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10.1371%2Fjournal.pone.0008829
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introduction
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However, few successful strategies to prevent HIV transmissions currently exist [>>1<<]–[5]. Novel approaches to prevent HIV transmission, including effective vaccines, are being considered and developed [6]. In particular, antiretroviral pre-exposure prophylaxis (PrEP) has been postulated to be a potentially highly
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Novel approaches to prevent HIV transmission, including effective vaccines, are being considered and developed [>>6<<]. In particular, antiretroviral pre-exposure prophylaxis (PrEP) has been postulated to be a potentially highly effective prevention modality [7]–[15]. There are many reasons to consider implementing targeted antiretroviral PrEP until less
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In particular, antiretroviral pre-exposure prophylaxis (PrEP) has been postulated to be a potentially highly effective prevention modality [>>7<<]–[15]. There are many reasons to consider implementing targeted antiretroviral PrEP until less toxic, easier to deliver and more potent prevention methods become available. Candidate antiretroviral drugs for PrEP already exist.
n3:mentions
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In particular, antiretroviral pre-exposure prophylaxis (PrEP) has been postulated to be a potentially highly effective prevention modality [7]–[>>15<<]. There are many reasons to consider implementing targeted antiretroviral PrEP until less toxic, easier to deliver and more potent prevention methods become available. Candidate antiretroviral drugs for PrEP already exist. Antiretrovirals
n3:mentions
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associated costs, these should not distract from the vast prospective positive impact of PrEP: targeted PrEP has been mathematically modeled to avert up to 3 million new infections over a 10 year period in Sub-Saharan Africa alone [>>16<<]. Antiretroviral PrEP could benefit numerous groups at risk of either vaginal, rectal or intravenous HIV exposure:
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Antiretroviral PrEP could benefit numerous groups at risk of either vaginal, rectal or intravenous HIV exposure: discordant couples, high risk women, men who have sex with men and injection drug users [>>13<<]. Topical microbicides may be identified that block mucosal HIV transmission [17]–[19]. However, as illustrated by several setbacks in recent clinical trials (i.e. Microbicides Development Program study 301using 0.5% Pro 2000/5)
n3:mentions
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Topical microbicides may be identified that block mucosal HIV transmission [>>17<<]–[19]. However, as illustrated by several setbacks in recent clinical trials (i.e. Microbicides Development Program study 301using 0.5% Pro 2000/5) microbicide development and implementation lags far behind that of clinically approved
n3:mentions
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as illustrated by several setbacks in recent clinical trials (i.e. Microbicides Development Program study 301using 0.5% Pro 2000/5) microbicide development and implementation lags far behind that of clinically approved antiretrovirals [>>13<<], [20], [21]. In addition, it should be noted that topical interventions will not prevent intravenous HIV transmission.
n3:mentions
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by several setbacks in recent clinical trials (i.e. Microbicides Development Program study 301using 0.5% Pro 2000/5) microbicide development and implementation lags far behind that of clinically approved antiretrovirals [13], [>>20<<], [21]. In addition, it should be noted that topical interventions will not prevent intravenous HIV transmission.
n3:mentions
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by several setbacks in recent clinical trials (i.e. Microbicides Development Program study 301using 0.5% Pro 2000/5) microbicide development and implementation lags far behind that of clinically approved antiretrovirals [13], [20], [>>21<<]. In addition, it should be noted that topical interventions will not prevent intravenous HIV transmission.
n3:mentions
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To this end, we chose the humanized Bone marrow/Liver/Thymus (BLT) mouse as our experimental system [>>22<<].
