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Guido Silvestri - One of the best experts on this subject based on the ideXlab platform.
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dualtropic cxcr6 ccr5 simian immunodeficiency virus siv infection of Sooty Mangabey primary lymphocytes distinct coreceptor use in natural versus pathogenic hosts of siv
Journal of Virology, 2015Co-Authors: Sarah Tc Elliott, Thomas H. Vanderford, Nicholas Francella, Katherine S. Wetzel, Steven Bryan, Dino C. Romero, Nadeene E. Riddick, Farida Shaheen, Cynthia A. Derdeyn, Guido SilvestriAbstract:ABSTRACT Natural-host Sooty Mangabeys (SM) infected with simian immunodeficiency virus (SIV) exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4 + T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which have been linked to low expression of the canonical SIV entry receptor CCR5 on CD4 + T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by SIV in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIV smm in vitro . Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIV infection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4 + T cell subset targeting compared with that in nonnatural hosts, enabling SIV to maintain high-level replication without leading to widespread CD4 + T cell loss. IMPORTANCE Natural hosts of SIV, such as Sooty Mangabeys, sustain high viral loads but do not develop disease, while nonnatural hosts, like rhesus macaques, develop AIDS. Understanding this difference may help elucidate mechanisms of pathogenesis. Natural hosts have very low levels of the SIV entry coreceptor CCR5, suggesting that restricted entry may limit infection of certain target cells, although it is unclear how the virus replicates so robustly. Here we show that in Sooty Mangabey lymphocytes, infection is mediated by the alternative entry coreceptor CXCR6, as well as CCR5. In rhesus macaque lymphocytes, however, infection occurs entirely through CCR5. The use of CXCR6 for entry, combined with very low CCR5 levels, may redirect the virus to different cell targets in natural hosts. It is possible that differential targeting may favor infection of nonessential cells and limit infection of critical cells in natural hosts, thus contributing to benign outcome of infection.
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Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV
Journal of virology, 2015Co-Authors: Sarah Tc Elliott, Thomas H. Vanderford, Nicholas Francella, Katherine S. Wetzel, Steven Bryan, Dino C. Romero, Nadeene E. Riddick, Farida Shaheen, Cynthia A. Derdeyn, Guido SilvestriAbstract:ABSTRACT Natural-host Sooty Mangabeys (SM) infected with simian immunodeficiency virus (SIV) exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4 + T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which have been linked to low expression of the canonical SIV entry receptor CCR5 on CD4 + T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by SIV in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIV smm in vitro . Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIV infection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4 + T cell subset targeting compared with that in nonnatural hosts, enabling SIV to maintain high-level replication without leading to widespread CD4 + T cell loss. IMPORTANCE Natural hosts of SIV, such as Sooty Mangabeys, sustain high viral loads but do not develop disease, while nonnatural hosts, like rhesus macaques, develop AIDS. Understanding this difference may help elucidate mechanisms of pathogenesis. Natural hosts have very low levels of the SIV entry coreceptor CCR5, suggesting that restricted entry may limit infection of certain target cells, although it is unclear how the virus replicates so robustly. Here we show that in Sooty Mangabey lymphocytes, infection is mediated by the alternative entry coreceptor CXCR6, as well as CCR5. In rhesus macaque lymphocytes, however, infection occurs entirely through CCR5. The use of CXCR6 for entry, combined with very low CCR5 levels, may redirect the virus to different cell targets in natural hosts. It is possible that differential targeting may favor infection of nonessential cells and limit infection of critical cells in natural hosts, thus contributing to benign outcome of infection.
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Double negative (CD3+CD4−CD8−) T cells from Sooty Mangabeys are predominantly effector memory cells.
