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heightened cytotoxic responses and impaired biogenesis contribute to early pathogenesis in the oral mucosa of simian immunodeficiency virus-infected rhesus macaques.simian immunodeficiency virus (siv) infection disseminated into the oropharyngeal tissues of rhesus macaques 6 weeks following intravenous inoculation. severe local cd4(+) t-cell depletion coincided with increases in nk cell and proinflammatory biomarkers and the disruption of growth-associated gene transcription, demonstrating the rapid establishment of pathogenesis in the oral mucosa.200919091994
protective attenuated lentivirus immunization induces siv-specific t cells in the genital tract of rhesus monkeys.live attenuated lentivirus immunization is the only vaccine strategy that elicits consistent protection against intravaginal challenge with pathogenic simian immunodeficiency virus (siv). to determine the mechanism of protection in rhesus monkeys infected with attenuated simian-human immunodeficiency virus (shiv)89.6, a detailed analysis of siv gag-specific t-cell responses in several tissues including the genital tract was performed. six months after shiv infection, antiviral t-cell responses w ...200819079181
early divergence in neutrophil apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates.we used pathogenic and nonpathogenic simian models of siv infection of chinese and indian rhesus macaque (rms) and african green monkeys (agms), respectively, to investigate the relationship between polymorphonuclear neutrophil (pmn) death and the extent of viral replication and disease outcome. in this study, we showed that pmn death increased early during the acute phase of siv infection in chinese rms and coincided with the peak of viral replication on day 14. the level of pmn death was signi ...200819050281
mucosal prior to systemic application of recombinant adenovirus boosting is more immunogenic than systemic application twice but confers similar protection against siv-challenge in dna vaccine-primed macaques.we investigated the immunogenicity and efficacy of a bimodal prime/boost vaccine regimen given by various routes in the simian immunodeficiency virus (siv) rhesus monkey model for aids. twelve animals were immunized with siv dna-vectors followed by the application of a recombinant adenovirus (rad5) expressing the same genes either intramuscularly (i.m.) or by oropharyngeal spray. the second rad5-application was given i.m. all vaccinees plus six controls were challenged orally with sivmac239 12 w ...200919027133
frequency of the major histocompatibility complex mamu-a*01 allele in a closed breeding colony of rhesus monkey (macaca mulatta) from brazil.rhesus monkeys are relevant models for human diseases. the simian immunodeficiency virus (siv) infection is an useful macaque model for assessing human immunodeficiency virus (hiv) vaccine strategies. susceptibility and resistance to viruses have been associated with particular major histocompatibility complex (mhc) molecules. several epitopes in the hiv structural and non-structural protein restricted by distinct mhc class i haplotypes are important targets for human cytotoxic t lymphocytes, wh ...200919018945
immune control of an siv challenge by a t-cell-based vaccine in rhesus monkeys.a recombinant adenovirus serotype 5 (rad5) vector-based vaccine for hiv-1 has recently failed in a phase 2b efficacy study in humans. consistent with these results, preclinical studies have demonstrated that rad5 vectors expressing simian immunodeficiency virus (siv) gag failed to reduce peak or setpoint viral loads after siv challenge of rhesus monkeys (macaca mulatta) that lacked the protective mhc class i allele mamu-a*01 (ref. 3). here we show that an improved t-cell-based vaccine regimen us ...200918997770
differential cd4+ t-lymphocyte apoptosis and bystander t-cell activation in rhesus macaques and sooty mangabeys during acute simian immunodeficiency virus infection.in contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (siv) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. to determine whether these differences are species specific and predicted by the early host response to siv in primary infection, we longitudinally examined t-lymphocyte apoptosis, immune activation, and the siv-specific cellular immune response in experimentally infected rhesus macaques (rm) and sooty ...200918987149
rhesus lymphocryptovirus type 1-associated b-cell nasal lymphoma in siv-infected rhesus macaques.epstein-barr virus (ebv) is a worldwide endemic gamma herpesvirus of the genus lymphocryptovirus (lcv) that infects more than 90% of the world's population. ebv has been associated with a variety of malignancies, but it has a demonstrated role in lymphomas, especially in immunosuppressed individuals. lymphomas of the nasal cavity, paranasal sinuses, and nasopharynx are uncommon and constitute less than 5% of all extranodal lymphomas. sinonasal non-hodgkin's lymphomas have been reported in patien ...200818984796
correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody activities with reduced acute viremia following intrarectal simian immunodeficiency virus sivmac251 challenge of rhesus macaques.cell-mediated immunity and neutralizing antibodies contribute to control of human immunodeficiency virus/simian immunodeficiency virus (hiv/siv) infection, but the role of nonneutralizing antibodies is not defined. previously, we reported that sequential oral/oral or intranasal/oral (i/o) priming with replication-competent adenovirus type 5 host range mutant (ad5hr)-siv recombinants, followed by intramuscular envelope protein boosting, elicited systemic and mucosal cellular immunity and exhibite ...200918971271
relevance of studying t cell responses in siv-infected rhesus macaques.hiv infection, once established, is never cleared. rare individuals do, however, control viral replication to low levels. these successful immune responses are primarily linked to certain class i mhc alleles (mhc-i). because of this association, many aids vaccines in development are designed to generate virus-specific cd8+ t cells. the merck step phase 2b efficacy trial of one such vaccine was recently halted, and declared a failure. thus, basic questions regarding what constitutes an effective ...200818964016
shiv-1157i and passaged progeny viruses encoding r5 hiv-1 clade c env cause aids in rhesus monkeys.infection of nonhuman primates with simian immunodeficiency virus (siv) or chimeric simian-human immunodeficiency virus (shiv) strains is widely used to study lentiviral pathogenesis, antiviral immunity and the efficacy of aids vaccine candidates. shiv challenges allow assessment of anti-hiv-1 envelope responses in primates. as such, shivs should mimic natural hiv-1 infection in humans and, to address the pandemic, encode hiv-1 env components representing major viral subtypes worldwide.200818928523
effect of therapeutic immunization using ad5/35 and mva vectors on siv infection of rhesus monkeys undergoing antiretroviral therapy.antiretroviral therapy (art) effectively slows the progression of aids. however, drug resistance and/or toxicity can limit the utility of art in many patients. in this study, we assessed whether a viral vector-based vaccine can be used as a therapeutic vaccine in simian immunodeficiency virus (siv)-infected monkeys. the effect of vaccinating sivmac239-infected rhesus monkeys with an siv gag and gp120-expressing adenovirus (ad) vector vaccine and a modified vaccinia ankara (mva) vaccine was explo ...200918923453
glycerol monolaurate does not alter rhesus macaque (macaca mulatta) vaginal lactobacilli and is safe for chronic use.glycerol monolaurate (gml) is a fatty acid monoester that inhibits growth and exotoxin production of vaginal pathogens and cytokine production by vaginal epithelial cells. because of these activities, and because of the importance of cytokine-mediated immune activation in human immunodeficiency virus type 1 (hiv-1) transmission to women, our laboratories are performing studies on the potential efficacy of gml as a topical microbicide to interfere with hiv-1 transmission in the simian immunodefic ...200818838587
