Last data update: Jun 03, 2024. (Total: 46935 publications since 2009)
Records 1-15 (of 15 Records) |
Query Trace: Hendry RM [original query] |
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Increases in endogenous or exogenous progestins promote virus-target cell interactions within the non-human primate female reproductive tract
Carias AM , Allen SA , Fought AJ , Kotnik Halavaty K , Anderson MR , Jimenez ML , McRaven MD , Gioia CJ , Henning TR , Kersh EN , Smith JM , Pereira LE , Butler K , McNicholl SJ , Hendry RM , Kiser PF , Veazey RS , Hope TJ . PLoS Pathog 2016 12 (9) e1005885 Currently, there are mounting data suggesting that HIV-1 acquisition in women can be affected by the use of certain hormonal contraceptives. However, in non-human primate models, endogenous or exogenous progestin-dominant states are shown to increase acquisition. To gain mechanistic insights into this increased acquisition, we studied how mucosal barrier function and CD4+ T-cell and CD68+ macrophage density and localization changed in the presence of natural progestins or after injection with high-dose DMPA. The presence of natural or injected progestins increased virus penetration of the columnar epithelium and the infiltration of susceptible cells into a thinned squamous epithelium of the vaginal vault, increasing the likelihood of potential virus interactions with target cells. These data suggest that increasing either endogenous or exogenous progestin can alter female reproductive tract barrier properties and provide plausible mechanisms for increased HIV-1 acquisition risk in the presence of increased progestin levels. |
Live virus vaccines based on a vesicular stomatitis virus (VSV) backbone: Standardized template with key considerations for a risk/benefit assessment.
Clarke DK , Hendry RM , Singh V , Rose JK , Seligman SJ , Klug B , Kochhar S , Mac LM , Carbery B , Chen RT . Vaccine 2016 34 (51) 6597-6609 The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety of live, recombinant viral vaccines incorporating genes from heterologous viral and other microbial pathogens in their genome (so-called "chimeric virus vaccines"). Many such viral vector vaccines are now at various stages of clinical evaluation. Here, we introduce an attenuated form of recombinant vesicular stomatitis virus (rVSV) as a potential chimeric virus vaccine for HIV-1, with implications for use as a vaccine vector for other pathogens. The rVSV/HIV-1 vaccine vector was attenuated by combining two major genome modifications. These modifications acted synergistically to greatly enhance vector attenuation and the resulting rVSV vector demonstrated safety in sensitive mouse and non-human primate neurovirulence models. This vector expressing HIV-1 gag protein has completed evaluation in two Phase I clinical trials. In one trial the rVSV/HIV-1 vector was administered in a homologous two-dose regimen, and in a second trial with pDNA in a heterologous prime boost regimen. No serious adverse events were reported nor was vector detected in blood, urine or saliva post vaccination in either trial. Gag specific immune responses were induced in both trials with highest frequency T cell responses detected in the prime boost regimen. The rVSV/HIV-1 vector also demonstrated safety in an ongoing Phase I trial in HIV-1 positive participants. Additionally, clinical trial material has been produced with the rVSV vector expressing HIV-1 env, and Phase I clinical evaluation will initiate in the beginning of 2016. In this paper, we use a standardized template describing key characteristics of the novel rVSV vaccine vectors, in comparison to wild type VSV. The template facilitates scientific discourse among key stakeholders by increasing transparency and comparability of information. The Brighton Collaboration V3SWG template may also be useful as a guide to the evaluation of other recombinant viral vector vaccines. |
Rectal application of a highly osmolar personal lubricant in a macaque model induces acute cytotoxicity but does not increase risk of SHIV infection