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a complete, systemic, self-renewing reconstitution of all major human hematopoietic lineages including T, B, monocyte/macrophage, dendritic and natural killer cells that facilitates the generation of functional human immune responses [>>22<<]–[26]. The levels of HIV receptor and co-receptor expression in BLT mice reflect those observed in humans and the pathogenesis of CCR5 tropic HIV-1 in BLT mice mirrors descriptions of HIV pathogenesis in infected individuals [24], [26].
n3:mentions
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systemic, self-renewing reconstitution of all major human hematopoietic lineages including T, B, monocyte/macrophage, dendritic and natural killer cells that facilitates the generation of functional human immune responses [22]–[>>26<<]. The levels of HIV receptor and co-receptor expression in BLT mice reflect those observed in humans and the pathogenesis of CCR5 tropic HIV-1 in BLT mice mirrors descriptions of HIV pathogenesis in infected individuals [24], [26].
n3:mentions
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The levels of HIV receptor and co-receptor expression in BLT mice reflect those observed in humans and the pathogenesis of CCR5 tropic HIV-1 in BLT mice mirrors descriptions of HIV pathogenesis in infected individuals [>>24<<], [26]. Particularly relevant to this study is the broad and systemic reconstitution of BLT mice with human immune cells necessary for HIV-1 replication and transmission (CD4+ T cells, macrophages and dendritic cells) that encompasses the
n3:mentions
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The levels of HIV receptor and co-receptor expression in BLT mice reflect those observed in humans and the pathogenesis of CCR5 tropic HIV-1 in BLT mice mirrors descriptions of HIV pathogenesis in infected individuals [24], [>>26<<]. Particularly relevant to this study is the broad and systemic reconstitution of BLT mice with human immune cells necessary for HIV-1 replication and transmission (CD4+ T cells, macrophages and dendritic cells) that encompasses the
n3:mentions
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for HIV-1 replication and transmission (CD4+ T cells, macrophages and dendritic cells) that encompasses the peripheral blood and the rectal and vaginal mucosa rendering BLT mice susceptible to intravenous and mucosal HIV-1 infection [>>22<<], [24], [26]. Furthermore, systemic PrEP with a combination of antiretrovirals (FTC:
n3:mentions
n2:17057712
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HIV-1 replication and transmission (CD4+ T cells, macrophages and dendritic cells) that encompasses the peripheral blood and the rectal and vaginal mucosa rendering BLT mice susceptible to intravenous and mucosal HIV-1 infection [22], [>>24<<], [26]. Furthermore, systemic PrEP with a combination of antiretrovirals (FTC: emtricitabine and TDF:
n3:mentions
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replication and transmission (CD4+ T cells, macrophages and dendritic cells) that encompasses the peripheral blood and the rectal and vaginal mucosa rendering BLT mice susceptible to intravenous and mucosal HIV-1 infection [22], [24], [>>26<<]. Furthermore, systemic PrEP with a combination of antiretrovirals (FTC: emtricitabine and TDF:
n3:mentions
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of antiretrovirals (FTC: emtricitabine and TDF: tenofovir disoproxil fumarate) prevents vaginal HIV-1 transmission in BLT mice establishing this model as a novel system for in vivo preclinical evaluation of HIV prevention modalities [>>24<<].