bone marrow-based homeostatic proliferation of mature t cells in nonhuman primates: implications for aids pathogenesis.bone marrow (bm) is the key hematopoietic organ in mammals and is involved in the homeostatic proliferation of memory cd8(+) t cells. here we expanded on our previous observation that bm is a preferential site for t-cell proliferation in simian immunodeficiency virus (siv)-infected sooty mangabeys (sms) that do not progress to aids despite high viremia. we found high levels of mature t-cell proliferation, involving both naive and memory cells, in healthy sms and rhesus macaques (rms). in additio ...200918832134
glycosylation of gp41 of simian immunodeficiency virus shields epitopes that can be targets for neutralizing antibodies.human immunodeficiency virus type 1 and simian immunodeficiency virus possess three closely spaced, highly conserved sites for n-linked carbohydrate attachment in the extracellular domain of the transmembrane protein gp41. we infected rhesus monkeys with a variant of cloned sivmac239 lacking the second and third sites or with a variant strain lacking all three of sivmac239's glycosylation sites in gp41. for each mutation, asparagine (n) in the canonical n-x-s/t recognition sequence for carbohydr ...200818829751
simian immunodeficiency virus (siv)-specific cd8+ t-cell responses in vervet african green monkeys chronically infected with sivagm.african green monkeys (agm) do not develop overt signs of disease following simian immunodeficiency virus (siv) infection. while it is still unknown how natural hosts like agm can cope with this lentivirus infection, a large number of investigations have shown that cd8(+) t-cell responses are critical for the containment of aids viruses in humans and asian nonhuman primates. here we have compared the phenotypes of t-cell subsets and magnitudes of siv-specific cd8(+) t-cell responses in vervet ag ...200818829748
intestinal double-positive cd4+cd8+ t cells of neonatal rhesus macaques are proliferating, activated memory cells and primary targets for sivmac251 infection.peripheral blood and thymic double-positive (dp) cd4(+)cd8(+) t cells from neonates have been described earlier, but the function and immunophenotypic characteristics of other tissue-derived dp t cells are not clearly understood. here, we demonstrate the functional and immunophenotypic characteristics of dp cells in 6 different tissues, including thymus from normal neonatal rhesus macaques (macaca mulatta) between 0 and 21 days of age. in general, intestinal dp t cells of neonates have higher pe ...200818820133
divergent tlr7 and tlr9 signaling and type i interferon production distinguish pathogenic and nonpathogenic aids virus infections.pathogenic hiv infections of humans and simian immunodeficiency virus (siv) infections of rhesus macaques are characterized by generalized immune activation and progressive cd4(+) t cell depletion. in contrast, natural reservoir hosts for siv, such as sooty mangabeys, do not progress to aids and show a lack of aberrant immune activation and preserved cd4(+) t cell populations, despite high levels of siv replication. here we show that sooty mangabeys have substantially reduced levels of innate im ...200818806803
with minimal systemic t-cell expansion, cd8+ t cells mediate protection of rhesus macaques immunized with attenuated simian-human immunodeficiency virus shiv89.6 from vaginal challenge with simian immunodeficiency virus.the presence, at the time of challenge, of antiviral effector t cells in the vaginal mucosa of female rhesus macaques immunized with live-attenuated simian-human immunodeficiency virus 89.6 (shiv89.6) is associated with consistent and reproducible protection from pathogenic simian immunodeficiency virus (siv) vaginal challenge (18). here, we definitively demonstrate the protective role of the siv-specific cd8(+) t-cell response in shiv-immunized monkeys by cd8(+) lymphocyte depletion, an interve ...200818787003
monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies.here the authors discuss evidence in human and animal models supporting two opposing views regarding the pathogenesis of human immunodeficiency virus (hiv) in the central nervous system (cns): (1) hiv infection in the cns is a compartmentalized infection, with the virus-infected macrophages entering the cns early, infecting resident microglia and astrocytes, and achieving a state of latency with evolution toward a fulminant cns infection late in the course of disease; or alternatively, (2) event ...200818780233
adenoviral hepatitis in a siv-infected rhesus monkey (macaca mulatta).a 5-year-old female rhesus monkey infected with simian immunodeficiency virus became clinically suspicious with anorexia, increasing weakness and apathy eighty-five weeks after the tonsillar virus inoculation and was euthanised due to a poor prognosis.200818773508
rhesus macaque rhadinovirus-associated non-hodgkin lymphoma: animal model for kshv-associated malignancies.rhesus macaque rhadinovirus (rrv) is closely related to kaposi sarcoma-associated herpesvirus (kshv) and is associated with the development of b-cell hyperplasia and persistent lymphadenopathy resembling multicentric castleman disease in rhesus macaques (rms) coinfected with simian immunodeficiency virus (siv). here we investigated whether rms experimentally infected with siv and rrv can develop other disease manifestations observed in hiv- and kshv-infected patients. as reported earlier, inocul ...200818757778
sequential priming with simian immunodeficiency virus (siv) dna vaccines, with or without encoded cytokines, and a replicating adenovirus-siv recombinant followed by protein boosting does not control a pathogenic sivmac251 mucosal challenge.previously, combination dna/nonreplicating adenovirus (ad)- or poxvirus-vectored vaccines have strongly protected against shiv(89.6p), dnas expressing cytokines have modulated immunity elicited by dna vaccines, and replication-competent ad-recombinant priming and protein boosting has strongly protected against simian immunodeficiency virus (siv) challenge. here we evaluated a vaccine strategy composed of these promising components. seven rhesus macaques per group were primed twice with multigeni ...200818753198
potent simian immunodeficiency virus-specific cellular immune responses in the breast milk of simian immunodeficiency virus-infected, lactating rhesus monkeys.breast milk transmission of hiv is a leading cause of infant hiv/aids in the developing world. remarkably, only a small minority of breastfeeding infants born to hiv-infected mothers contract hiv via breast milk exposure, raising the possibility that immune factors in the breast milk confer protection to the infants who remain uninfected. to model hiv-specific immunity in breast milk, lactation was pharmacologically induced in mamu-a*01(+) female rhesus monkeys. the composition of lymphocyte sub ...200818714039
the role of production frequency in the sharing of simian immunodeficiency virus-specific cd8+ tcrs between macaques.in some epitope-specific responses, t cells bearing identical tcrs occur in many mhc-matched individuals. the sharing of public tcrs is unexpected, given the enormous potential diversity of the tcr repertoire. we have previously studied the sharing of tcr beta-chains in the cd8(+) t cell responses to two influenza epitopes in mice. analysis of these tcrbeta repertoires suggests that, even with unbiased v(d)j recombination mechanisms, some tcrbetas can be produced more frequently than others, by ...200818684950
