. To compare these features with those observed in another natural host, the mandrill (MND), we conducted a cross-sectional survey of the 23 SIV-infected and 25 uninfected MNDs from the only semifree colony of mandrills available worldwide. Viral loads (VLs) were determined and phenotypic and functional analysis of peripheral blood- and lymph node-derived lymphocytes was performed. We found that mandrills chronically infected with SIVmnd-1 or SIVmnd-2 have similar levels of viral replication, and we observed a trend toward lower CD4+ T cell counts in chronically SIVmnd-2-infected MNDs than SIVmnd-1-infected MNDs. No correlation between CD4+ T cell counts and VLs in SIV-infected MNDs could be established. Of note, the levels of T cell activation, proliferation, and apoptosis were comparable between SIVmnd-1- and SIVmnd-2-infected MNDs and to those observed in uninfected animals, with the only exception being an increase in tumor necrosis factor alpha-producing CD8+ T cells in SIVmnd-2-infected MNDs. Overall, these findings recapitulate previous observations in SIV-infected SMs and AGMs and lend further evidence to the hypothesis that low levels of immune activation protect natural SIV hosts from disease progression.
  Journal of Virology 09/2011; 85(24):13077-87. · 5.40 Impact Factor
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  Available from: PubMed Central

  Article: Functional cure of SIVagm infection in rhesus macaques results in complete recovery of CD4+ T cells and is reverted by CD8+ cell depletion.

  Ivona Pandrea, Thaidra Gaufin, Rajeev Gautam, Jan Kristoff, Daniel Mandell, David Montefiori, Brandon F Keele, Ruy M Ribeiro, Ronald S Veazey, Cristian Apetrei
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  ABSTRACT: Understanding the mechanism of infection control in elite controllers (EC) may shed light on the correlates of control of disease progression in HIV infection. However, limitations have prevented a clear understanding of the mechanisms of elite controlled infection, as these studies can only be performed at randomly selected late time points in infection, after control is achieved, and the access to tissues is limited. We report that SIVagm infection is elite-controlled in rhesus macaques (RMs) and therefore can be used as an animal model for EC HIV infection. A robust acute infection, with high levels of viral replication and dramatic mucosal CD4(+) T cell depletion, similar to pathogenic HIV-1/SIV infections of humans and RMs, was followed by complete and durable control of SIVagm replication, defined as: undetectable VLs in blood and tissues beginning 72 to 90 days postinoculation (pi) and continuing at least 4 years; seroreversion; progressive recovery of mucosal CD4(+) T cells, with complete recovery by 4 years pi; normal levels of T cell immune activation, proliferation, and apoptosis; and no disease progression. This "functional cure" of SIVagm infection in RMs could be reverted after 4 years of control of infection by depleting CD8 cells, which resulted in transient rebounds of VLs, thus suggesting that control may be at least in part immune mediated. Viral control was independent of MHC, partial APOBEC restriction was not involved in SIVagm control in RMs and Trim5 genotypes did not impact viral replication. This new animal model of EC lentiviral infection, in which complete control can be predicted in all cases, permits research on the early events of infection in blood and tissues, before the defining characteristics of EC are evident and when host factors are actively driving the infection towards the EC status.
  PLoS Pathogens 08/2011; 7(8):e1002170. · 9.13 Impact Factor
• Article: CD4-like immunological function by CD4- T cells in multiple natural hosts of simian immunodeficiency virus.