n3:mentions
n2:18198941
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In addition, rectal transmission is also likely to account for a significant number of transmissions to women [>>27<<]. We hypothesized that systemic antiretroviral PrEP can provide protection from rectal and intravenous HIV-1 transmission. We tested this hypothesis by treating BLT mice systemically with FTC/TDF prior to exposure and we determined that
n3:mentions
n2:11242155
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_:vb6874055
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materials and methods
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BLT mice were prepared essentially as previously described [>>22<<]–[26]. Briefly, thy/liv implanted [28] NOD/SCID or NOD/SCID-gamma chain null mice (The Jackson Laboratories, Bar Harbor, ME) were transplanted with autologous human fetal liver CD34+ cells (Advanced Bioscience Resources, Alameda, CA) and
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BLT mice were prepared essentially as previously described [22]–[>>26<<]. Briefly, thy/liv implanted [28] NOD/SCID or NOD/SCID-gamma chain null mice (The Jackson Laboratories, Bar Harbor, ME) were transplanted with autologous human fetal liver CD34+ cells (Advanced Bioscience Resources, Alameda, CA) and
n3:mentions
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Briefly, thy/liv implanted [>>28<<] NOD/SCID or NOD/SCID-gamma chain null mice (The Jackson Laboratories, Bar Harbor, ME) were transplanted with autologous human fetal liver CD34+ cells (Advanced Bioscience Resources, Alameda, CA) and monitored for human reconstitution in
n3:mentions
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mice (The Jackson Laboratories, Bar Harbor, ME) were transplanted with autologous human fetal liver CD34+ cells (Advanced Bioscience Resources, Alameda, CA) and monitored for human reconstitution in peripheral blood by flow cytometry [>>22<<], [24], [26]. Mice were maintained at the Animal Resources Center of University of Texas Southwestern Medical Center (UTSWMC) in accordance with protocols approved by the UTSWMC Institutional Animal Care and Use Committee.
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(The Jackson Laboratories, Bar Harbor, ME) were transplanted with autologous human fetal liver CD34+ cells (Advanced Bioscience Resources, Alameda, CA) and monitored for human reconstitution in peripheral blood by flow cytometry [22], [>>24<<], [26]. Mice were maintained at the Animal Resources Center of University of Texas Southwestern Medical Center (UTSWMC) in accordance with protocols approved by the UTSWMC Institutional Animal Care and Use Committee.
n3:mentions
n2:18198941
Subject Item
_:vb6874061
rdf:type
n3:Context
rdf:value
Laboratories, Bar Harbor, ME) were transplanted with autologous human fetal liver CD34+ cells (Advanced Bioscience Resources, Alameda, CA) and monitored for human reconstitution in peripheral blood by flow cytometry [22], [24], [>>26<<]. Mice were maintained at the Animal Resources Center of University of Texas Southwestern Medical Center (UTSWMC) in accordance with protocols approved by the UTSWMC Institutional Animal Care and Use Committee.
n3:mentions
n2:17389241
Subject Item
_:vb6874062
rdf:type
n3:Context
rdf:value
Tissues were harvested and then evaluated by molecular, microscopic and flow cytometric analyses for evidence of HIV infection as we have previously described [>>22<<], [24], [26].
n3:mentions
n2:17057712
Subject Item
_:vb6874063
rdf:type
n3:Context
rdf:value
Tissues were harvested and then evaluated by molecular, microscopic and flow cytometric analyses for evidence of HIV infection as we have previously described [22], [>>24<<], [26]. Briefly, minced and/or digested tissues were disrupted and filtered through a 70 µm cell strainer. Liver and lung mononuclear cells were isolated using a Percoll gradient. In other tissues, red blood cells were lysed (ACK lysing
n3:mentions
n2:18198941
Subject Item
_:vb6874064
rdf:type
n3:Context
rdf:value
Tissues were harvested and then evaluated by molecular, microscopic and flow cytometric analyses for evidence of HIV infection as we have previously described [22], [24], [>>26<<]. Briefly, minced and/or digested tissues were disrupted and filtered through a 70 µm cell strainer. Liver and lung mononuclear cells were isolated using a Percoll gradient. In other tissues, red blood cells were lysed (ACK lysing buffer).
n3:mentions
n2:17389241
Subject Item
_:vb6874065
rdf:type
n3:Context
rdf:value
Stocks of HIV-1JR-CSF [>>29<<] were prepared, titered and p24 content was determined as we have previously described [30], [31].
n3:mentions
n2:3646751
Subject Item
_:vb6874066
rdf:type
n3:Context
rdf:value
Stocks of HIV-1JR-CSF [29] were prepared, titered and p24 content was determined as we have previously described [>>30<<], [31]. Briefly, virus supernatants were collected following transient transfection of 293T cells with the plasmid molecular clone of JR-CSF.