prevention of siv rectal transmission and priming of t cell responses in macaques after local pre-exposure application of tenofovir gel.the rectum is particularly vulnerable to hiv transmission having only a single protective layer of columnar epithelium overlying tissue rich in activated lymphoid cells; thus, unprotected anal intercourse in both women and men carries a higher risk of infection than other sexual routes. in the absence of effective prophylactic vaccines, increasing attention is being given to the use of microbicides and preventative antiretroviral (arv) drugs. to prevent mucosal transmission of hiv, a microbicide ...200818684007
gag-specific cytotoxic t-lymphocyte-based control of primary simian immunodeficiency virus replication in a vaccine trial.gag-specific cytotoxic t lymphocytes (ctls) exert strong suppressive pressure on human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) replication. however, it has remained unclear whether they can actually contain primary viral replication. recent trials of prophylactic vaccines inducing virus-specific t-cell responses have indicated their potential to confer resistance against primary siv replication in rhesus macaques, while the immunological determinant for this vaccine- ...200818667518
reduced protection from simian immunodeficiency virus sivmac251 infection afforded by memory cd8+ t cells induced by vaccination during cd4+ t-cell deficiency.adaptive cd4(+) and cd8(+) t-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (hiv/siv) replication. here, we have designed a study with indian rhesus macaques to more directly assess the role of cd8 siv-specific responses in control of viral replication. macaques were immunized with a dna prime-modified vaccinia virus ankara (mva)-siv boost regimen under normal conditions or under conditions of antibody-induced cd4(+) t-cell deficien ...200818667509
potent antibody-mediated neutralization and evolution of antigenic escape variants of simian immunodeficiency virus strain sivmac239 in vivo.here, we describe the evolution of antigenic escape variants in a rhesus macaque that developed unusually high neutralizing antibody titers to sivmac239. by 42 weeks postinfection, 50% neutralization of sivmac239 was achieved with plasma dilutions of 1:1,000. testing of purified immunoglobulin confirmed that the neutralizing activity was antibody mediated. despite the potency of the neutralizing antibody response, the animal displayed a typical viral load profile and progressed to terminal aids ...200818667507
cd4 deficits and disease course acceleration can be driven by a collapse of the cd8 response in rhesus macaques infected with simian immunodeficiency virus.defects in memory cd4+ t cells correlate with development of aids in monkeys infected with simian immunodeficiency virus, but the early events leading to these deficits are unknown. we explored the role of cells specific to simian immunodeficiency virus and cd8 cells in the determination of cd4 failure and rapid disease course.200818614867
capsid proteins from human immunodeficiency virus type 1 and simian immunodeficiency virus sivmac can coassemble into mature cores of infectious viruses.we have recently shown that the gag polyproteins from human immunodeficiency virus type 1 (hiv-1) and hiv-2 can coassemble and functionally complement each other. during virion maturation, the gag polyproteins undergo proteolytic cleavage to release mature proteins including capsid (ca), which refolds and forms the outer shell of a cone-shaped mature core. less than one-half of the ca proteins present within the hiv-1 virion are required to form the mature core. therefore, it is unclear whether ...200818579598
chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects.the reverse transcriptase (rt) inhibitor tenofovir (tfv) is highly effective in the simian immunodeficiency virus (siv) macaque model of human immunodeficiency virus infection. the current report describes extended safety and efficacy data on 32 animals that received prolonged (>or=1- to 13-year) daily subcutaneous tfv regimens. the likelihood of renal toxicity (proximal renal tubular dysfunction [prtd]) correlated with plasma drug concentrations, which depended on the dosage regimen and age-rel ...200818573931
nonhuman primate models and the failure of the merck hiv-1 vaccine in humans.the adenovirus type 5 (ad5)-based vaccine developed by merck failed to either prevent hiv-1 infection or suppress viral load in subsequently infected subjects in the step human phase 2b efficacy trial. analogous vaccines had previously also failed in the simian immunodeficiency virus (siv) challenge-rhesus macaque model. in contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (shiv89.6p) in macaques did not predict the human trial results. ...200818535579
ccaat/enhancer binding protein beta is a major mediator of inflammation and viral replication in the gastrointestinal tract of simian immunodeficiency virus-infected rhesus macaques.the gastrointestinal tract (git) is a major target of infection with human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv). chronic git disease and inflammation are common sequelae to hiv/siv infection. nonetheless, the molecular mechanisms that cause and maintain git dysfunction remain unclear. we investigated the contribution of ccaat/enhancer-binding protein beta (c/ebpbeta) to git disease and viral replication in jejunum and colon collected at necropsy from 12 siv-infect ...200818535173
[comparison of intravenous and intrarectal sivmac239 infections in rhesus monkeys of chinese origin].to investigate the biological and clinical features of chinese rhesus monkeys after intravenous (iv) and intrarectal (ir) challenge with sivmac239 in rhesus monkeys of chinese origin, and compare the differences between the routes of infection.200818505116
mhc class i characterization of indonesian cynomolgus macaques.cynomolgus macaques (macaca fascicularis) are quickly becoming a useful model for infectious disease and transplantation research. even though cynomolgus macaques from different geographic regions are used for these studies, there has been limited characterization of full-length major histocompatibility complex (mhc) class i immunogenetics of distinct geographic populations. here, we identified 48 mhc class i cdna nucleotide sequences in eleven indonesian cynomolgus macaques, including 41 novel ...200818504574
the role of the armadillo and sooty mangabey monkey in human leprosy.the armadillo was the first animal model of leprosy. its role in the transmission of leprosy remains controversial. the sooty mangabey model of leprosy led to the discovery that rhesus monkeys were more susceptible to leprosy when coinfected with simian immunodeficiency virus (siv), but that leprosy may play a protective role against acquired immunodeficiency syndrome (aids) mortality. recently, molecular methods have been developed for leprosy and may help resolve the role of zoonoses in lepros ...200818477141
increased expression of monocyte cd44v6 correlates with the deveopment of encephalitis in rhesus macaques infected with simian immunodeficiency virus.in people infected with human immunodeficiency virus type 1 (hiv-1), the accumulation of macrophages in the brain correlates with encephalitis and dementia. we hypothesized that a pattern of surface marker expression in blood monocytes may serve as a marker for central nervous system (cns) disease. using the simian immunodeficiency virus (siv)-rhesus monkey model, we analyzed functionally relevant surface markers on monocytes and macrophages from the blood and brain in animals that did or did no ...200818471064