  Carol Vinton, Nichole R Klatt, Levelle D Harris, Judith A Briant, Brigitte E Sanders-Beer, Richard Herbert, Ruth Woodward, Guido Silvestri, Ivona Pandrea, Cristian Apetrei, Vanessa M Hirsch, Jason M Brenchley
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  ABSTRACT: Many species of African nonhuman primates are natural hosts for individual strains of simian immunodeficiency virus (SIV). These infected animals do not, however, develop AIDS. Here we show that multiple species of African nonhuman primate species characteristically have low frequencies of CD4(+) T cells and high frequencies of both T cells that express only the alpha-chain of CD8 and double-negative T cells. These subsets of T cells are capable of eliciting functions generally associated with CD4(+) T cells, yet these cells lack surface expression of the CD4 protein and are, therefore, poor targets for SIV in vivo. These data demonstrate that coevolution with SIV has, in several cases, involved downregulation of receptors for the virus by otherwise-susceptible host target cells. Understanding the genetic factors that lead to downregulation of these receptors may lead to therapeutic interventions that mimic this modulation in progressive infections.
  Journal of Virology 06/2011; 85(17):8702-8. · 5.40 Impact Factor
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  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
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  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
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  Available from: Meredith Hunter

  Article: Vesicular stomatitis virus-simian retrovirus type 2 vaccine protects macaques from detectable infection and B-cell destruction.

  Rajeev Gautam, Arun Iyer, Meredith Hunter, Arpita Das, Tessa Williams, Jason Dufour, Cristian Apetrei, K Gus Kousoulas, Preston A Marx
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  ABSTRACT: Natural infection with simian retrovirus (SRV) has long been recognized in rhesus macaques (RMs) and may result in an AIDS-like disease. Importantly, SRV infections persist as a problem in recently imported macaques. Therefore, there is a clear need to control SRV spread in macaque colonies. We developed a recombinant vesicular stomatitis virus (VSV)-SRV vaccine consisting of replication-competent hybrid VSVs that express SRV gag and env in separate vectors. The goal of this study was to assess the immunogenicity and protective efficacy of the VSV-SRV serotype 2 vaccine prime-boost approach in RMs. The VSV-SRV vector (expressing either SRV gag or env) vaccines were intranasally administered in 4 RMs, followed by a boost 1 month after the first vaccination. Four RMs served as controls and received the VSV vector alone. Two months after the boost, all animals were intravenously challenged with SRV-2 and monitored for 90 days. After the SRV-2 challenge, all four controls became infected, and viral loads (VLs) ranged from 10(6) to 10(8) SRV RNA copies/ml of plasma. Two animals in the control group developed simian AIDS within 7 to 8 weeks postinfection and were euthanized. Anemia and weight loss were observed in the remaining controls. During acute infection, severe B-cell depletion and no significant changes in T-cell population were observed in the control group. Control RMs with greater preservation of B cells and lower VLs survived longer. SRV-2 was undetectable in vaccinated animals, which remained healthy, with no clinical or biological signs of infection and preservation of B cells. Our study showed that the VSV-SRV vaccine is a strong approach for preventing clinically relevant type D retrovirus infection and disease in RMs, with protection of 4/4 RMs from SRV infection and prevention of B-cell destruction. B-cell protection was the strongest correlate of the long-term survival of all vaccinated and control RMs.
  Journal of Virology 06/2011; 85(12):5889-96. · 5.40 Impact Factor
• Article: Pattern of SIVagm infection in patas monkeys suggests that host adaptation to simian immunodeficiency virus infection may result in resistance to infection and virus extinction.

  Cristian Apetrei, Thaidra Gaufin, Rajeev Gautam, Carol Vinton, Vanessa Hirsch, Mark Lewis, Jason Brenchley, Ivona Pandrea
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  ABSTRACT: Patas monkeys were not reported to carry species‐specific simian immunodeficiency virus (SIV), but cross‐species transmission of SIVagm to patas monkeys occurred in the wild. We report that patas monkeys share immunophenotypic features with natural hosts of SIV; that is, low levels of CD4+ T cells and low CCR5 expression on CD4+ T cells. In 1 patas monkey with undetectable levels of CD4+ T cells, experimental exposure to SIVagm did not result in infection. The other experimentally infected patas monkeys showed an infection pattern similar to SIV infection in natural hosts. Thus, down‐regulation of CD4 and CCR5 expression on CD4+ T cells may effectively control human immunodeficiency virus acquisition and result in SIV extinction.
  The Journal of Infectious Diseases 11/2010; 202 Suppl 3:S371-6. · 6.41 Impact Factor
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  Available from: Pierre Roques

  Article: Island biogeography reveals the deep history of SIV.