n3:mentions
n2:12388705
Subject Item
_:vb6874067
rdf:type
n3:Context
rdf:value
Stocks of HIV-1JR-CSF [29] were prepared, titered and p24 content was determined as we have previously described [30], [>>31<<]. Briefly, virus supernatants were collected following transient transfection of 293T cells with the plasmid molecular clone of JR-CSF.
n3:mentions
n2:15827185
Subject Item
_:vb6874068
rdf:type
n3:Context
rdf:value
HIV-1 exposures were performed essentially as previously described using a total volume of 2–10 µL (rectal: 170 ng p24) or 200 µL (intravenous: 58 ng p24) [>>26<<], [32]. Intravenous HIV-1 exposures were administered via the tail vein. FTC/TDF dosing was based on published efficacy in BLT mice [24]. To prepare FTC/TDF for BLT mouse administration Truvada® capsules (Gilead, Foster City, CA) were
n3:mentions
n2:17389241
Subject Item
_:vb6874069
rdf:type
n3:Context
rdf:value
HIV-1 exposures were performed essentially as previously described using a total volume of 2–10 µL (rectal: 170 ng p24) or 200 µL (intravenous: 58 ng p24) [26], [>>32<<]. Intravenous HIV-1 exposures were administered via the tail vein. FTC/TDF dosing was based on published efficacy in BLT mice [24]. To prepare FTC/TDF for BLT mouse administration Truvada® capsules (Gilead, Foster City, CA) were dissolved
n3:mentions
n2:11460027
Subject Item
_:vb6874070
rdf:type
n3:Context
rdf:value
FTC/TDF dosing was based on published efficacy in BLT mice [>>24<<]. To prepare FTC/TDF for BLT mouse administration Truvada® capsules (Gilead, Foster City, CA) were dissolved in deionized water with 10% DMSO then sterile filtered (0.22µm).
n3:mentions
n2:18198941
Subject Item
_:vb6874071
rdf:type
n3:Context
rdf:value
The FTC/TDF solution was administered intraperitoneally (daily injections of 3.5 mg FTC and 5.2 mg TDF) prior or subsequent to exposure to HIV-1, as indicated in Figure 1A and the text [>>24<<], [33]–[35].
n3:mentions
n2:18198941
Subject Item
_:vb6874072
rdf:type
n3:Context
rdf:value
The FTC/TDF solution was administered intraperitoneally (daily injections of 3.5 mg FTC and 5.2 mg TDF) prior or subsequent to exposure to HIV-1, as indicated in Figure 1A and the text [24], [>>33<<]–[35].
n3:mentions
n2:7695253
Subject Item
_:vb6874073
rdf:type
n3:Context
rdf:value
The FTC/TDF solution was administered intraperitoneally (daily injections of 3.5 mg FTC and 5.2 mg TDF) prior or subsequent to exposure to HIV-1, as indicated in Figure 1A and the text [24], [33]–[>>35<<].
n3:mentions
n2:17668043
Subject Item
_:vb6874074
rdf:type
n3:Context
rdf:value
7.8 pg/ml), levels of viral RNA in plasma (Amplicor, Roche, assay sensitivity of 400 RNA copies per ml) and levels of viral DNA in peripheral blood cells (real time PCR analysis, assay sensitivity of 10 copies) as previously described [>>22<<], [24], [26], [31].
n3:mentions
n2:17057712
Subject Item
_:vb6874075
rdf:type
n3:Context
rdf:value
levels of viral RNA in plasma (Amplicor, Roche, assay sensitivity of 400 RNA copies per ml) and levels of viral DNA in peripheral blood cells (real time PCR analysis, assay sensitivity of 10 copies) as previously described [22], [>>24<<], [26], [31].