Vishwanathan SA , Morris MR , Wolitski RJ , Luo W , Rose CE , Blau DM , Tsegaye T , Zaki SR , Garber DA , Jenkins LT , Henning TC , Patton DL , Hendry RM , McNicholl JM , Kersh EN . PLoS One 2015 10 (4) e0120021 BACKGROUND: Personal lubricant use is common during anal intercourse. Some water-based products with high osmolality and low pH can damage genital and rectal tissues, and the polymer polyquaternium 15 (PQ15) can enhance HIV replication in vitro. This has raised concerns that lubricants with such properties may increase STD/HIV infection risk, although in vivo evidence is scarce. We use a macaque model to evaluate rectal cytotoxicity and SHIV infection risk after use of a highly osmolar (>8,000 mOsm/kg) water-based lubricant with pH of 4.4, and containing PQ15. METHODS: Cytotoxicity was documented by measuring inflammatory cytokines and epithelial tissue sloughing during six weeks of repeated, non-traumatic lubricant or control buffer applications to rectum and anus. We measured susceptibility to SHIVSF162P3 infection by comparing virus doses needed for rectal infection in twenty-one macaques treated with lubricant or control buffer 30 minutes prior to virus exposure. RESULTS: Lubricant increased pro-inflammatory cytokines and tissue sloughing while control buffer (phosphate buffered saline; PBS) did not. However, the estimated AID50 (50% animal infectious dose) was not different in lubricant- and control buffer-treated macaques (p = 0.4467; logistic regression models). CONCLUSIONS: Although the test lubricant caused acute cytotoxicity in rectal tissues, it did not increase susceptibility to infection in this macaque model. Thus neither the lubricant-induced type/extent of inflammation nor the presence of PQ15 affected infection risk. This study constitutes a first step in the in vivo evaluation of lubricants with regards to HIV transmission. |
A polyvalent clade B virus-like particle HIV vaccine combined with partially protective oral preexposure prophylaxis prevents simian-human immunodeficiency virus infection in macaques and primes for virus-amplified immunity
Ross TM , Pereira LE , Luckay A , McNicholl JM , Garcia-Lerma JG , Heneine W , Eugene HS , Pierce-Paul BR , Zhang J , Hendry RM , Smith JM . AIDS Res Hum Retroviruses 2014 30 (11) 1072-81 Vaccination and preexposure prophylaxis (PrEP) with antiretrovirals have shown only partial protection from HIV-1 infection in human trials. Oral Truvada (emtricitabine/tenofovir disoproxil fumarate) is FDA approved as PrEP but partial adherence reduces efficacy. If combined as biomedical preventions (CBP), an HIV vaccine could protect when PrEP adherence is low and PrEP could prevent vaccine breakthroughs. The efficacy of combining oral PrEP with an HIV vaccine has not been evaluated in humans. We determined the efficacy of combining a DNA/virus-like particle (VLP) vaccine with partially effective intermittent PrEP in Indian rhesus macaques (RM). Eight RM received intramuscular inoculations of five DNA plasmids encoding four HIV-1 Clade B primary isolate Envs and SIVmac239 Gag (at weeks 0 and 4), followed by intramuscular and intranasal inoculations of homologous Gag VLPs and four Env VLPs (at weeks 12, 16, and 53). At week 61, we initiated weekly rectal exposures with heterologous SHIV162p3 (10 TCID50) along with oral Truvada (TDF, 22 mg/kg; FTC 20 mg/kg) dosing 2 h before and 22 h after each exposure. This PrEP regimen previously demonstrated 50% efficacy. Five controls (no vaccine, no PrEP) received weekly SHIV162p3. All controls were infected after a median of four exposures; the mean peak plasma viral load (VL) was 3.9x10(7) vRNA copies/ml. CBP protected seven of eight (87.5%) RM. The one infected CBP RM had a reduced peak VL of 8.8x10(5) copies/ml. SHIV exposures during PrEP amplified Gag and Env antibody titers in protected RM. These results suggest that combining oral PrEP with HIV vaccines could enhance protection against HIV-1 infection. |
Pharmacokinetic and safety analyses of tenofovir and tenofovir-emtricitabine vaginal tablets in pigtailed macaques
Pereira LE , Clark MR , Friend DR , Garber DA , McNicholl JM , Hendry RM , Doncel GF , Smith JM . Antimicrob Agents Chemother 2014 58 (5) 2665-74 Vaginal rapidly disintegrating tablets (RDTs) containing tenofovir (TFV) or TFV and emtricitabine (FTC) were evaluated for safety and pharmacokinetics in pigtailed macaques. Two separate animal groups (n = 4) received TFV (10 mg) or TFV-FTC (10 mg each) RDTs, administered near the cervix. A third group (n = 4) received 1 ml TFV gel. Blood plasma, vaginal tissue biopsy specimens, and vaginal fluids were collected before and after product application at 0, 0.5, 1, 4, and 24 h. A disintegration time of <30 min following vaginal application of the RDTs was noted, with negligible effects on local inflammatory cytokines, vaginal pH, and microflora. TFV pharmacokinetics were generally similar for both RDTs and gel, with peak median