  Michael Worobey, Paul Telfer, Sandrine Souquière, Meredith Hunter, Clint A Coleman, Michael J Metzger, Patricia Reed, Maria Makuwa, Gail Hearn, Shaya Honarvar, Pierre Roques, Cristian Apetrei, Mirdad Kazanji, Preston A Marx
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  ABSTRACT: Simian immunodeficiency virus (SIV) lineages have been identified that are endemic to Bioko Island. The time the island formed offers a geological time scale calibration point for dating the most recent common ancestor of SIV. The Bioko viruses cover the whole range of SIV genetic diversity, and each Bioko SIV clade is most closely related to viruses circulating in hosts of the same genus on the African mainland rather than to SIVs of other Bioko species. Our phylogeographic approach establishes that SIV is ancient and at least 32,000 years old. Our conservative calibration point and analyses of gene sequence saturation and dating bias suggest it may be much older.
  Science 09/2010; 329(5998):1487. · 31.20 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
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  Available from: PubMed Central

  Article: Where the wild things are: pathogenesis of SIV infection in African nonhuman primate hosts.

  Ivona Pandrea, Cristian Apetrei
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  ABSTRACT: African nonhuman primates that are natural hosts of simian immunodeficiency virus (SIV) are generally spared from disease progression. Pathogenic and nonpathogenic SIV infections share some major features: high viral replication, massive acute depletion of mucosal CD4(+) T cells, and partial control of the virus by both adaptive and innate immune responses. A key distinction of natural SIV infections is rapid and active control of immune activation and apoptosis of T cells that contributes to the integrity of mucosal barrier and lack of microbial translocation. This allows partial recovery of CD4(+) T cells and preservation of the function of other immune cell subsets. A better understanding of the mechanisms underlying the lack of disease in natural hosts for SIV infection will likely provide important clues as to the therapy of HIV-1 infection.
  Current HIV/AIDS Reports 02/2010; 7(1):28-36.
• Article: Experimental depletion of CD8⁺cells in acutely SIVagm-Infected African Green Monkeys results in increased viral replication

  Thaidra Gaufin, Ruy Ribeiro, Rajeev Gautam, Jason Dufour, Daniel Mandell, Cristian Apetrei, Ivona Pandrea
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  ABSTRACT: Abstract Background In vivo CD8⁺cell depletions in pathogenic SIV infections identified a key role for cellular immunity in controlling viral load (VL) and disease progression. However, similar studies gave discordant results in chronically-infected SMs, leading some authors to propose that in natural hosts, SIV replication is independent of cellular immunity. To assess the role of cellular immune responses in the control of SIV replication in natural hosts, we investigated the impact of CD8⁺cell depletion during acute SIV infection in AGMs. Results Nine AGMs were infected with SIVagm.sab and were followed up to day 225 p.i. Four were intravenously infused with the cM-T807 antibody on days 0 (50 mg/kg), 6, and 13 (10 mg/kg, respectively) post infection (p.i.). CD8⁺cells were depleted for up to 28 days p.i. in peripheral blood and LNs in all treated AGMs. Partial CD8⁺T cell depletion occurred in the intestine. SIVagm VLs peaked at similar levels in both groups (10⁷-10⁸RNA copies/ml). However, while VLs were controlled in undepleted AGMs, reaching set-point levels (10⁴-10⁵RNA copies/ml) by day 28 p.i., high VLs (>10⁶RNA copies/ml) were maintained by day 21 p.i. in CD8-depleted AGMs. By day 42 p.i., VLs were comparable between the two groups. The levels of immune activation and proliferation remained elevated up to day 72 p.i. in CD8-depleted AGMs and returned to preinfection levels in controls by day 28 p.i. None of the CD8-depleted animals progressed to AIDS. Conclusion CD8⁺cells are responsible for a partial control of postacute viral replication in SIVagm.sab-infected AGMs. In contrast to macaques, the SIVagm-infected AGMs are able to control viral replication after recovery of the CD8⁺T cells and avoid disease progression.
  Retrovirology. 01/2010;
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  Available from: PubMed Central

  Article: Experimental depletion of CD8+ cells in acutely SIVagm-infected African Green Monkeys results in increased viral replication.

