Last data update: May 06, 2024. (Total: 46732 publications since 2009)
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Query Trace: Hendry M[original query] |
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Detection of B.1.351 SARS-CoV-2 Variant Strain - Zambia, December 2020.
Mwenda M , Saasa N , Sinyange N , Busby G , Chipimo PJ , Hendry J , Kapona O , Yingst S , Hines JZ , Minchella P , Simulundu E , Changula K , Nalubamba KS , Sawa H , Kajihara M , Yamagishi J , Kapin'a M , Kapata N , Fwoloshi S , Zulu P , Mulenga LB , Agolory S , Mukonka V , Bridges DJ . MMWR Morb Mortal Wkly Rep 2021 70 (8) 280-282 The first laboratory-confirmed cases of coronavirus disease 2019 (COVID-19), the illness caused by SARS-CoV-2, in Zambia were detected in March 2020 (1). Beginning in July, the number of confirmed cases began to increase rapidly, first peaking during July-August, and then declining in September and October (Figure). After 3 months of relatively low case counts, COVID-19 cases began rapidly rising throughout the country in mid-December. On December 18, 2020, South Africa published the genome of a SARS-CoV-2 variant strain with several mutations that affect the spike protein (2). The variant included a mutation (N501Y) associated with increased transmissibility.(†)(,)(§) SARS-CoV-2 lineages with this mutation have rapidly expanded geographically.(¶)(,)** The variant strain (PANGO [Phylogenetic Assignment of Named Global Outbreak] lineage B.1.351(††)) was first detected in the Eastern Cape Province of South Africa from specimens collected in early August, spread within South Africa, and appears to have displaced the majority of other SARS-CoV-2 lineages circulating in that country (2). As of January 10, 2021, eight countries had reported cases with the B.1.351 variant. In Zambia, the average number of daily confirmed COVID-19 cases increased 16-fold, from 44 cases during December 1-10 to 700 during January 1-10, after detection of the B.1.351 variant in specimens collected during December 16-23. Zambia is a southern African country that shares substantial commerce and tourism linkages with South Africa, which might have contributed to the transmission of the B.1.351 variant between the two countries. |
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. |
Unique safety issues associated with virus-vectored vaccines: Potential for and theoretical consequences of recombination with wild type virus strains.
Condit RC , Williamson AL , Sheets R , Seligman SJ , Monath TP , Excler JL , Gurwith M , Bok K , Robertson JS , Kim D , Michael Hendry R , Singh V , Mac LM , Chen RT . Vaccine 2016 34 (51) 6610-6616 In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration. To provide an appropriate context for understanding the potential for recombination of virus-vectored vaccines, we review briefly the current status of virus-vectored vaccines, mechanisms of recombination between viruses, experience with recombination involving live attenuated vaccines in the field, and concerns raised previously in the literature regarding recombination of virus-vectored vaccines with wild type virus strains. We then present a discussion of the major variables that could influence recombination between a virus-vectored vaccine and circulating wild type virus and the consequences of such recombination, including intrinsic recombination properties of the parent virus used as a vector; sequence relatedness of vector and wild virus; virus host range, pathogenesis and transmission; replication competency of vector in target host; mechanism of vector attenuation; additional factors potentially affecting virulence; and circulation of multiple recombinant vectors in the same target population. Finally, we present some guiding principles for vector design and testing intended to anticipate and mitigate the potential for and consequences of recombination of virus-vectored vaccines with wild type pathogenic virus strains. |
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. |
The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG).
Chen RT , Carbery B , Mac L , Berns KI , Chapman L , Condit RC , Excler JL , Gurwith M , Hendry M , Khan AS , Khuri-Bulos N , Klug B , Robertson JS , Seligman SJ , Sheets R , Williamson AL . Vaccine 2014 33 (1) 73-5 Recombinant viral vectors provide an effective means for heterologous antigen expression in vivo and thus represent promising platforms for developing novel vaccines against human pathogens from Ebola to tuberculosis. An increasing number of candidate viral vector vaccines are entering human clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to improve our ability to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating greater public acceptance when licensed. |
Neurovirulence and immunogenicity of attenuated recombinant vesicular stomatitis viruses in nonhuman primates
Clarke DK , Nasar F , Chong S , Johnson JE , Coleman JW , Lee M , Witko SE , Kotash CS , Abdullah R , Megati S , Luckay A , Nowak B , Lackner A , Price RE , Little P , Kalyan N , Randolf V , Javadian A , Zamb TJ , Parks CL , Egan MA , Eldridge J , Hendry M , Udem SA . J Virol 2014 88 (12) 6690-6701 In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation. IMPORTANCE: The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans. |
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. |
Evaluation of pigtail macaques as a model for the effects of copper intrauterine devices on HIV infection
Engel RM , Morris M , Henning T , Ritter JM , Jones TL , Dietz S , Ayers J , Vishwanathan SA , Jenkins L , Zaki S , Wildemeersch D , Garber D , Powell N , Michael Hendry R , McNicholl J , Kersh EN . J Med Primatol 2013 43 (5) 349-59 BACKGROUND: Long-acting, hormonal contraception may increase HIV risk. Copper intrauterine devices (IUDs) could serve as non-hormonal alternatives. We pilot a pigtail macaque model for evaluating HIV susceptibility factors during copper IUD use. METHODS: Frameless and flexible GyneFix(R) copper IUDs were surgically implanted into three SHIVSF 162p3 -positive macaques via hysterotomy and monitored for up to 4 months. Four macaques served as non-IUD controls. RESULTS: All animals retained the devices without complications. No consistent change in vaginal viral RNA or inflammatory cytokines was seen. Two animals had altered menstrual cycles and experienced marked thinning of vaginal epithelium after IUD insertion. Histological examination of uterine tissue at necropsy revealed endometrial ulceration and lymphocytic inflammation with glandular loss at sites of direct IUD contact. CONCLUSIONS: Although the need for insertion surgery could limit its usefulness, this model will allow studies on copper IUDs and SHIV shedding, disease progression, and HIV susceptibility factors. |