2013Co-Authors: Vasudha Sundaravaradan, Mirko Paiardini, Guido Silvestri, Luca Micci, Alexandra M Ortiz, Ramsey Saleem, Melanie A. Gasper, James Else, John D. Aitchison, Donald L. SodoraAbstract:(A) Phenotypic assessment of T cell subsets (CD3+) depicting DN T cells (CD4−CD8− in the lower left quadrant) in Sooty Mangabey PBMC. Further assessment of naïve (CD95−) and memory DN subsets were performed based on CD95 and CD28 expression. Characterization of central memory (CM: CD95+CD62L+) and effector memory (EM: CD95+CD62L−) DN T cells are depicted. (B) DN T cells from uninfected Mangabeys (open symbols) and SIV-infected Mangabeys (filled symbols) were evaluated as Naïve, memory, CM and EM subsets and the relative percentage of each is depicted. DN T cells in the PBMCs are primarily memory cells (CD95+) with a predominant effector memory phenotype.
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Nonpathogenic Simian Immunodeficiency Virus Infections
Cold Spring Harbor Perspectives in Medicine, 2011Co-Authors: Nichole R. Klatt, Guido Silvestri, Vanessa M. HirschAbstract:The simian immunodeficiency viruses (SIVs) are a diverse group of viruses that naturally infect a wide range of African primates, including African green monkeys (AGMs) and Sooty Mangabey monkeys (SMs). Although natural infection is widespread in feral populations of AGMs and SMs, this infection generally does not result in immunodeficiency. However, experimental inoculation of Asian macaques results in an immunodeficiency syndrome remarkably similar to human AIDS. Thus, natural nonprogressive SIV infections appear to represent an evolutionary adaptation between these animals and their primate lentiviruses. Curiously, these animals maintain robust virus replication but have evolved strategies to avoid disease progression. Adaptations observed in these primates include phenotypic changes to CD4+ T cells, limited chronic immune activation, and altered mucosal immunity. It is probable that these animals have achieved a unique balance between T-cell renewal and proliferation and loss through activation-induced apoptosis, and virus-induced cell death. A clearer understanding of the mechanisms underlying the lack of disease progression in natural hosts for SIV infection should therefore yield insights into the pathogenesis of AIDS and may inform vaccine design.
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divergent host responses during primary simian immunodeficiency virus sivsm infection of natural Sooty Mangabey and nonnatural rhesus macaque hosts
Journal of Virology, 2005Co-Authors: Guido Silvestri, Harold M. Mcclure, Andrew Fedanov, Stephanie Germon, Natalia Kozyr, William J Kaiser, David A Garber, Mark B Feinberg, Silvija I StapransAbstract:To understand how natural Sooty Mangabey hosts avoid AIDS despite high levels of simian immunodeficiency virus (SIV) SIVsm replication, we inoculated Mangabeys and nonnatural rhesus macaque hosts with an identical inoculum of uncloned SIVsm. The unpassaged virus established infection with high-level viral replication in both macaques and Mangabeys. A species-specific, divergent immune response to SIV was evident from the first days of infection and maintained in the chronic phase, with macaques showing immediate and persistent T-cell proliferation, whereas Mangabeys displayed little T-cell proliferation, suggesting subdued cellular immune responses to SIV. Importantly, only macaques developed (CD4+)-T-cell depletion and AIDS, thus indicating that in Mangabeys limited immune activation is a key mechanism to avoid immunodeficiency despite high levels of SIVsm replication. These studies demonstrate that it is the host response to infection, rather than properties inherent to the virus itself, that causes immunodeficiency in SIV-infected nonhuman primates.
Amitinder Kaur - One of the best experts on this subject based on the ideXlab platform.
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Acute SIV infection in Sooty Mangabey monkeys is characterized by rapid virus clearance from lymph nodes and absence of productive infection in germinal centers.