efficient entry inhibition of human and nonhuman primate immunodeficiency virus by cell surface-expressed gp41-derived peptides.membrane-anchored c-peptides (for example, mac46) derived from human immunodeficiency virus type 1 (hiv-1) envelope glycoprotein gp41 effectively inhibit hiv-1 entry in cell lines and primary human cd4+ cells in vitro. here we evaluated this gene therapy approach in animal models of aids. we adapted the hiv gp41-derived mac46 vector construct for use in rhesus monkeys. simian immunodeficiency virus (siv and shiv) sequence-adapted mac46 peptides, and the original hiv-1-derived mac46 expressed on ...200818449216
incomplete protection against simian immunodeficiency virus vaginal transmission in rhesus macaques by a topical antiviral agent revealed by repeat challenges.the rising prevalence of human immunodeficiency virus type 1 (hiv-1) infection in women, especially in resource-limited settings, accentuates the need for accessible, inexpensive, and female-controlled preexposure prophylaxis strategies to prevent mucosal transmission of the virus. while many compounds can inactivate hiv-1 in vitro, evaluation in animal models for mucosal transmission of virus may help identify which approaches will be effective in vivo. macaques challenged intravaginally with p ...200818434406
in vivo natural killer cell depletion during primary simian immunodeficiency virus infection in rhesus monkeys.the contribution of natural killer (nk) cells to the immune containment of human immunodeficiency virus infection remains undefined. to directly assess the role of nk cells in an aids animal model, we depleted rhesus monkeys of >88% of cd3(-) cd16(+) cd159a(+) nk cells at the time of primary simian immunodeficiency virus (siv) infection by using anti-cd16 antibody. during the first 11 days following siv inoculation, when nk cell depletion was most profound, a trend toward higher levels of siv re ...200818434394
tissue-specific restriction of cyclophilin a-independent hiv-1- and siv-derived lentiviral vectors.the host factor alpha isoform of the tripartite motif 5 (trim5alpha) restricts human immunodeficiency virus type 1 (hiv-1) infection in certain non-human primate species. restriction of hiv-1 is enhanced by binding of the viral capsid to cyclophilin a (cypa) in target cells, although cypa is not absolutely required for restriction in rhesus macaque cells. simian immunodeficiency virus (siv) is not restricted by rhesus macaque trim5alpha and its capsid does not bind to cypa. here, the effect of l ...200818385767
comprehensive immunological evaluation reveals surprisingly few differences between elite controller and progressor mamu-b*17-positive simian immunodeficiency virus-infected rhesus macaques.the association between particular major histocompatibility complex class i (mhc-i) alleles and control of human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) replication implies that certain cd8(+) t-lymphocyte (cd8-tl) responses are better able than others to control viral replication in vivo. however, possession of favorable alleles does not guarantee improved prognosis or viral control. in rhesus macaques, the mhc-i allele mamu-b*17 is correlated with reduced viremia a ...200818385251
simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes salmonella dissemination from the gut.salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas hiv-infected individuals develop a life-threatening bacteremia. here we show that simian immunodeficiency virus (siv) infection results in depletion of t helper type 17 (th17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to s. typhimurium dissemination. in siv-negative macaques, the gene expression profile induced by s. typhimurium in ligated ileal loop ...200818376406
increased loss of ccr5+ cd45ra- cd4+ t cells in cd8+ lymphocyte-depleted simian immunodeficiency virus-infected rhesus monkeys.previously we have shown that cd8(+) t cells are critical for containment of simian immunodeficiency virus (siv) viremia and that rapid and profound depletion of cd4(+) t cells occurs in the intestinal tract of acutely infected macaques. to determine the impact of siv-specific cd8(+) t-cell responses on the magnitude of the cd4(+) t-cell depletion, we investigated the effect of cd8(+) lymphocyte depletion during primary siv infection on cd4(+) t-cell subsets and function in peripheral blood, lym ...200818367534
contribution of cd8+ t cells to containment of viral replication and emergence of mutations in mamu-a*01-restricted epitopes in simian immunodeficiency virus-infected rhesus monkeys.here, we investigated the containment of virus replication in simian immunodeficiency virus (siv) infection by cd8(+) lymphocytes. escape mutations in mamu-a*01 epitopes appeared first in siv tat tl8 and then in siv gag p11c. the appearance of escape mutations in siv gag p11c was coincident with compensatory changes outside of the epitope. eliminating cd8(+) lymphocytes from rhesus monkeys during primary infection resulted in more rapid disease progression that was associated with preservation o ...200818367519
transmission of simian immunodeficiency virus carrying multiple cytotoxic t-lymphocyte escape mutations with diminished replicative ability can result in aids progression in rhesus macaques.cytotoxic t-lymphocyte (ctl) responses frequently select for immunodeficiency virus mutations that result in escape from ctl recognition with viral fitness costs. the replication in vivo of such viruses carrying not single but multiple escape mutations in the absence of the ctl pressure has remained undetermined. here, we have examined the replication of simian immunodeficiency virus (siv) with five gag mutations selected in a macaque possessing the major histocompatibility complex haplotype 90- ...200818337572
antigenic stimulation in the simian model of hiv infection yields dilated cardiomyopathy through effects of tnfalpha.to investigate a role for endogenous myocardial cytokine production in the development of hiv-associated cardiomyopathy.200818316999
abrogation of aids vaccine-induced cytotoxic t-lymphocyte efficacy in vivo due to a change in viral epitope flanking sequences.a current promising aids vaccine strategy is to elicit cd8(+) cytotoxic t lymphocyte (ctl) responses that broadly recognize highly-diversified hivs. in our previous vaccine trial eliciting simian immunodeficiency virus (siv) mac239 gag-specific ctl responses, a group of burmese rhesus macaques possessing a major histocompatibility complex haplotype 90-120-ia have shown vaccine-based viral control against a homologous sivmac239 challenge. vaccine-induced gag(206-216) epitope-specific ctl response ...200818316225
metabolic markers of neuronal injury correlate with siv cns disease severity and inoculum in the macaque model of neuroaids.in vivo mr spectroscopy (mrs) studies have shown reductions in naa/cr levels in patients with severe neurocognitive deficits due to aids dementia complex (adc), also known as neuroaids. the relationship between the cellular changes within the brain during neuroaids and the role of naa/cr as a metabolic marker remains unclear. in order to clarify the relationship between naa/cr and disease severity we utilized the simian immunodeficiency virus (siv)/macaque model of encephalitis. high-field proto ...200818306400
viral and host correlates of serum resistin in simian aids.resistin is an adipocytokine with a proposed dual role in metabolism and inflammation. in light of the ability to promote inflammatory responses, adipocytokines may prove key factors in modulating the host response to hiv. this study utilizes the simian immunodeficiency virus (siv) model of hiv/aids to investigate changes in serum resistin levels following dietary intervention and siv infection and determine associations with measures of body composition and disease severity. resistin levels, bo ...200818275346