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. |
Evaluation of the lymphocyte trafficking drug FTY720 in vaginal tissues
Tsuiki A , Luo W , Henning T , Vishwanathan S , Dinh C , Adams D , Sweeney E , Mitchell J , Bachman S , Sharma P , Powell N , Hendry M , McNicholl J , Kersh E . J Med Primatol 2013 42 (2) 89-100 BACKGROUND: FTY720 is an immunomodulatory agent that reduces lymphocytes in peripheral tissues and circulation. Such agents may be effective as vaginal microbicides for HIV prevention. Systemic or vaginal application of FTY720 may reduce lymphocyte concentrations in genital tissues, reducing HIV target cell numbers. METHODS: Five female pigtail macaques received topical vaginal gel FTY720 (n = 2), intravenous (IV) FTY720 (n = 2), or placebo gel (n = 1) in this pilot study. Circulating and mucosal lymphocytes and genital mucosa, cytokines, and tissue histology were analyzed to document topical and IV FTY720 effects. RESULTS: Topical and IV FTY720 appeared to decrease the levels of cervicovaginal IL-8, IL-1ra, and genital inflammatory cells. Small sample size precluded statistical analysis. Topical administration had no overt adverse effects. CONCLUSIONS: This study introduces FTY720 as an immunomodulatory agent for the vaginal mucosa, compares topical effects to those of IV administration, and provides the basis for future studies involving FTY720 for HIV prevention. |
Relaxation of adaptive evolution during the HIV-1 infection owing to reduction of CD4+ T cell counts.
Leal E , Casseb J , Hendry M , Busch MP , Diaz RS . PLoS One 2012 7 (6) e39776 BACKGROUND: The first stages of HIV-1 infection are essential to establish the diversity of virus population within host. It has been suggested that adaptation to host cells and antibody evasion are the leading forces driving HIV evolution at the initial stages of AIDS infection. In order to gain more insights on adaptive HIV-1 evolution, the genetic diversity was evaluated during the infection time in individuals contaminated by the same viral source in an epidemic cluster. Multiple sequences of V3 loop region of the HIV-1 were serially sampled from four individuals: comprising a single blood donor, two blood recipients, and another sexually infected by one of the blood recipients. The diversity of the viral population within each host was analyzed independently in distinct time points during HIV-1 infection. RESULTS: Phylogenetic analysis identified multiple HIV-1 variants transmitted through blood transfusion but the establishing of new infections was initiated by a limited number of viruses. Positive selection (d(N)/d(S)>1) was detected in the viruses within each host in all time points. In the intra-host viruses of the blood donor and of one blood recipient, X4 variants appeared respectively in 1993 and 1989. In both patients X4 variants never reached high frequencies during infection time. The recipient, who X4 variants appeared, developed AIDS but kept narrow and constant immune response against HIV-1 during the infection time. CONCLUSION: Slowing rates of adaptive evolution and increasing diversity in HIV-1 are consequences of the CD4+ T cells depletion. The dynamic of R5 to X4 shift is not associated with the initial amplitude of humoral immune response or intensity of positive selection. |
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. |
Generation of a dual RT Env SHIV that is infectious in rhesus macaques
Smith JM , Dauner A , Li B , Srinivasan P , Mitchell J , Hendry M , Ellenberger D , Butera S , Otten RA . J Med Primatol 2010 39 (4) 213-23 BACKGROUND: The best current animal model for HIV infection and evaluation of antiviral compounds is the Simian-human immunodeficiency virus (SHIV)/macaque system. There are multiple recombinant SHIVs available, but these viruses have limitations in evaluating combination drug strategies for prevention. Drug combinations that target reverse transcriptase (RT, either nRTI or nnRTI) and envelope (entry or fusion inhibitors) have to be tested separately, which does not permit the assessment of additive, synergistic, or antagonistic effects of ARV combinations. We describe construction of a dual SHIV containing both HIV RT and a CCR5-specific HIV envelope gene in a simian immunodeficiency virus backbone. METHODS: The RT Env SHIV molecular clone was constructed using RT SHIV and SHIV162p3 sequences as templates to generate RT Env SHIV. RT Env SHIV was expanded in vitro in CD8-depleted macaque peripheral blood mononuclear cells (PBMC). Recombinant virus was used to infect a rhesus macaque (4.3 x 10(4) tissue culture infectious dose [TCID(50)], intravenously [IV]). A second passage in a macaque by IV transfer of 10 ml of blood obtained from the first infection was also done. The in vivo adapted virus stock from these macaques was used to produce high titer stocks in vitro and used to rectally infect an additional macaque. RESULTS: Peak viral load reached 6 x 10(5) vRNA copies/ml in plasma in both IV-exposed macaques and remained detectable in the one animal for 16 weeks after infection. A viral stock (1.68 x 10(4) TCID(50)) derived from the second macaque passage has been produced in CD8-depleted rhesus PBMC and was successfully used to demonstrate mucosal transmission. The resulting RT Env SHIV retained the sensitivity to HIV RT and entry inhibitors of its parental viruses. CONCLUSIONS: The objective of this study was to develop and characterize a SHIV recombinant virus for evaluating the efficacy of ART and microbicide products that target both HIV RT and/or Env-mediated entry. RT Env SHIV can productively infect macaques by both the IV and mucosal route, making it a valuable tool for transmission studies. |
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