n3:mentions
n2:18198941
Subject Item
_:vb6874076
rdf:type
n3:Context
rdf:value
levels of viral RNA in plasma (Amplicor, Roche, assay sensitivity of 400 RNA copies per ml) and levels of viral DNA in peripheral blood cells (real time PCR analysis, assay sensitivity of 10 copies) as previously described [22], [24], [>>26<<], [31]. Analysis for systemic infection was performed on tissues harvested from infected mice or on cells isolated from the indicated tissues utilizing in situ hybridization, real time PCR analysis and co-culture with PHA activated
n3:mentions
n2:17389241
Subject Item
_:vb6874077
rdf:type
n3:Context
rdf:value
of viral RNA in plasma (Amplicor, Roche, assay sensitivity of 400 RNA copies per ml) and levels of viral DNA in peripheral blood cells (real time PCR analysis, assay sensitivity of 10 copies) as previously described [22], [24], [26], [>>31<<]. Analysis for systemic infection was performed on tissues harvested from infected mice or on cells isolated from the indicated tissues utilizing in situ hybridization, real time PCR analysis and co-culture with PHA activated allogeneic
n3:mentions
n2:15827185
Subject Item
_:vb6874078
rdf:type
n3:Context
rdf:value
performed on tissues harvested from infected mice or on cells isolated from the indicated tissues utilizing in situ hybridization, real time PCR analysis and co-culture with PHA activated allogeneic human PBMC as previously described [>>22<<], [24], [26]. In the case of breakthrough infection, it is possible that any developed drug resistance mutants could revert back to wild-type in the absence of drug selection following the completion of PrEP.
n3:mentions
n2:17057712
Subject Item
_:vb6874079
rdf:type
n3:Context
rdf:value
on tissues harvested from infected mice or on cells isolated from the indicated tissues utilizing in situ hybridization, real time PCR analysis and co-culture with PHA activated allogeneic human PBMC as previously described [22], [>>24<<], [26]. In the case of breakthrough infection, it is possible that any developed drug resistance mutants could revert back to wild-type in the absence of drug selection following the completion of PrEP.
n3:mentions
n2:18198941
Subject Item
_:vb6874080
rdf:type
n3:Context
rdf:value
tissues harvested from infected mice or on cells isolated from the indicated tissues utilizing in situ hybridization, real time PCR analysis and co-culture with PHA activated allogeneic human PBMC as previously described [22], [24], [>>26<<]. In the case of breakthrough infection, it is possible that any developed drug resistance mutants could revert back to wild-type in the absence of drug selection following the completion of PrEP.
n3:mentions
n2:17389241
Subject Item
_:vb6874081
rdf:type
n3:Context
rdf:value
No described resistance mutations in reverse transcriptase were observed [>>36<<]–[39].
n3:mentions
n2:7514855
Subject Item
_:vb6874082
rdf:type
n3:Context
rdf:value
No described resistance mutations in reverse transcriptase were observed [36]–[>>39<<].
n3:mentions
n2:12384348
Subject Item
_:vb6874083
rdf:type
n4:Section
dc:title
results
n4:contains
_:vb6874088 _:vb6874089 _:vb6874084 _:vb6874085 _:vb6874086 _:vb6874087
Subject Item
_:vb6874084
rdf:type
n3:Context
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This study models application of antiretroviral PrEP in a manner that closely resembles planned or ongoing PrEP clinical trials evaluating the efficacy of Truvada® [FTC co-formulated with TDF] [>>13<<]. Systemic PrEP models routine daily systemic administration of antiretrovirals (not temporally associated with a specific high-risk event) that continues until a general behavior pattern of high-risk actions ceases.
n3:mentions
n2:19811670
Subject Item
_:vb6874085
rdf:type
n3:Context
rdf:value
We have previously shown that systemic PrEP efficiently blocks vaginal HIV-1 transmission in BLT mice [>>24<<]. Here we sought to determine whether systemic PrEP also can prevent rectal HIV-1 transmission.