vaccine protection by live, attenuated simian immunodeficiency virus in the absence of high-titer antibody responses and high-frequency cellular immune responses measurable in the periphery.an attenuated derivative of simian immunodeficiency virus strain 239 deleted of v1-v2 sequences in the envelope gene (siv239deltav1-v2) was used for vaccine/challenge experiments in rhesus monkeys. peak levels of viral rna in plasma of 10(4) to 10(6.5) copies/ml in the weeks immediately following inoculation of siv239deltav1-v2 were 10- to 1,000-fold lower than those observed with parental siv239 ( approximately 10(7.3) copies/ml). viral loads consistently remained below 200 copies/ml after 8 we ...200818272584
genital ulcers facilitate rapid viral entry and dissemination following intravaginal inoculation with cell-associated simian immunodeficiency virus sivmac239.here we report the results of studies in the simian immunodeficiency virus (siv)-rhesus macaque model of intravaginal transmission of human immunodeficiency virus type 1 in the setting of genital ulcerative diseases. we document preferential association of vrna with induced ulcers during the first days of infection and show that allogeneic cells of the inoculum traffic from the vaginal lumen to lymphatic tissues. this surprisingly rapid systemic dissemination in this cell-associated siv challeng ...200818272571
dermatitis in a rhesus macaque (macaca mulatta) experimentally infected with simian immunodeficiency virus.dermatopathies are common with human immunodeficiency virus (hiv) infection, affecting an estimated 90% of hiv patients. opportunistic infections are common and include viral, bacterial and fungal etiologies. dermal eruptions from highly active anti-retroviral therapy (haart) or antibiotics such as trimethoprim-sulfamethoxazole (tms) are also common, and can be challenging to differentiate from other causes of dermatitis. presented is a challenging dermatology case involving a six year old male ...200818269525
soluble pd-1 rescues the proliferative response of simian immunodeficiency virus-specific cd4 and cd8 t cells during chronic infection.phenotypic and functional studies of the programmed death-1 (pd-1) molecule on cd4(+) and cd8(+) t cells were performed on peripheral blood mononuclear cells from uninfected and simian immunodeficiency virus (siv)-infected rhesus macaques. these data demonstrated a rapid upregulation of pd-1 expression on tetramer-positive cd8(+) t cells from mamua.01(+) siv-infected macaques upon infection. upregulation of pd-1 on total cd8(+) t cells was not detectable. in contrast, cd4(+) t-cell pd-1 expressi ...200818266718
vaccination of rhesus macaques with a vif-deleted simian immunodeficiency virus proviral dna vaccine.studies in non-human primates, with simian immunodeficiency virus (siv) and simian/human immunodeficiency virus (shiv) have demonstrated that live-attenuated viral vaccines are highly effective; however these vaccine viruses maintain a low level of pathogenicity. lentivirus attenuation associated with deletion of the viral vif gene carries a significantly reduced risk for pathogenicity, while retaining the potential for virus replication of low magnitude in the host. this report describes a vif- ...200818261756
effect of morphine on the neuropathogenesis of sivmac infection in indian rhesus macaques.morphine is known to prevent the development of cell-mediated immune (cmi) responses and enhance expression of the ccr5 receptor in monocyte macrophages. we undertook a study to determine the effect of morphine on the neuropathogenesis and immunopathogenesis of simian immunodeficiency virus (siv) infection in indian rhesus macaques. hypothetically, the effect of morphine would be to prevent the development of cmi responses to siv and to enhance the infection in macrophages. sixteen rhesus macaqu ...200818247128
use of an anti-cd16 antibody for in vivo depletion of natural killer cells in rhesus macaques.non-human primates serve as key animal models for a variety of viral infections. to evaluate the contribution of natural killer (nk) cells to the immune-mediated control of these viruses in macaque monkeys, we have described a method for depleting nk cells in vivo by administration of anti-human cd16 mouse monoclonal antibody. using a fluorometric nk-cell cytotoxicity assay, we show that most nk-cell cytotoxicity in rhesus monkey peripheral blood mononuclear cells resides in the cd16(+) and/or c ...200818201184
selective downregulation of rhesus macaque and sooty mangabey major histocompatibility complex class i molecules by nef alleles of simian immunodeficiency virus and human immunodeficiency virus type 2.human immunodeficiency virus type 1 (hiv-1) nef downregulates hla-a and -b molecules, but not hla-c or -e molecules, based on amino acid differences in their cytoplasmic domains to simultaneously evade cytotoxic t lymphocyte (ctl) and natural killer cell surveillance. rhesus macaques and sooty mangabeys express orthologues of hla-a, -b, and -e, but not hla-c, and many of these molecules have unique amino acid differences in their cytoplasmic tails. we found that these differences also resulted i ...200818199657
impact of glycosylation on antigenicity of simian immunodeficiency virus siv239: induction of rapid v1/v2-specific non-neutralizing antibody and delayed neutralizing antibody following infection with an attenuated deglycosylated mutant.infection of rhesus macaques with a deglycosylation mutant, delta5g, derived from siv239, a pathogenic clone of simian immunodeficiency virus (siv), led to robust acute-phase viral replication followed by a chronic phase with undetectable viral load. this study examined whether humoral responses in delta5g-infected animals played any role in the control of infection. neutralizing antibodies (nabs) were elicited more efficiently in delta5g-infected animals than in siv239-infected animals. however ...200818198387
immune-response profiles induced by human immunodeficiency virus type 1 vaccine dna, protein or mixed-modality immunization: increased protection from pathogenic simian-human immunodeficiency virus viraemia with protein/dna combination.current data suggest that prophylactic human immunodeficiency virus type 1 (hiv) vaccines will be most efficacious if they elicit a combination of adaptive humoral and t-cell responses. here, we explored the use of different vaccine strategies in heterologous prime-boost regimes and evaluated the breadth and nature of immune responses in rhesus monkeys induced by epidermally delivered plasmid dna or recombinant hiv proteins formulated in the as02a adjuvant system. these immunogens were administe ...200818198386
clinical measles after measles virus challenge in simian immunodeficiency virus-infected measles virus-vaccinated rhesus monkeys.understanding the impact of human immunodeficiency virus (hiv) infection on the clinical manifestations and kinetics of measles virus (mv) replication in mv-vaccinated and unvaccinated individuals is important for developing successful vaccine strategies for measles eradication. to model the pathogenesis of mv infection in mv-vaccinated and unvaccinated individuals infected with hiv, previously vaccinated and unvaccinated rhesus monkeys infected with simian immunodeficiency virus (siv) were chal ...200718190259
differential cd4+ versus cd8+ t-cell responses elicited by different poxvirus-based human immunodeficiency virus type 1 vaccine candidates provide comparable efficacies in primates.poxvirus vectors have proven to be highly effective for boosting immune responses in diverse vaccine settings. recent reports reveal marked differences in the gene expression of human dendritic cells infected with two leading poxvirus-based human immunodeficiency virus (hiv) vaccine candidates, new york vaccinia virus (nyvac) and modified vaccinia virus ankara (mva). to understand how complex genomic changes in these two vaccine vectors translate into antigen-specific systemic immune responses, ...200818184713