concentrations in vaginal tissues and vaginal secretions being on the order of 10(4) to 10(5) ng/g (147 to 571 muM) and 10(6) ng/g (12 to 34 mM), respectively, at 1 to 4 h postdose. At 24 h, however, TFV vaginal tissue levels were more sustained after RDT dosing, with median TFV concentrations being approximately 1 log higher than those with gel dosing. FTC pharmacokinetics after combination RDT dosing were similar to those of TFV, with peak median vaginal tissue and fluid levels being on the order of 10(4) ng/g (374 muM) and 10(6) ng/g (32 mM), respectively, at 1 h postdose with levels in fluid remaining high at 24 h. RDTs are a promising alternative vaginal dosage form, delivering TFV and/or FTC at levels that would be considered inhibitory to simian-human immunodeficiency virus in the macaque vaginal microenvironment over a 24-h period. |
Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges
Smith JM , Rastogi R , Teller RS , Srinivasan P , Mesquita PM , Nagaraja U , McNicholl JM , Hendry RM , Dinh CT , Martin A , Herold BC , Kiser PF . Proc Natl Acad Sci U S A 2013 110 (40) 16145-50 Topical preexposure prophylaxis interrupts HIV transmission at the site of mucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitor tenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gel application. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs) may improve efficacy by providing long-term sustained drug delivery leading to constant mucosal antiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinical pipeline, 100% efficacy in a repeated macaque vaginal challenge model has not been achieved. Here we describe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate (TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRs generated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remained seronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue culture infectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of four exposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associated with tenofovir levels in vaginal fluid [mean 1.8 x 10(5) ng/mL (range 1.1 x 10(4) to 6.6 x 10(5) ng/mL)] and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support further advancement of TDF IVRs as well as the concept that extended duration drug delivery devices delivering topical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans. |
Susceptibility to repeated, low-dose, rectal SHIVSF162P3 challenge is independent of TRIM5 genotype in rhesus macaques.
Butler K , Morgan JS , Hanson DL , Adams DR , Garcia-Lerma G , Heneine PW , Ellenberger D , Hendry RM , McNicholl JM , Johnson W , Kersh EN . AIDS Res Hum Retroviruses 2013 29 (7) 1091-4 Infections following repeated, low-dose (RLD), mucosal S(H)IV exposures of macaques are used to model sexual HIV exposures for biomedical prevention testing. Different susceptibilities among animals can complicate study designs. In rhesus macaques, TRIM5 alleles Q, CypA, and TFP, are resistance factors for infection with some S(H)IV strains, but not for SIVmac239 due to its capsid properties. SIVmac239-derived SHIVSF162P3 has been demonstrated to reproducibly infect mucosally in vaginal and rectal RLD models. To further test the suitability of SHIVSF162P3 for RLD models, we studied the influence of TRIM5 genotype on susceptibility to rectal RLD infection and on plasma viremia by analyzing 43 male Indian rhesus macaques from control arms of completed studies. The median number of exposures required for infection was: 3 (Q/Q, n=4) (TRIM5 alleles, number of macaques, respectively); 4 (Q/CypA, n=7), 3 (TFP/Q, n=15); 3 (TFP/TFP, n=15); 2 (TFP/CypA, n=2); TRIM5CypA/CypA was not represented in our study. Median peak viremia (log10 viral copies/mL) in infected animals was: 7.4 (Q/Q, n=4); 7.2 (Q/CypA, n=6), 7.3 (TFP/Q, n=13); 7.1 (TFP/TFP, n=15); 6.5 (TFP/CypA; n=2). Neither susceptibility nor peak viremia were significantly different (log-rank test, Kruskal Wallis test, respectively). Rhesus macaques' susceptibility to RLD SHIVSF162P3 is independent of TRIM5 TFP, CypA, and Q alleles, with the limitation that the power to detect any impact of CypA/CypA and TFP/CypA genotypes was nonexistent or low, due to absence or infrequency, respectively. The finding that TRIM5 alleles do not restrict mucosal infection or ensuing replication rates suggests that SHIVSF162P3 is indeed suitable for RLD experimentation. |
Reduced inflammation and CD4 loss in acute SHIV infection during oral PrEP