n3:mentions
n2:18198941
Subject Item
_:vb6874086
rdf:type
n3:Context
rdf:value
As depicted in Figure 1A, test BLT mice (n = 9) were exposed to a single dose of HIV-1 (CCR5-tropic primary isolate JR-CSF [>>29<<]) on the third of seven days of consecutive dosing with FTC/TDF.
n3:mentions
n2:3646751
Subject Item
_:vb6874087
rdf:type
n3:Context
rdf:value
antiretrovirals to prevent intravenous HIV-1 transmission in BLT mice by administering a seven-day course of systemic PrEP with FTC/TDF as described previously for the vaginal and above for the rectal exposure experiments (Figure 1A) [>>24<<]. We exposed BLT mice (n = 8) intravenously to a single dose of HIV-1JR-CSF 3 hours after the administration of the third of 7 consecutive daily doses of FTC/TDF (Figure 1A).
n3:mentions
n2:18198941
Subject Item
_:vb6874088
rdf:type
n3:Context
rdf:value
Sequence analysis of the entire reverse transcriptase gene from these treated, infected mice demonstrated the absence of mutations associated with resistance to either FTC or TDF [>>37<<]. All tissues analyzed by each method for each of the mice used for these experiments are detailed in Table 2. In all cases, infection was confirmed by every criterion utilized (Figures 4 and 5; Table 2).
n3:mentions
n2:19106428
Subject Item
_:vb6874089
rdf:type
n3:Context
rdf:value
In the case of the single breakthrough transmission (mouse #42), sequence analysis of the entire reverse transcriptase gene indicated that transmission was not due to the development of drug resistance [>>37<<]. Together, these results demonstrated that systemic administration of FTC/TDF PrEP can efficiently prevent intravenous infection with HIV-1 and illustrates the significant potential of PrEP to prevent intravenous HIV transmission in
n3:mentions
n2:19106428
Subject Item
_:vb6874090
rdf:type
n4:Section
dc:title
discussion
n4:contains
_:vb6874108 _:vb6874109 _:vb6874110 _:vb6874111 _:vb6874104 _:vb6874105 _:vb6874106 _:vb6874107 _:vb6874100 _:vb6874101 _:vb6874102 _:vb6874103 _:vb6874096 _:vb6874097 _:vb6874098 _:vb6874099 _:vb6874112 _:vb6874092 _:vb6874093 _:vb6874094 _:vb6874095 _:vb6874091
Subject Item
_:vb6874091
rdf:type
n3:Context
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Even though rectal HIV exposure is the main mode of transmission among men who have sex with men, this route is also likely to account for a significant number of transmissions to women [>>27<<]. Intravenous HIV exposure occurs primarily among injection drug users and is a growing health concern in many nations [42]. Unlike mucosal exposure with its intrinsic physical and biological barriers, the direct exposure of virus to the
n3:mentions
n2:11242155
Subject Item
_:vb6874092
rdf:type
n3:Context
rdf:value
Intravenous HIV exposure occurs primarily among injection drug users and is a growing health concern in many nations [>>42<<]. Unlike mucosal exposure with its intrinsic physical and biological barriers, the direct exposure of virus to the blood stream results in more efficient transmission. Our results provide clear pre-clinical evidence of the potential
n3:mentions
n2:18817968
Subject Item
_:vb6874093
rdf:type
n3:Context
rdf:value
In one study, we showed that systemic PrEP with FTC/TDF can effectively prevent vaginal HIV-1 transmission in BLT mice [>>24<<]. The second study used rhesus macaques to show that intermittent or daily systemic PrEP with FTC/TDF can protect from rectal SHIV transmission in a low-dose repeat exposure model [43]. Collectively, these two reports and the current data
n3:mentions
n2:18198941
Subject Item
_:vb6874094
rdf:type
n3:Context
rdf:value
The second study used rhesus macaques to show that intermittent or daily systemic PrEP with FTC/TDF can protect from rectal SHIV transmission in a low-dose repeat exposure model [>>43<<]. Collectively, these two reports and the current data show that antiretroviral PrEP with FTC/TDF can afford extensive protection from vaginal, rectal and intravenous HIV-1 transmission.