novel application of nonhuman primate tethering system for evaluation of acute phase sivmac251 infection in rhesus macaques (macaca mulatta).infection of rhesus macaques with simian immunodeficiency virus (siv) is the preferred animal model for the development and testing of human immunodeficiency virus (hiv) vaccines, and animals protected from siv challenge by live attenuated vaccines are an invaluable tool for determining immune correlates of protection. the acute phase of siv infection, in which immune responses are most critical for slowing disease progression, occurs within the first 4 weeks of exposure. the small window of tim ...200718158735
il-15 treatment during acute simian immunodeficiency virus (siv) infection increases viral set point and accelerates disease progression despite the induction of stronger siv-specific cd8+ t cell responses.in this study, we examined the effect of in vivo treatment of acutely siv-infected mamu-a*01+ rhesus macaques with il-15. il-15 treatment during acute infection increased viral set point by 3 logs and accelerated the development of simian aids in two of six animals with one developing early minimal lesion siv meningoencephalitis. although il-15 induced a 2- to 3-fold increase in siv-specific cd8+ t cell and nk cell numbers at peak viremia and reduced lymph node (ln) siv-infected cells, this had ...200818097036
mhc class i haplotypes associated with survival time in simian immunodeficiency virus (siv)-infected rhesus macaques.in both human immunodeficiency virus-infected humans and simian immunodeficiency virus (siv)-infected macaques, genes encoded in the major histocompatibility complex (mhc) class i region are important determinants of disease progression. however, compared to the human human lymphocyte antigen complex, the macaque mhc region encodes many more class i genes. macaques with the same immunodominant class i genes express additional mhc genes with the potential to influence the disease course. we there ...200818094710
patterns of cd8+ immunodominance may influence the ability of mamu-b*08-positive macaques to naturally control simian immunodeficiency virus sivmac239 replication.certain major histocompatibility complex (mhc) class i alleles are strongly associated with control of human immunodeficiency virus and simian immunodeficiency virus (siv). cd8(+) t cells specific for epitopes restricted by these molecules may be particularly effective. understanding how cd8(+) t cells contribute to control of viral replication should yield important insights for vaccine design. we have recently identified an indian rhesus macaque mhc class i allele, mamu-b*08, associated with e ...200818057253
gastrointestinal disease in simian immunodeficiency virus-infected rhesus macaques is characterized by proinflammatory dysregulation of the interleukin-6-janus kinase/signal transducer and activator of transcription3 pathway.gastrointestinal disease and inflammation are common sequelae of human and simian immunodeficiency virus (siv) infection. nevertheless, the molecular mechanisms that lead to gastrointestinal dysfunction remain unclear. we investigated regulation of the interleukin (il)-6-jak-stat3 pathway in jejunum and colon, collected at necropsy, from 10 siv-infected macaques with diarrhea (group 1), 10 non-siv-infected macaques with diarrhea (group 2), and 7 control uninfected macaques (group 3). all group 1 ...200718055558
new insights into the neuroimmunity of siv infection by magnetic resonance spectroscopy.(1)h magnetic resonance spectroscopy (mrs) was employed to noninvasively monitor neuronal injury in eight rhesus macaques infected with simian immunodeficiency virus (siv), whose immune system was compromised by cd8 t lymphocyte depletion and treated with highly active antiretroviral therapy (haart). siv infection and cd8 depletion resulted in a rapid decline in cerebral n-acetylaspartate (naa) levels, a sensitive marker of neuronal health. within 3 months of siv infection and cd8 depletion, fou ...200618040781
dynamics of t- and b-lymphocyte turnover in a natural host of simian immunodeficiency virus.increased lymphocyte turnover is a hallmark of pathogenic lentiviral infection. to investigate perturbations in lymphocyte dynamics in natural hosts with nonpathogenic simian immunodeficiency virus (siv) infection, the nucleoside analog bromodeoxyuridine (brdu) was administered to six naturally siv-infected and five siv-negative sooty mangabeys. as a measure of lymphocyte turnover, we estimated the mean death rate by fitting a mathematical model to the fraction of brdu-labeled cells during a 2-w ...200818032490
early divergence in lymphoid tissue apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates.the events that contribute to the progression to aids during the acute phase of a primate lentiviral infection are still poorly understood. in this study, we used pathogenic and nonpathogenic simian models of simian immunodeficiency virus (siv) infection of rhesus macaques (rms) and african green monkeys (agms), respectively, to investigate the relationship between apoptosis in lymph nodes and the extent of viral replication, immune activation, and disease outcome. here, we show that, in sivmac2 ...200818032487
chronic alcohol accentuates simian acquired immunodeficiency syndrome-associated wasting.survival following human immunodeficiency virus (hiv) infection has improved significantly following the advent of highly active antiretroviral therapy. a large percentage of hiv-infected patients consume and abuse alcohol. erosion of lean body mass is an important contributing factor to patient morbidity and mortality, and is a common feature of both chronic alcohol (alc) consumption and acquired immunodeficiency syndrome (aids). we hypothesized that alcohol-induced loss in lean body mass is li ...200818028526
determination of virus burst size in vivo using a single-cycle siv in rhesus macaques.a single-cycle simian immunodeficiency virus (scsiv) that undergoes only one round of infection and replication was constructed to calculate the total number of virons produced by an siv-infected cell in vivo. four mamu-a*01 rhesus macaques were inoculated on two occasions 11 weeks apart with the scsiv by ex vivo infection and i.v. reinfusion of autologous cells. after each inoculation, plasma viral loads peaked between 1 and 2.5 days and then declined exponentially in one or two phases to below ...200718025463
cd8+ t cells from siv elite controller macaques recognize mamu-b*08-bound epitopes and select for widespread viral variation.it is generally accepted that cd8+ t cell responses play an important role in control of immunodeficiency virus replication. the association of hla-b27 and -b57 with control of viremia supports this conclusion. however, specific correlates of viral control in individuals expressing these alleles have been difficult to define. we recently reported that transient in vivo cd8+ cell depletion in simian immunodeficiency virus (siv)-infected elite controller (ec) macaques resulted in a brief period of ...200718000532
complications of gastric catheters implanted in rhesus macaques (macaca mulatta).as part of a study addressing chronic alcohol consumption and simian immunodeficiency virus, 31 rhesus macaques (macaca mulatta) were implanted with gastric catheters used to deliver alcohol or isocaloric sucrose (control). once implanted, the animals wore jackets and were housed in specialized cages modified with swivels and tethers. during the course of the study, 3 animals developed clinical signs indicating possible instability of the implanted gastric catheter. all 3 animals were found to h ...200717994670
the major histocompatibility complex class ii alleles mamu-drb1*1003 and -drb1*0306 are enriched in a cohort of simian immunodeficiency virus-infected rhesus macaque elite controllers.the role of cd4(+) t cells in the control of human immunodeficiency virus (hiv) and simian immunodeficiency virus (siv) replication is not well understood. even though strong hiv- and siv-specific cd4(+) t-cell responses have been detected in individuals that control viral replication, major histocompatibility complex class ii (mhc-ii) molecules have not been definitively linked with slow disease progression. in a cohort of 196 sivmac239-infected indian rhesus macaques, a group of macaques contr ...200817989178