  Thaidra Gaufin, Ruy M Ribeiro, Rajeev Gautam, Jason Dufour, Daniel Mandell, Cristian Apetrei, Ivona Pandrea
  [show abstract] [hide abstract]
  ABSTRACT: In vivo CD8+ cell depletions in pathogenic SIV infections identified a key role for cellular immunity in controlling viral load (VL) and disease progression. However, similar studies gave discordant results in chronically-infected SMs, leading some authors to propose that in natural hosts, SIV replication is independent of cellular immunity. To assess the role of cellular immune responses in the control of SIV replication in natural hosts, we investigated the impact of CD8+ cell depletion during acute SIV infection in AGMs. Nine AGMs were infected with SIVagm.sab and were followed up to day 225 p.i. Four were intravenously infused with the cM-T807 antibody on days 0 (50 mg/kg), 6, and 13 (10 mg/kg, respectively) post infection (p.i.). CD8+ cells were depleted for up to 28 days p.i. in peripheral blood and LNs in all treated AGMs. Partial CD8+ T cell depletion occurred in the intestine. SIVagm VLs peaked at similar levels in both groups (107-108 RNA copies/ml). However, while VLs were controlled in undepleted AGMs, reaching set-point levels (104-105 RNA copies/ml) by day 28 p.i., high VLs (>106 RNA copies/ml) were maintained by day 21 p.i. in CD8-depleted AGMs. By day 42 p.i., VLs were comparable between the two groups. The levels of immune activation and proliferation remained elevated up to day 72 p.i. in CD8-depleted AGMs and returned to preinfection levels in controls by day 28 p.i. None of the CD8-depleted animals progressed to AIDS. CD8+ cells are responsible for a partial control of postacute viral replication in SIVagm.sab-infected AGMs. In contrast to macaques, the SIVagm-infected AGMs are able to control viral replication after recovery of the CD8+ T cells and avoid disease progression.
  Retrovirology 01/2010; 7:42. · 6.47 Impact Factor
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  Available from: Jessica C Engram

  Article: A novel CCR5 mutation common in sooty mangabeys reveals SIVsmm infection of CCR5-null natural hosts and efficient alternative coreceptor use in vivo.

  Nadeene E Riddick, Emilia A Hermann, Lamorris M Loftin, Sarah T Elliott, Winston C Wey, Barbara Cervasi, Jessica Taaffe, Jessica C Engram, Bing Li, James G Else, Yingying Li, Beatrice H Hahn, Cynthia A Derdeyn, Donald L Sodora, Cristian Apetrei, Mirko Paiardini, Guido Silvestri, Ronald G Collman
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  ABSTRACT: In contrast to HIV infection in humans and SIV in macaques, SIV infection of natural hosts including sooty mangabeys (SM) is non-pathogenic despite robust virus replication. We identified a novel SM CCR5 allele containing a two base pair deletion (Δ2) encoding a truncated molecule that is not expressed on the cell surface and does not support SIV entry in vitro. The allele was present at a 26% frequency in a large SM colony, along with 3% for a CCR5Δ24 deletion allele that also abrogates surface expression. Overall, 8% of animals were homozygous for defective CCR5 alleles and 41% were heterozygous. The mutant allele was also present in wild SM in West Africa. CD8+ and CD4+ T cells displayed a gradient of CCR5 expression across genotype groups, which was highly significant for CD8+ cells. Remarkably, the prevalence of natural SIVsmm infection was not significantly different in animals lacking functional CCR5 compared to heterozygous and homozygous wild-type animals. Furthermore, animals lacking functional CCR5 had robust plasma viral loads, which were only modestly lower than wild-type animals. SIVsmm primary isolates infected both homozygous mutant and wild-type PBMC in a CCR5-independent manner in vitro, and Envs from both CCR5-null and wild-type infected animals used CXCR6, GPR15 and GPR1 in addition to CCR5 in transfected cells. These data clearly indicate that SIVsmm relies on CCR5-independent entry pathways in SM that are homozygous for defective CCR5 alleles and, while the extent of alternative coreceptor use in SM with CCR5 wild type alleles is uncertain, strongly suggest that SIVsmm tropism and host cell targeting in vivo is defined by the distribution and use of alternative entry pathways in addition to CCR5. SIVsmm entry through alternative pathways in vivo raises the possibility of novel CCR5-negative target cells that may be more expendable than CCR5+ cells and enable the virus to replicate efficiently without causing disease in the face of extremely restricted CCR5 expression seen in SM and several other natural host species.
  PLoS Pathogens 01/2010; 6(8):e1001064. · 9.13 Impact Factor
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  Available from: Jessica C Engram