n3:mentions
n2:18254653
Subject Item
_:vb6874095
rdf:type
n3:Context
rdf:value
Therefore broad antiretroviral use can result in increased emergence of resistance to the drug(s) when infections do occur [>>11<<]. Spread of resistant viruses could limit the efficacy of current therapeutic interventions using these same drugs, although it should be noted that the fitness of multidrug resistant viruses for mucosal transmission has yet to be fully
n3:mentions
n2:17598929
Subject Item
_:vb6874096
rdf:type
n3:Context
rdf:value
It should be noted that sequence analysis of the entire reverse transcriptase gene revealed that this one transmission event was not the direct result of the appearance of mutations associated with drug-resistance [>>37<<]. The molecular basis for transmission of wild type virus after venous exposure in the presence of PrEP remains to be determined.
n3:mentions
n2:19106428
Subject Item
_:vb6874097
rdf:type
n3:Context
rdf:value
Experiments performed using non-human primates have provided evidence for the use of tenofovir (PMPA) to prevent intravenous infection by SIVmne in long-tailed macaques [>>44<<] and successful antiretroviral PrEP in rhesus macaques exposed rectally to either SIVmac251/32H or SHIVSF162P3 have also been reported with this compound [45], [46].
n3:mentions
n2:7502044
Subject Item
_:vb6874098
rdf:type
n3:Context
rdf:value
(PMPA) to prevent intravenous infection by SIVmne in long-tailed macaques [44] and successful antiretroviral PrEP in rhesus macaques exposed rectally to either SIVmac251/32H or SHIVSF162P3 have also been reported with this compound [>>45<<], [46]. Topical and systemic PrEP with one or more fusion inhibitors protected from vaginal SHIV transmission in rhesus macaques [47], [48].
n3:mentions
n2:18684007
Subject Item
_:vb6874099
rdf:type
n3:Context
rdf:value
to prevent intravenous infection by SIVmne in long-tailed macaques [44] and successful antiretroviral PrEP in rhesus macaques exposed rectally to either SIVmac251/32H or SHIVSF162P3 have also been reported with this compound [45], [>>46<<]. Topical and systemic PrEP with one or more fusion inhibitors protected from vaginal SHIV transmission in rhesus macaques [47], [48].
n3:mentions
n2:16960777
Subject Item
_:vb6874100
rdf:type
n3:Context
rdf:value
Topical and systemic PrEP with one or more fusion inhibitors protected from vaginal SHIV transmission in rhesus macaques [>>47<<], [48]. Systemic PrEP with FTC/TDF was shown to prevent rectal SHIV transmission in rhesus macaques [43] and in yet another non-human primate model, 2 pig-tailed macaques were protected from intravenous challenge with simian-tropic HIV
n3:mentions
n2:16258536
Subject Item
_:vb6874101
rdf:type
n3:Context
rdf:value
Topical and systemic PrEP with one or more fusion inhibitors protected from vaginal SHIV transmission in rhesus macaques [47], [>>48<<]. Systemic PrEP with FTC/TDF was shown to prevent rectal SHIV transmission in rhesus macaques [43] and in yet another non-human primate model, 2 pig-tailed macaques were protected from intravenous challenge with simian-tropic HIV (stHIV)
n3:mentions
n2:16273102
Subject Item
_:vb6874102
rdf:type
n3:Context
rdf:value
Systemic PrEP with FTC/TDF was shown to prevent rectal SHIV transmission in rhesus macaques [>>43<<] and in yet another non-human primate model, 2 pig-tailed macaques were protected from intravenous challenge with simian-tropic HIV (stHIV) by systemic PrEP with efavirenz plus FTC/TDF [49].