disruption of excitatory amino acid transporters in brains of siv-infected rhesus macaques is associated with microglia activation.glutamate-mediated neurodysfunction in human immunodeficiency virus (hiv) infection has been primarily suggested by in vitro studies. the regulation of glutamatergic neurotransmission in inflammation is a complex interaction between activation of immune mediators and adaptive changes in the functional elements of the glutamatergic synapse. we have used simian immunodeficiency virus (siv)-infected macaques to answer the questions (i) whether perturbation of glutamate neurotransmission is evident ...200817986224
memantine upregulates bdnf and prevents dopamine deficits in siv-infected macaques: a novel pharmacological action of memantine.n-methyl-d-aspartate (nmda) receptor activation is involved in the pathogenetic cascades of neurodegenerative disorders including human immunodeficiency virus (hiv) dementia. memantine, an uncompetitive nmda receptor antagonist, which has been recently approved for the treatment of alzheimer's disease, is being discussed as a potential adjunctive therapeutic substance for hiv dementia. we used simian immunodeficiency virus-infected rhesus macaques to assess the effects of memantine on brain dysf ...200817971830
pharmacokinetics, toxicity, and functional studies of the selective kv1.3 channel blocker 5-(4-phenoxybutoxy)psoralen in rhesus macaques.the small molecule 5-(4-phenoxybutoxy)psoralen (pap-1) is a selective blocker of the voltage-gated potassium channel kv1.3 that is highly expressed in cell membranes of activated effector memory t cells (tems). the blockade of kv1.3 results in membrane depolarization and inhibition of tem proliferation and function. in this study, the in vitro effects of pap-1 on t cells and the in vivo toxicity and pharmacokinetics (pk) were examined in rhesus macaques (rm) with the ultimate aim of utilizing pa ...200717959847
aids virus specific cd8+ t lymphocytes against an immunodominant cryptic epitope select for viral escape.cryptic major histocompatibility complex class i epitopes have been detected in several pathogens, but their importance in the immune response to aids viruses remains unknown. here, we show that mamu-b*17(+) simian immunodeficiency virus (siv)mac239-infected rhesus macaques that spontaneously controlled viral replication consistently made strong cd8(+) t lymphocyte (cd8-tl) responses against a cryptic epitope, rhlafkclw (crw9). importantly, crw9-specific cd8-tl selected for viral variation in vi ...200717954573
adjuvanting a dna vaccine with a tlr9 ligand plus flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus.dna vaccines offer promising strategies for immunization against infections. however, their clinical use requires improvements in immunogenicity. we explored the efficacy of toll-like receptor (tlr) ligands (tlr-ls) on augmenting the immunogenicity of a dna prime-modified vaccinia virus ankara (mva) boost vaccine against siv. rhesus macaques were injected with fms-like tyrosine kinase 3 (flt3)-ligand (fl) to expand dendritic cells (dcs) and were primed with a dna vaccine encoding immunodeficienc ...200717954572
comparison of plasma viremia and antibody responses in macaques inoculated with envelope variants of single-cycle simian immunodeficiency virus differing in infectivity and cellular tropism.molecular differences in the envelope glycoproteins of human immunodeficiency virus type 1 and simian immunodeficiency virus (siv) determine virus infectivity and cellular tropism. to examine how these properties contribute to productive infection in vivo, rhesus macaques were inoculated with strains of single-cycle siv (scsiv) engineered to express three different envelope glycoproteins with full-length (tm(open)) or truncated (tm(stop)) cytoplasmic tails. the 239 envelope uses ccr5 for infecti ...200817942538
comparative evaluation of oral and intranasal priming with replication-competent adenovirus 5 host range mutant (ad5hr)-simian immunodeficiency virus (siv) recombinant vaccines on immunogenicity and protective efficacy against siv(mac251).oral, replication-competent ad-hiv vaccines are advancing to human trials. previous evaluation of protective efficacy in non-human primates has primarily followed upper respiratory tract administrations. here we compared sequential oral (o/o) versus intranasal/oral (i/o) priming of rhesus macaques with ad5 host range mutant-siv recombinants expressing siv env/rev, gag, and nef genes followed by boosting with siv gp120 protein. cellular immune responses in pbmc were stronger and more frequent aft ...200717935840
interaction of siv/shiv infection and morphine on plasma oxidant/antioxidant balance in macaque.a homeostatic balance exists between the cellular generation of oxidant species and endogenous antioxidants under normal physiological conditions. human immunodeficiency virus (hiv) infection is known to affect this balance causing oxidative stress. however, the interaction of hiv infection with a substance abuse on cellular oxidant/antioxidant system is sparse. this study was designed in order to investigate the interactive effect of morphine abuse and simian immunodeficiency virus/ simian huma ...200817934700
autoimmunity and hiv/simian immunodeficiency virus infection: a two edged sword.the purpose of this review is to provide an overview of the spectrum of autoimmune responses that we have so far characterized in the simian immunodeficiency virus (siv)-infected disease susceptible rhesus macaques, the potential role of the lymphopenic state for the generation of the autoimmune response and the important new finding that such autoimmune response in fact can serve to provide both clinical benefit and clinical disease depending on the stage of the disease and the nature of the ho ...200717931192
comparative requirements for the restriction of retrovirus infection by trim5alpha and trimcyp.the restriction factors, trim5alpha in most primates and trimcyp in owl monkeys, block infection of various retroviruses soon after virus entry into the host cell. rhesus monkey trim5alpha (trim5alpha rh) inhibits human immunodeficiency virus (hiv-1) and feline immunodeficiency virus (fiv) more potently than human trim5alpha (trim5alpha hu). trimcyp restricts infection of hiv-1, simian immunodeficiency virus of african green monkeys (siv agm) and fiv. early after infection, trimcyp, like trim5al ...200717920096
increased apobec3g expression is associated with extensive g-to-a hypermutation in viral dna in rhesus macaque brain during lentiviral infection.apobec3g restricts retrovirus replication through inducing guanosine-to-adenosine (g-to-a) hypermutations in viral dna. its role in brain "intrinsic immunity" has not been elucidated nor has it been convincingly demonstrated which brain cell compartments produce this defense factor in human immunodeficiency virus (hiv) infection, acquired immunodeficiency syndrome (aids), and antiretroviral therapy. here, we investigated by immunohistochemistry and in situ hybridization the cell-specific regulat ...200717917584
cd4+ ccr5+ t-cell dynamics during simian immunodeficiency virus infection of chinese rhesus macaques.simian immunodeficiency virus (siv) infection of rhesus macaques (rms) provides a reliable model to study the relationship between lentivirus replication, cellular immune responses, and cd4+ t-cell dynamics. here we investigated, using sivmac251-infected rms of a chinese genetic background (which experience a slower disease progression than indian rms), the dynamics of cd4+ ccr5+ t cells, as this subset of memory/activated cd4+ t cells is both a preferential target of virus replication and a mar ...200717898067