PloS one, 2013Co-Authors: Amanda J. Martinot, Amitinder Kaur, Daniel C. Anderson, Mareike Meythaler, Lu-ann Pozzi, Karen Boisvert, Heather Knight, D. G. Walsh, Susan V. Westmoreland, Shawn P. O'neilAbstract:Lymphoid tissue immunopathology is a characteristic feature of chronic HIV/SIV infection in AIDS-susceptible species, but is absent in SIV-infected natural hosts. To investigate factors contributing to this difference, we compared germinal center development and SIV RNA distribution in peripheral lymph nodes during primary SIV infection of the natural host Sooty Mangabey and the non-natural host pig-tailed macaque. Although SIV-infected cells were detected in the lymph node of both species at two weeks post infection, they were confined to the lymph node paracortex in immune-competent Mangabeys but were seen in both the paracortex and the germinal center of SIV-infected macaques. By six weeks post infection, SIV-infected cells were no longer detected in the lymph node of Sooty Mangabeys. The difference in localization and rate of disappearance of SIV-infected cells between the two species was associated with trapping of cell-free virus on follicular dendritic cells and higher numbers of germinal center CD4+ T lymphocytes in macaques post SIV infection. Our data suggests that fundamental differences in the germinal center microenvironment prevent productive SIV infection within the lymph node germinal centers of natural hosts contributing to sustained immune competency.
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Phenotypic characterization of Sooty Mangabey NKT clones.
2013Co-Authors: Namita Rout, James G. Else, Simon Yue, Michelle Connole, Mark A. Exley, Amitinder KaurAbstract:A) Histogram plots gated on representative NKT clones showing surface expression of NK cell markers (CD16, CD56, NKG2D, and CD161), chemokine receptors (CCR5 and CXCR3), and memory markers (CD95, CD28, and CD45RA), and intracellular expression of cytolytic molecules (granzyme B and perforin). B) Mean % for each phenotypic marker on 5 to 71 NKT clones. Error bars denote standard error of mean (SEM). C) Memory phenotype of NKT lymphocytes in comparison to CD8+ and DN T lymphocytes in the peripheral blood of one SIV-negative Sooty Mangabey. Dot plots showing CD95 vs CD28 staining on each subset of T lymphocytes (top panel) and distribution of CCR7 and CD28 on the CD95+ memory lymphocytes (bottom panel).
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T lymphocyte subset distribution of Sooty Mangabey NKT lymphocytes.
2013Co-Authors: Namita Rout, James G. Else, Simon Yue, Michelle Connole, Mark A. Exley, Amitinder KaurAbstract:A) Representative contour plots showing surface expression of CD4 and CD8 molecules on ex vivo circulating T and Vα24+CD1d TM+ NKT lymphocytes in two Sooty Mangabeys (SM #1 and SM #2). B) Contour plots showing surface expression pattern of CD4 and CD8 molecules on representative NKT clones. C) Distribution of CD4+ (CD4+8−), CD8+ (CD8+4−), DN (CD4−8−) and DP (CD4+8+) T lymphocyte subsets in ex vivo NKT lymphocytes in 13 SIV-negative Sooty Mangabeys (left panel) and in 57 NKT clones derived from sorted 6B11+ T lymphocytes of one SIV-negative Sooty Mangabey (right panel).
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Identification of NKT lymphocytes in the peripheral blood of Sooty Mangabeys.
2013Co-Authors: Namita Rout, James G. Else, Simon Yue, Michelle Connole, Mark A. Exley, Amitinder KaurAbstract:A) Representative dot plots showing gating strategy for identification of NKT lymphocytes. On the CD3+ T lymphocyte population, the co-staining for Vα24 and CD1d tetramers loaded with PBS-57 (CD1d TM) and 6B11 are shown in the bottom panel. Unloaded tetramers (shown in the left of bottom panel) served as a control for non-specific staining. B) Representative dot plots of sorted NKT clones in one SIV-negative Sooty Mangabey stained with anti-Vα24 and CD1d TM or 6B11 antibody. C) Frequency of peripheral blood NKT lymphocytes in 50 SIV-negative Sooty Mangabeys. Horizontal bar denotes mean. The background staining with unloaded CD1d TM for one animal (which was above 0.002%) and the corresponding Vα24+CD1d TM+ frequency are shown in red. D) Positive correlation between the frequency of Vα24+CD1d TM+ T lymphocytes and Vα24+6B11+ T lymphocytes in the peripheral blood of 50 SIV-negative Sooty Mangabeys.