Kersh EN , Luo W , Zheng Q , Adams DR , Hanson D , Youngpairoj AS , Cong ME , Butler K , Hendry RM , McNicholl JM , Heneine W , Garcia-Lerma JG . J Infect Dis 2012 206 (5) 770-9 BACKGROUND: The impact of Pre-exposure Prophylaxis (PrEP) with anti-retrovirals on breakthrough HIV or SHIV infection is not fully documented. We addressed the hypothesis that SHIV(SF162P3) infection despite active PrEP results in altered early immune parameters compared to untreated infection. METHODS: Eleven rhesus macaques were infected during repeated, rectal, low-dose SHIV(SF162P3) exposures while receiving concurrent, oral PrEP (Truvada, n=2, or GS7340, n=4), or as untreated controls (n=5). We measured SHIV RNA, inflammatory cytokines, CD4 cells, and SHIV-specific and memory T cells until 20 weeks post peak viremia. RESULTS: SHIV infection during PrEP resulted in 100-fold lower peak viremia and lower IL-15, IL-18, and IL-1Ra levels compared to controls (p<0.05; Wilcoxon rank-sum test). Unlike controls, PrEP-treated macaques showed no significant CD4 reduction during acute infection, and developed more SHIV-specific central memory T cells relative to controls. Following in-vivo CD8(+) cell depletion, viremia rose to similar levels, indicating that CD8(+) cells were critical for viral control in both groups. CONCLUSIONS: PrEP with anti-retrovirals has beneficial effects on early SHIV infection even when infection is not prevented. While long-term immune control could not be examined in this SHIV infection model, our results suggest that PrEP results in improved early disease parameters in breakthrough infections. |
Safe and sustained vaginal delivery of pyrimidinedione HIV-1 inhibitors from polyurethane intravaginal rings
Johnson TJ , Srinivasan P , Albright TH , Watson-Buckheit K , Rabe L , Martin A , Pau CP , Hendry RM , Otten R , McNicholl J , Buckheit R Jr , Smith J , Kiser PF . Antimicrob Agents Chemother 2012 56 (3) 1291-9 The potent antiretroviral pyrimidinediones IQP-0528 (PYD1) and IQP-0532 (PYD2) were formulated in polyurethane intravaginal rings (IVRs) as prophylactic drug delivery systems to prevent the sexual transmission of HIV-1. To aid in the selection of a pyrimidinedione candidate and the optimal loading of the drug in the IVR delivery system, four pyrimidinedione IVR formulations (PYD1 at 0.5 wt% [PYD1(0.5wt%)], PYD1(1wt%), PYD2(4wt%), and PYD2(14wt%)) were evaluated in pigtail macaques over 28 days for safety and pyrimidinedione vaginal biodistribution. Kinetic analysis of vaginal proinflammatory cytokines, native microflora, and drug levels suggested that all formulations were safe, but only the high-loaded PYD2(14wt%) IVR demonstrated consistently high pyrimidinedione vaginal fluid and tissue levels over the 28-day study. This formulation delivered drug in excess of 10 mug/ml to vaginal fluid and 1 mug/g to vaginal tissue, a level over 1,000 times the in vitro 50% effective concentration. The in vitro release of PYD1 and PYD2 under nonsink conditions correlated well with in vivo release, both in amount and in kinetic profile, and therefore may serve as a more biologically relevant means of evaluating release in vitro than typically employed sink conditions. Lastly, the pyrimidinediones in the IVR formulation were chemically stable after 90 days of storage at elevated temperature, and the potent nanomolar-level antiviral activity of both molecules was retained after in vitro release. Altogether, these results point to the successful IVR formulation and vaginal biodistribution of the pyrimidinediones and demonstrate the usefulness of the pigtail macaque model in evaluating and screening antiretroviral IVR formulations prior to preclinical and clinical evaluation. |
Development of a pigtail macaque model of sexually transmitted infection/HIV coinfection using Chlamydia trachomatis, Trichomonas vaginalis, and SHIV(SF162P3)
Henning T , Fakile Y , Phillips C , Sweeney E , Mitchell J , Patton D , Sturdevant G , Caldwell HD , Secor WE , Papp J , Hendry RM , McNicholl J , Kersh E . J Med Primatol 2011 40 (4) 214-23 BACKGROUND: Sexually transmitted infections (STIs) are associated with an increased risk of HIV infection. To model the interaction between STIs and HIV infection, we evaluated the capacity of the pigtail macaque model to sustain triple infection with Trichomonas vaginalis, Chlamydia trachomatis, and SHIV(SF162P3) . METHODS: Seven SHIV(SF162P3) -infected pigtail macaques were inoculated with T. vaginalis only (n = 2), C. trachomatis only (n = 1), both T. vaginalis and C. trachomatis (n = 2), or control media (no STI; n = 2). Infections were confirmed by culture and/or nucleic acid testing. Genital mucosa was visualized by colposcopy. RESULTS: Characteristic gynecologic signs were observed for both STIs, but not in control animals. Manifestations were most prominent at days 7-10 post-infection. STIs persisted between 4 and 6 weeks and were cleared with antibiotics. CONCLUSIONS: These pilot studies demonstrate the first successful STI-SHIV triple infection of pigtail macaques, with clinical presentation of genital STI symptoms similar to those observed in humans. |