atraumatic oral spray immunization with replication-deficient viral vector vaccines.the development of needle-free vaccines is one of the recently defined "grand challenges in global health" (h. varmus, r. klausner, r. klausner, r. zerhouni, t. acharya, a. s. daar, and p. a. singer, science 302:398-399, 2003). to explore whether a natural pathway to the inductive site of the mucosa-associated lymphatic tissue could be exploited for atraumatic immunization purposes, replication-deficient viral vector vaccines were sprayed directly onto the tonsils of rhesus macaques. tonsillar i ...200717898066
live attenuated lentivirus infection elicits polyfunctional simian immunodeficiency virus gag-specific cd8+ t cells with reduced apoptotic susceptibility in rhesus macaques that control virus replication after challenge with pathogenic sivmac239.hiv-specific cd8+ t cells that secrete multiple cytokines in response to ag stimulation are associated with the control of virus replication during chronic hiv infection. to determine whether the presence of polyfunctional cd8+ t cell responses distinguishes protected and unprotected monkeys in a live attenuated lentivirus model, siv gag peptide-specific cd8+ t cell responses of simian hiv (shiv) 89.6-vaccinated, sivmac239-challenged rhesus macaques were compared in two monkeys that controlled c ...200717878372
siv infection decreases sympathetic innervation of primate lymph nodes: the role of neurotrophins.the sympathetic nervous system regulates immune responses in part through direct innervation of lymphoid organs. recent data indicate that viral infections can alter the structure of lymph node innervation. to determine the molecular mechanisms underlying sympathetic denervation during simian immunodeficiency virus (siv) infection, we assessed the expression of neurotrophic factors and neuromodulatory cytokines within lymph nodes from experimentally infected rhesus macaques. transcription of ner ...200817870298
novel trim5 isoforms expressed by macaca nemestrina.the trim5 family of proteins contains a ring domain, one or two b boxes, and a coiled-coil domain. the trim5alpha isoform also encodes a c-terminal b30.2(spry) domain, differences within which define the breadth and potency of trim5alpha-mediated retroviral restriction. because macaca nemestrina animals are susceptible to some human immunodeficiency virus (hiv) isolates, we sought to determine if differences exist in the trim5 gene and transcripts of these animals. we identified a two-nucleotide ...200717804491
induction of cd8+ cells able to suppress ccr5-tropic simian immunodeficiency virus sivmac239 replication by controlled infection of cxcr4-tropic simian-human immunodeficiency virus in vaccinated rhesus macaques.recent recombinant viral vector-based aids vaccine trials inducing cellular immune responses have shown control of cxcr4-tropic simian-human immunodeficiency virus (shiv) replication but difficulty in containment of pathogenic ccr5-tropic simian immunodeficiency virus (siv) in rhesus macaques. in contrast, controlled infection of live attenuated siv/shiv can confer the ability to contain siv superchallenge in macaques. the specific immune responses responsible for this control may be induced by ...200717728225
progressive cd4+ central memory t cell decline results in cd4+ effector memory insufficiency and overt disease in chronic siv infection.primary simian immunodeficiency virus (siv) infections of rhesus macaques result in the dramatic depletion of cd4(+) ccr5(+) effector-memory t (t(em)) cells from extra-lymphoid effector sites, but in most infections, an increased rate of cd4(+) memory t cell proliferation appears to prevent collapse of effector site cd4(+) t(em) cell populations and acute-phase aids. eventually, persistent siv replication results in chronic-phase aids, but the responsible mechanisms remain controversial. here, w ...200717724130
personality and serotonin transporter genotype interact with social context to affect immunity and viral set-point in simian immunodeficiency virus disease.from the beginning of the aids epidemic, stress has been a suspected contributor to the wide variation seen in disease progression, and some evidence supports this idea. not all individuals respond to a stressor in the same way, however, and little is known about the biological mechanisms by which variations in individuals' responses to their environment affect disease-relevant immunologic processes. using the simian immunodeficiency virus/rhesus macaque model of aids, we explored how personalit ...200817719201
neuroinvasion of fluorescein-positive monocytes in acute simian immunodeficiency virus infection.monocytes and macrophages play a central role in the pathogenesis of human immunodeficiency virus (hiv)-associated dementia. they represent prominent targets for hiv infection and are thought to facilitate viral neuroinvasion and neuroinflammatory processes. however, many aspects regarding monocyte brain recruitment in hiv infection remain undefined. the nonhuman primate model of aids is uniquely suited for examination of the role of monocytes in the pathogenesis of aids-associated encephalitis. ...200717715237
acute loss of intestinal cd4+ t cells is not predictive of simian immunodeficiency virus virulence.the predictive value of acute gut-associated lymphoid tissue (galt) cd4+ t cell depletion in lentiviral infections was assessed by comparing three animal models illustrative of the outcomes of siv infection: pathogenic infection (sivsmm infection of rhesus macaques (rh)), persistent nonprogressive infection (sivagm infection of african green monkeys (agm)), and transient, controlled infection (sivagm infection of rh). massive acute depletion of galt cd4+ t cells was a common feature of acute siv ...200717709518
severe depletion of mucosal cd4+ t cells in aids-free simian immunodeficiency virus-infected sooty mangabeys.hiv-infected humans and siv-infected rhesus macaques experience a rapid and dramatic loss of mucosal cd4+ t cells that is considered to be a key determinant of aids pathogenesis. in this study, we show that nonpathogenic siv infection of sooty mangabeys (sms), a natural host species for siv, is also associated with an early, severe, and persistent depletion of memory cd4+ t cells from the intestinal and respiratory mucosa. importantly, the kinetics of the loss of mucosal cd4+ t cells in sms is s ...200717709517
social stress enhances sympathetic innervation of primate lymph nodes: mechanisms and implications for viral pathogenesis.behavioral processes regulate immune system function in part via direct sympathetic innervation of lymphoid organs, but little is known about the factors that regulate the architecture of neural fibers in lymphoid tissues. in the present study, we find that experimentally imposed social stress can enhance the density of catecholaminergic neural fibers within axillary lymph nodes from adult rhesus macaques. this effect is linked to increased transcription of the key sympathetic neurotrophin nerve ...200717699667
infectivity and neutralization of simian immunodeficiency virus with flag epitope insertion in gp120 variable loops.a flag epitope tag was substituted within variable loop 1 (v1), 2 (v2), or 4 (v4) of the gp120 envelope glycoprotein of simian immunodeficiency virus strain 239 (siv239) to evaluate the extent to which each variable loop may serve as a target for antibody-mediated neutralization. two sites within each variable loop of siv239 were chosen for individual epitope tag insertions. flag epitope substitutions were also made in the v1, v2, and v4 loops of a neutralization-sensitive derivative of siv239, ...200717686865
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