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Comparison of NKT lymphocytes in AIDS-susceptible and AIDS-resistant nonhuman primate species.
2013Co-Authors: Namita Rout, James G. Else, Simon Yue, Mark A. Exley, Justin Greene, David O'connor, Paul R. Johnson, Amitinder KaurAbstract:A) Dot-plots of ex vivo peripheral blood NKT lymphocytes in one SIV-negative Sooty Mangabey (SM), rhesus macaque (RM) and cynomolgus macaque (CM). Gated CD3+ T lymphocytes co-staining for Vα24 and CD1d tetramers loaded with PBS-57 were used to identify NKT lymphocytes (top panel). Co-staining for Vα24 and unloaded CD1d tetramers served as a negative control (bottom panel). B) Frequency of peripheral blood NKT lymphocytes in SIV-negative SM (n = 50), RM (n = 48) and CM (n = 15). Dotted line at 0.002% denotes the cut-off for the lower limit of flow cytometric detection of NKT lymphocytes. C) Representative contour plots of CD4 and CD8 surface expression on NKT lymphocytes in SM, RM and CM. D) Frequencies of NKT subsets with CD4+CD8− (CD4 SP), CD8+CD4− (CD8 SP), CD4+CD8+ (CD4/8 DP), and CD4−CD8− (CD4/8 DN) phenotype in SIV-negative SM (n = 12), RM (n = 15), and CM (n = 15). * P
Preston A. Marx - One of the best experts on this subject based on the ideXlab platform.
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A Divergent Simian Immunodeficiency Virus from Sooty Mangabey with an Atypical Tat–TAR Structure
AIDS research and human retroviruses, 2001Co-Authors: Lisa A. Chakrabarti, Amara Luckay, Preston A. MarxAbstract:SIVsm, the simian immunodeficiency virus that naturally infects Sooty Mangabeys in West Africa, is the closest lentiviral relative of human immunodeficiency virus type 2 (HIV-2). To determine the genetic characteristics of SIVsm in its natural host, we sequenced the full-length genome of SIVsmSL92b, a primary isolate obtained from a pet Sooty Mangabey in Sierra Leone. SIVsmSL92b proved to be the most divergent member of the HIV-2/SIVsm lineage found thus far, having as much as 35% nucleotide divergence from other HIV-2 genomes. A phylogenetic association between SIVsmSL92b and HIV-2 PA subtype E, which had been previously revealed by the analysis of partial gag sequences, was extended to the pol gene. SIVsmSL92b showed several divergent features, including a short Tat protein of 104 residues and an atypical TAR structure. Specifically, only one of the duplicate TAR elements contained the conserved hexanucleotide loop sequence CUGGGX important for Tat-cyclin T1 binding. These features suggested that the mechanism of SIVsmSL92b Tat and TAR interaction differed from that described for HIV-2. Taken together, these findings indicated that the structural diversity within the HIV-2/SIVsm lineage was greater than previously appreciated.
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a divergent simian immunodeficiency virus from Sooty Mangabey with an atypical tat tar structure
AIDS Research and Human Retroviruses, 2001Co-Authors: Lisa A. Chakrabarti, Amara Luckay, Preston A. MarxAbstract:SIVsm, the simian immunodeficiency virus that naturally infects Sooty Mangabeys in West Africa, is the closest lentiviral relative of human immunodeficiency virus type 2 (HIV-2). To determine the genetic characteristics of SIVsm in its natural host, we sequenced the full-length genome of SIVsmSL92b, a primary isolate obtained from a pet Sooty Mangabey in Sierra Leone. SIVsmSL92b proved to be the most divergent member of the HIV-2/SIVsm lineage found thus far, having as much as 35% nucleotide divergence from other HIV-2 genomes. A phylogenetic association between SIVsmSL92b and HIV-2 PA subtype E, which had been previously revealed by the analysis of partial gag sequences, was extended to the pol gene. SIVsmSL92b showed several divergent features, including a short Tat protein of 104 residues and an atypical TAR structure. Specifically, only one of the duplicate TAR elements contained the conserved hexanucleotide loop sequence CUGGGX important for Tat-cyclin T1 binding. These features suggested that the mechanism of SIVsmSL92b Tat and TAR interaction differed from that described for HIV-2. Taken together, these findings indicated that the structural diversity within the HIV-2/SIVsm lineage was greater than previously appreciated.