  Article: CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells.

  Nichole R Klatt, Emi Shudo, Alex M Ortiz, Jessica C Engram, Mirko Paiardini, Benton Lawson, Michael D Miller, James Else, Ivona Pandrea, Jacob D Estes, Cristian Apetrei, Joern E Schmitz, Ruy M Ribeiro, Alan S Perelson, Guido Silvestri
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  ABSTRACT: While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV) and late (day 177 post-SIV) chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.
  PLoS Pathogens 01/2010; 6(1):e1000747. · 9.13 Impact Factor
• Article: Effect of B-cell depletion on viral replication and clinical outcome of simian immunodeficiency virus infection in a natural host.

  Thaidra Gaufin, Melissa Pattison, Rajeev Gautam, Crystal Stoulig, Jason Dufour, Jeanne MacFarland, Daniel Mandell, Coty Tatum, Matthew H Marx, Ruy M Ribeiro, David Montefiori, Cristian Apetrei, Ivona Pandrea
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  ABSTRACT: Simian immunodeficiency virus (SIV)-infected African nonhuman primates do not progress to AIDS in spite of high and persistent viral loads (VLs). Some authors consider the high viral replication observed in chronic natural SIV infections to be due to lower anti-SIV antibody titers than those in rhesus macaques, suggesting a role of antibodies in controlling viral replication. We therefore investigated the impact of antibody responses on the outcome of acute and chronic SIVagm replication in African green monkeys (AGMs). Nine AGMs were infected with SIVagm.sab. Four AGMs were infused with 50 mg/kg of body weight anti-CD20 (rituximab; a gift from Genentech) every 21 days, starting from day -7 postinfection up to 184 days. The remaining AGMs were used as controls and received SIVagm only. Rituximab-treated AGMs were successfully depleted of CD20 cells in peripheral blood, lymph nodes (LNs), and intestine, as shown by the dynamics of CD20+ and CD79a+ cells. There was no significant difference in VLs between CD20-depleted AGMs and control monkeys: peak VLs ranged from 10(7) to 10(8) copies/ml; set-point values were 10(4) to 10(5) SIV RNA copies/ml. Levels of acute mucosal CD4+ T-cell depletion were similar for treated and nontreated animals. SIVagm seroconversion was delayed for the CD20-depleted AGMs compared to results for the controls. There was a significant difference in both the timing and magnitude of neutralizing antibody responses for CD20-depleted AGMs compared to results for controls. CD20 depletion significantly altered the histological structure of the germinal centers in the LNs and Peyer's patches. Our results, although obtained with a limited number of animals, suggest that humoral immune responses play only a minor role in the control of SIV viral replication during acute and chronic SIV infection in natural hosts.
  Journal of Virology 09/2009; 83(20):10347-57. · 5.40 Impact Factor