n3:mentions
n2:18254653
Subject Item
_:vb6874103
rdf:type
n3:Context
rdf:value
rectal SHIV transmission in rhesus macaques [43] and in yet another non-human primate model, 2 pig-tailed macaques were protected from intravenous challenge with simian-tropic HIV (stHIV) by systemic PrEP with efavirenz plus FTC/TDF [>>49<<]. Additional preclinical studies in macaques testing antiretroviral HIV-1 prevention modalities have focused on post-exposure prophylaxis, not pre-exposure regimens [44], [50]–[54].
n3:mentions
n2:19255423
Subject Item
_:vb6874104
rdf:type
n3:Context
rdf:value
Additional preclinical studies in macaques testing antiretroviral HIV-1 prevention modalities have focused on post-exposure prophylaxis, not pre-exposure regimens [>>44<<], [50]–[54].
n3:mentions
n2:7502044
Subject Item
_:vb6874105
rdf:type
n3:Context
rdf:value
Additional preclinical studies in macaques testing antiretroviral HIV-1 prevention modalities have focused on post-exposure prophylaxis, not pre-exposure regimens [44], [>>50<<]–[54]. The use of multiple animal models and different classes/combinations of drugs in these studies makes it difficult to make direct comparisons and to extrapolate potential outcomes. The current study represents a significant advance
n3:mentions
n2:17132170
Subject Item
_:vb6874106
rdf:type
n3:Context
rdf:value
Additional preclinical studies in macaques testing antiretroviral HIV-1 prevention modalities have focused on post-exposure prophylaxis, not pre-exposure regimens [44], [50]–[>>54<<]. The use of multiple animal models and different classes/combinations of drugs in these studies makes it difficult to make direct comparisons and to extrapolate potential outcomes. The current study represents a significant advance
n3:mentions
n2:11085587
Subject Item
_:vb6874107
rdf:type
n3:Context
rdf:value
This limitation exists because there is still no evidence of efficacy for antiretrovirals in preventing vaginal, rectal or intravenous transmission in humans [>>7<<], [10], [12], [15], [55].
n3:mentions
n2:17438318
Subject Item
_:vb6874108
rdf:type
n3:Context
rdf:value
This limitation exists because there is still no evidence of efficacy for antiretrovirals in preventing vaginal, rectal or intravenous transmission in humans [7], [>>10<<], [12], [15], [55].
n3:mentions
n2:16195446
Subject Item
_:vb6874109
rdf:type
n3:Context
rdf:value
This limitation exists because there is still no evidence of efficacy for antiretrovirals in preventing vaginal, rectal or intravenous transmission in humans [7], [10], [>>12<<], [15], [55].
n3:mentions
n2:16905792
Subject Item
_:vb6874110
rdf:type
n3:Context
rdf:value
This limitation exists because there is still no evidence of efficacy for antiretrovirals in preventing vaginal, rectal or intravenous transmission in humans [7], [10], [12], [>>15<<], [55]. It will be essential that ongoing human clinical trial data be compared to BLT and non-human primate studies in order to validate these useful models. Protection is likely to be dependent on the drug exposure levels achieved
n3:mentions
n2:12660549
Subject Item
_:vb6874111
rdf:type
n3:Context
rdf:value
This limitation exists because there is still no evidence of efficacy for antiretrovirals in preventing vaginal, rectal or intravenous transmission in humans [7], [10], [12], [15], [>>55<<]. It will be essential that ongoing human clinical trial data be compared to BLT and non-human primate studies in order to validate these useful models. Protection is likely to be dependent on the drug exposure levels achieved following
n3:mentions
n2:18382737
Subject Item
_:vb6874112
rdf:type
n3:Context
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The availability of a small animal model such as BLT mice for screening prevention modalities prior to or in conjunction with macaque and human studies is a great asset to the field [>>56<<].
n3:mentions
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28
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26
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22
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14
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6
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5
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