Mirko Paiardini - One of the best experts on this subject based on the ideXlab platform.
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Sooty Mangabey genome sequence provides insight into AIDS resistance in a natural SIV host
Nature, 2018Co-Authors: David Palesch, Zachary P Johnson, Beatrice H. Hahn, Steven E. Bosinger, Gregory K. Tharp, Thomas H. Vanderford, Mirko Paiardini, Ann Chahroudi, Frank Kirchhoff, Robert B. NorgrenAbstract:Whole-genome sequencing and comparative genomic analysis of immune-related genes of Cercocebus atys and Macaca mulatta identify candidate genes, such as ICAM2 and TLR4 , that may explain the AIDS resistance of C. atys . Sooty Mangabeys are a primate model for non-pathogenic simian immunodeficiency virus (SIV) infection. Guido Silvestri and colleagues sequenced the genome of a captive Sooty Mangabey from the Yerkes National Primate Research Center in Atlanta, Georgia. They compared this with the genomic sequences of other primates and suggest several candidate genes that may influence differences in SIV pathogenicity across nonhuman primates. The team also analysed genetic variation in the genomes of 10 Sooty Mangabeys from the same centre and the transcriptomes of 14 tissues. This work provides a resource for comparative genomics and studies on SIV pathogenicity. In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, Sooty Mangabeys ( Cercocebus atys ), is non-pathogenic despite high viraemia^ 1 . Here we sequenced and assembled the genome of a captive Sooty Mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C. atys and AIDS-susceptible species, such as humans and macaques, to identify candidates for host genetic factors that influence susceptibility. We identified several immune-related genes in the genome of C. atys that show substantial sequence divergence from macaques or humans. One of these sequence divergences, a C-terminal frameshift in the toll-like receptor-4 ( TLR4 ) gene of C. atys , is associated with a blunted in vitro response to TLR-4 ligands. In addition, we found a major structural change in exons 3–4 of the immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2); expression of this variant leads to reduced cell surface expression of ICAM-2. These data provide a resource for comparative genomic studies of HIV and/or SIV pathogenesis and may help to elucidate the mechanisms by which SIV-infected Sooty Mangabeys avoid AIDS.
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Sooty Mangabey genome sequence provides insight into AIDS resistance in a natural SIV host
Nature, 2018Co-Authors: David Palesch, Zachary P Johnson, Beatrice H. Hahn, Steven E. Bosinger, Gregory K. Tharp, Thomas H. Vanderford, Mirko Paiardini, Ann Chahroudi, Frank Kirchhoff, Robert B. NorgrenAbstract:In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, Sooty Mangabeys (Cercocebus atys), is non-pathogenic despite high viraemia. Here we sequenced and assembled the genome of a captive Sooty Mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C. atys and AIDS-susceptible species, such as humans and macaques, to identify candidates for host genetic factors that influence susceptibility. We identified several immune-related genes in the genome of C. atys that show substantial sequence divergence from macaques or humans. One of these sequence divergences, a C-terminal frameshift in the toll-like receptor-4 (TLR4) gene of C. atys, is associated with a blunted in vitro response to TLR-4 ligands. In addition, we found a major structural change in exons 3-4 of the immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2); expression of this variant leads to reduced cell surface expression of ICAM-2. These data provide a resource for comparative genomic studies of HIV and/or SIV pathogenesis and may help to elucidate the mechanisms by which SIV-infected Sooty Mangabeys avoid AIDS.
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Double negative (CD3+CD4−CD8−) T cells from Sooty Mangabeys are predominantly effector memory cells.