Protection against rectal transmission of an emtricitabine (FTC)-resistant SHIV162p3M184V mutant by intermittent prophylaxis with Truvada
Cong ME , Youngpairoj AS , Zheng Q , Aung W , Mitchell J , Sweeney E , Hanson DL , Hendry RM , Dobard C , Heneine W , Garcia-Lerma JG . J Virol 2011 85 (15) 7933-6 Daily pre-exposure prophylaxis (PrEP) with Truvada (FTC and TDF) is a novel HIV prevention strategy recently found to reduce HIV incidence among men who have sex with men. We used a macaque model of HIV transmission to investigate if Truvada maintains prophylactic efficacy against an FTC-resistant isolate containing the M184V mutation. Five macaques received a dose of Truvada 3 days before exposing them rectally to SHIV162p3(M184V) followed by a second dose 2h afterwards. Five untreated animals were used as controls. Virus exposures were done weekly for up to 14 weeks. Despite the high (>100-fold) level of FTC resistance conferred by M184V, all five treated animals were protected from infection while the five untreated macaques were infected (p=0.0008). Our results show that Truvada maintains high prophylactic efficacy against an FTC-resistant isolate. Increased susceptibility to tenofovir due to M184V and other factors including residual antiviral activity by FTC and/or reduced virus fitness due to M184V may have all contributed to the observed protection. |
High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques
Vishwanathan SA , Guenthner PC , Lin CY , Dobard C , Sharma S , Adams DR , Otten RA , Heneine W , Hendry RM , McNicholl JM , Kersh EN . J Acquir Immune Defic Syndr 2011 57 (4) 261-4 Fluctuations in susceptibility to HIV or SHIV during the menstrual cycle are currently not fully documented. To address this, time point of infection was determined in 19 adult female pigtail macaques vaginally challenged during their undisturbed menstrual cycles with repeated, low-dose SHIVSF162P3 exposures. Eighteen macaques (95%) first displayed viremia in the follicular phase, as compared to 1 macaque (5%) in the luteal phase (p<0.0001). Due to a viral eclipse phase, we estimated a window of most frequent virus transmission between days 24-31 of the menstrual cycle, in the late luteal phase. Thus, susceptibility to vaginal SHIV infection is significantly elevated in the second half of the menstrual cycle when progesterone levels are high, and when local immunity may be low. Such susceptibility windows have been postulated before but not definitively documented. Our data support findings of higher susceptibility to HIV in women during progesterone-dominated periods including pregnancy and contraceptive use. |
T cell chemo-vaccination effects after repeated mucosal SHIV exposures and oral pre-exposure prophylaxis
Kersh EN , Adams DR , Youngpairoj AS , Luo W , Zheng Q , Cong ME , Aung W , Mitchell J , Otten R , Hendry RM , Heneine W , McNicholl J , Garcia-Lerma JG . PLoS One 2011 6 (4) e19295 Pre-exposure prophylaxis (PrEP) with anti-viral drugs is currently in clinical trials for the prevention of HIV infection. Induction of adaptive immune responses to virus exposures during anti-viral drug administration, i.e., a "chemo-vaccination" effect, could contribute to PrEP efficacy. To study possible chemo-vaccination, we monitored humoral and cellular immune responses in nine rhesus macaques undergoing up to 14 weekly, low-dose SHIV(SF162P3) rectal exposures. Six macaques concurrently received PrEP with intermittent, oral Truvada; three were no-PrEP controls. PrEP protected 4 macaques from infection. Two of the four showed evidence of chemo-vaccination, because they developed anti-SHIV CD4(+) and CD8(+) T cells; SHIV-specific antibodies were not detected. Control macaques showed no anti-SHIV immune responses before infection. Chemo-vaccination-induced T cell responses were robust (up to 3,940 SFU/10(6) PBMCs), predominantly central memory cells, short-lived (≤22 weeks), and