2013Co-Authors: Vasudha Sundaravaradan, Mirko Paiardini, Guido Silvestri, Luca Micci, Alexandra M Ortiz, Ramsey Saleem, Melanie A. Gasper, James Else, John D. Aitchison, Donald L. SodoraAbstract:(A) Phenotypic assessment of T cell subsets (CD3+) depicting DN T cells (CD4−CD8− in the lower left quadrant) in Sooty Mangabey PBMC. Further assessment of naïve (CD95−) and memory DN subsets were performed based on CD95 and CD28 expression. Characterization of central memory (CM: CD95+CD62L+) and effector memory (EM: CD95+CD62L−) DN T cells are depicted. (B) DN T cells from uninfected Mangabeys (open symbols) and SIV-infected Mangabeys (filled symbols) were evaluated as Naïve, memory, CM and EM subsets and the relative percentage of each is depicted. DN T cells in the PBMCs are primarily memory cells (CD95+) with a predominant effector memory phenotype.
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low levels of siv infection in Sooty Mangabey central memory cd4 t cells are associated with limited ccr5 expression
Nature Medicine, 2011Co-Authors: Mirko Paiardini, Ann Chahroudi, Barbara Cervasi, Elane Reyesaviles, Luca Micci, Alexandra M Ortiz, Carol L VintonAbstract: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.
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Low levels of SIV infection in Sooty Mangabey central memory CD4 + T cells are associated with limited CCR5 expression
Nature medicine, 2011Co-Authors: Mirko Paiardini, Steven E. Bosinger, Ann Chahroudi, Barbara Cervasi, Luca Micci, Alexandra M Ortiz, Carol L Vinton, Elane Reyes-aviles, Shari N. Gordon, Nicholas FrancellaAbstract: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.
Beatrice H. Hahn - One of the best experts on this subject based on the ideXlab platform.
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Sooty Mangabey genome sequence provides insight into AIDS resistance in a natural SIV host
Nature, 2018Co-Authors: David Palesch, Zachary P Johnson, Beatrice H. Hahn, Steven E. Bosinger, Gregory K. Tharp, Thomas H. Vanderford, Mirko Paiardini, Ann Chahroudi, Frank Kirchhoff, Robert B. NorgrenAbstract:Whole-genome sequencing and comparative genomic analysis of immune-related genes of Cercocebus atys and Macaca mulatta identify candidate genes, such as ICAM2 and TLR4 , that may explain the AIDS resistance of C. atys . Sooty Mangabeys are a primate model for non-pathogenic simian immunodeficiency virus (SIV) infection. Guido Silvestri and colleagues sequenced the genome of a captive Sooty Mangabey from the Yerkes National Primate Research Center in Atlanta, Georgia. They compared this with the genomic sequences of other primates and suggest several candidate genes that may influence differences in SIV pathogenicity across nonhuman primates. The team also analysed genetic variation in the genomes of 10 Sooty Mangabeys from the same centre and the transcriptomes of 14 tissues. This work provides a resource for comparative genomics and studies on SIV pathogenicity. In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, Sooty Mangabeys ( Cercocebus atys ), is non-pathogenic despite high viraemia^ 1 . Here we sequenced and assembled the genome of a captive Sooty Mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C. atys and AIDS-susceptible species, such as humans and macaques, to identify candidates for host genetic factors that influence susceptibility. We identified several immune-related genes in the genome of C. atys that show substantial sequence divergence from macaques or humans. One of these sequence divergences, a C-terminal frameshift in the toll-like receptor-4 ( TLR4 ) gene of C. atys , is associated with a blunted in vitro response to TLR-4 ligands. In addition, we found a major structural change in exons 3–4 of the immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2); expression of this variant leads to reduced cell surface expression of ICAM-2. These data provide a resource for comparative genomic studies of HIV and/or SIV pathogenesis and may help to elucidate the mechanisms by which SIV-infected Sooty Mangabeys avoid AIDS.
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Sooty Mangabey genome sequence provides insight into AIDS resistance in a natural SIV host
Nature, 2018Co-Authors: David Palesch, Zachary P Johnson, Beatrice H. Hahn, Steven E. Bosinger, Gregory K. Tharp, Thomas H. Vanderford, Mirko Paiardini, Ann Chahroudi, Frank Kirchhoff, Robert B. NorgrenAbstract:In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, Sooty Mangabeys (Cercocebus atys), is non-pathogenic despite high viraemia. Here we sequenced and assembled the genome of a captive Sooty Mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C. atys and AIDS-susceptible species, such as humans and macaques, to identify candidates for host genetic factors that influence susceptibility. We identified several immune-related genes in the genome of C. atys that show substantial sequence divergence from macaques or humans. One of these sequence divergences, a C-terminal frameshift in the toll-like receptor-4 (TLR4) gene of C. atys, is associated with a blunted in vitro response to TLR-4 ligands. In addition, we found a major structural change in exons 3-4 of the immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2); expression of this variant leads to reduced cell surface expression of ICAM-2. These data provide a resource for comparative genomic studies of HIV and/or SIV pathogenesis and may help to elucidate the mechanisms by which SIV-infected Sooty Mangabeys avoid AIDS.
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Origins and evolution of AIDS viruses: estimating the time-scale.
Biochemical Society transactions, 2000Co-Authors: Paul M. Sharp, Vanessa M. Hirsch, Feng Gao, Elizabeth Bailes, Brigitte E. Beer, Beatrice H. HahnAbstract:The primate lentiviruses comprise SIV strains from various host species, as well as two viruses, HIV-1 and HIV-2, that cause AIDS in humans. The origins of HIV-1 and HIV-2 have been traced to cross-species transmissions from chimpanzees and Sooty Mangabey monkeys respectively. Two approaches have been taken to estimate the time-scale of the evolution of these viruses. Certain groups of SIV strains appear to have evolved in a host-dependent manner, implying a time-scale of many thousands or even millions of years. In stark contrast, molecular clock calculations have previously been used to estimate a time-scale of only tens or hundreds of years. Those calculations largely ignored heterogeneity of evolutionary rates across different sites within sequences. In fact, the distribution of rates at different sites seems extremely skewed in HIV-1, and so the time-depth of the primate lentivirus evolutionary tree may have been underestimated by at least a factor of ten. However, these date estimates still seem to be far too recent to be consistent with host-dependent evolution.
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vpx is required for dissemination and pathogenesis of siv sm pbj evidence of macrophage dependent viral amplification
Nature Medicine, 1998Co-Authors: Vanessa M. Hirsch, Beatrice H. Hahn, Mark E Sharkey, Charles R Brown, B Brichacek, Simoy Goldstein, J Wakefield, Russell Byrum, William R Elkins, Jeffrey D LifsonAbstract:The viral accessory protein Vpx is required for productive in vitro infection of macrophages by simian immunodeficiency virus from Sooty Mangabey monkeys (SIV SM ). To evaluate the roles of Vpx and macrophage infection in vivo , we inoculated pigtailed macaques intravenously or intrarectally with the molecularly cloned, macrophage tropic, acutely pathogenic virus SIV SM PBj 6.6, or accessory gene deletion mutants (ΔVpr or ΔVpx) of this virus. Both wild-type and SIV SM PBj ΔVpx viruses were readily transmitted across the rectal mucosa. A subsequent 'stepwise' process of local amplification of infection and dissemination was observed for wild-type virus, but not for SIV SM PBj ΔVpx, which also showed considerable impairment of the overall kinetics and extent of its replication. In animals co-inoculated with equivalent amounts of wild-type and SIV SM Pbj ΔVpx intravenously or intrarectally, the ΔVpx mutant was at a strong competitive disadvantage. Vpx-dependent viral amplification at local sites of initial infection, perhaps through a macrophage-dependent mechanism, may be a prerequisite for efficient dissemination of infection and pathogenic consequences after exposure through either mucosal or intravenous routes.