appeared intermittently and with changing specificities. The two chemo-vaccinated macaques were virus-challenged again after 28 weeks of rest, after T cell responses had waned. One macaque was not protected from infection. The other macaque concurrently received additional PrEP. It remained uninfected and T cell responses were boosted during the additional virus exposures. In summary, we document and characterize PrEP-induced T cell chemo-vaccination. Although not protective after subsiding in one macaque, chemo-vaccination-induced T cells warrant more comprehensive analysis during peak responses for their ability to prevent or to control infections after additional exposures. Our findings highlight the importance of monitoring these responses in clinical PrEP trials and suggest that a combination of vaccines and PrEP potentially might enhance efficacy. |
Hormonal synchronization of the menstrual cycles of pigtail macaques to facilitate biomedical research including modeling HIV susceptibility
Livingston L , Sweeney E , Mitchell J , Luo W , Paul K , Powell N , Hendry RM , McNicholl J , Kersh E . J Med Primatol 2011 40 (3) 164-70 BACKGROUND: Menstrual cycle synchronization of female pigtail macaques could prove an invaluable resource in studies of the reproductive tract, associated infections, and other potential research fields. We tested whether use of an oral progesterone and estradiol combination tablet could synchronize menstrual cycles following treatment discontinuation. METHODS: Daily desogestrel 0.075 mg and ethinyl estradiol 0.01 mg were administered orally to three pigtail macaques at visual onset of perineal sex swelling and were continued until all animals had received it for at least 45 days. The hormones were discontinued, and these three macaques and three controls were observed for menstruation and had blood progesterone and estrogen measured over an additional 2-month period. RESULTS: All treatment animals showed spontaneous menstrual cycle synchronization for 2 months after menstrual cycling resumed. CONCLUSION: Progesterone and estradiol combination therapy can be used in pigtail macaques to induce synchronized cycling that persists in the absence of on-going hormone treatments. |
Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States
Switzer WM , Jia H , Hohn O , Zheng H , Tang S , Shankar A , Bannert N , Simmons G , Hendry RM , Falkenberg VR , Reeves WC , Heneine W . Retrovirology 2010 7 57 BACKGROUND: XMRV, a xenotropic murine leukemia virus (MuLV)-related virus, was recently identified by PCR testing in 67% of persons with chronic fatigue syndrome (CFS) and in 3.7% of healthy persons from the United States. To investigate the association of XMRV with CFS we tested blood specimens from 51 persons with CFS and 56 healthy persons from the US for evidence of XMRV infection by using serologic and molecular assays. Blinded PCR and serologic testing were performed at the US Centers for Disease Control and Prevention (CDC) and at two additional laboratories. RESULTS: Archived blood specimens were tested from persons with CFS defined by the 1994 international research case definition and matched healthy controls from Wichita, Kansas and metropolitan, urban, and rural Georgia populations. Serologic testing at CDC utilized a Western blot (WB) assay that showed excellent sensitivity to MuLV and XMRV polyclonal or monoclonal antibodies, and no reactivity on sera from 121 US blood donors or 26 HTLV-and HIV-infected sera. Plasma from 51 CFS cases and plasma from 53 controls were all WB negative. Additional blinded screening of the 51 cases and 53 controls at the Robert Koch Institute using an ELISA employing recombinant Gag and Env XMRV proteins identified weak seroreactivity in one CFS case and a healthy control, which was not confirmed by immunofluorescence. PCR testing at CDC employed a gag and a pol nested PCR assay with a detection threshold of 10 copies in 1 ug of human DNA. DNA specimens from 50 CFS patients and 56 controls and 41 US blood donors were all PCR-negative. Blinded testing by a second nested gag PCR assay at the Blood Systems Research Institute was also negative for DNA specimens from the 50 CFS cases and 56 controls. CONCLUSIONS: We did not find any evidence of infection with XMRV in our U.S. study population of CFS patients or healthy controls by using multiple molecular and serologic assays. These data do not support an association of XMRV with CFS. |
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