MARY MORENO - Academia.edu (original) (raw)

Papers by MARY MORENO

Research paper thumbnail of The social impacts of payments for environmental services in Costa Rica. A quantitative field survey and analysis of the Virilla watershed

Research paper thumbnail of Valoración económica del uso de tecnologías de saneamiento ecológico para aguas residuales domiciliares

In Costa Rica only 4% of the population has Sanitary Sewage System (SSS) with treatment plant in ... more In Costa Rica only 4% of the population has Sanitary Sewage System (SSS) with treatment plant in operation. This has contributed to generate very high environmental costs, not only by the deterioration in quality and quantity of a vital natural resource like water, but also because this deterioration causes additional costs like the diseases and the diminution in the productivity of some economic activities that depend on this natural resources. If technologies of ecological sanitation are implemented, the environmental costs caused by traditional technologies are reduced significantly and their costs of implementation are relatively low for families. In the present work two models were specified in which each family of the Metropolitan area of San José (Costa Rica) incurs in an environmental cost of between U$305 (with Sanitary Sewage System - SSS) and US$ 509 (with septic tank and no treatment of served water - NTSW). Considering that 400,000 families live in this area the total a...

Research paper thumbnail of Propuesta metodológica para valorar el impacto de las actividades económicas en áreas costeras

The coastal areas are very important for the economic and social development of the countries; ne... more The coastal areas are very important for the economic and social development of the countries; nevertheless, they received negative impacts over their natural and environmental resources not only from those activities developed in these areas but also from others realized in the medium and high river basins. At the moment, some methodological frameworks allows the valuation of the services bring for the coastal ecosystems, nevertheless there are lack of some fundamental aspects like the incorporation, from the beginning of the process, of social aspects, the validation of results and the generation of recommendations that can be including in the management of the RENAs and that previously are validated by the involved actors. The methodology starts from the identification of the negative effect on the coastal RENAs, the identification of the main origins of the problem (Economic activities/population); the generation of physical, social and economic indicators; the economic valuatio...

Research paper thumbnail of Costa Rica: Building a Democratic Environmental Organizational Structure

Research paper thumbnail of Contributions of the Existence of National Parks and Biological Reserves in Costa Rica

Research paper thumbnail of Protected Areas-Not just for Biodiversity Conservation. The Contributions of Protected Areas to the Economic and Social Development in Bhutan, Costa Rica and Benin

Research paper thumbnail of The social impacts of carbon markets in Costa Rica

Research paper thumbnail of The social impacts of carbon markets in Costa Rica: A case study of the Huetar Norte region. Los impactos sociales de los mercados del carbono en Costa Rica: …

orton.catie.ac.cr

Resumen: This study assesses the impacts of the payments for environmental services (PES) program... more Resumen: This study assesses the impacts of the payments for environmental services (PES) programme in Costa Rica in relation to reforestation activities for the establishment of carbon sinks. The methodology used is the Sustainable Livelihoods Approach (SLA) ...

Research paper thumbnail of The social impacts of payments for environmental services in Costa Rica. A quantitative field survey and analysis of the Virilla watershed

International Institute for …, 2003

... Gross power generation by hydroelectric plants in the Virilla Watershed, CNFL (MWh) .11 Table... more ... Gross power generation by hydroelectric plants in the Virilla Watershed, CNFL (MWh) .11 Table 2.4 ... While no information was collected in this field survey from poorer households, the authors ... areas of the upper slopes to make way for dairy farms, ornamental plant production ...

Research paper thumbnail of Oral Administration of the Nucleoside EFdA (4’ -Ethynyl-2-Fluoro-2’ -Deoxyadenosine) Provides Rapid Suppression of HIV Viremia in Humanized Mice and Favorable Pharmacokinetic Properties in Mice and the Rhesus Macaque

Antimicrobial Agents and Chemotherapy, 2015

Like normal cellular nucleosides, the nucleoside reverse transcriptase (RT) inhibitor 22

Research paper thumbnail of Human immunodeficiency virus type 1 Nef-mediated downregulation of CD4 correlates with Nef enhancement of viral pathogenesis

Journal of virology, 2003

The nef gene products encoded by human immunodeficiency virus type 1 (HIV-1) and simian immunodef... more The nef gene products encoded by human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus type 1 (SIV-1) increase viral loads in infected hosts and accelerate clinical progression to AIDS. Nef exhibits a spectrum of biological activities, including the ability to downregulate surface expression of CD4 and major histocompatibility complex (MHC) class I antigens, to alter the state of T-cell activation, and to enhance the infectivity of viral particles. To determine which of these in vitro functions most closely correlates with the pathogenic effects of Nef in vivo, we constructed recombinant HIV-1 NL4-3 viruses carrying mutations within the nef gene that selectively impair these functions. These mutant viruses were evaluated for pathogenic potential in severe combined immunodeficiency (SCID) mice implanted with human fetal thymus and liver (SCID-hu Thy/Liv mice), in which virus-mediated depletion of thymocytes is known to be Nef dependent. Disruption of the polyp...

Research paper thumbnail of CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo

Journal of virology, 1998

CCR5-utilizing (R5) and CXCR4-utilizing (X4) strains of human immunodeficiency virus type 1 (HIV-... more CCR5-utilizing (R5) and CXCR4-utilizing (X4) strains of human immunodeficiency virus type 1 (HIV-1) have been studied intensively in vitro, but the pathologic correlates of such differential tropism in vivo remain incompletely defined. In this study, X4 and R5 strains of HIV-1 were compared for tropism and pathogenesis in SCID-hu Thy/Liv mice, an in vivo model of human thymopoiesis. The X4 strain NL4-3 replicates quickly and extensively in thymocytes in the cortex and medulla, causing significant depletion. In contrast, the R5 strain Ba-L initially infects stromal cells including macrophages in the thymic medulla, without any obvious pathologic consequence. After a period of 3 to 4 weeks, Ba-L infection slowly spreads through the thymocyte populations, occasionally culminating in thymocyte depletion after week 6 of infection. During the entire time of infection, Ba-L did not mutate into variants capable of utilizing CXCR4. Therefore, X4 strains are highly cytopathic after infection ...

Research paper thumbnail of Class I in the HIV1Infected Thymus MHC Predendritic Cells Up-Regulates IFN{alpha} Secretion by Type 2

Research paper thumbnail of Superior human leukocyte reconstitution and susceptibility to vaginal HIV transmission in humanized NOD scid IL2Rγ −/− (NSG) BLT mice

Virology, 2011

Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permi... more Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permitting study of early events in HIV pathogenesis and evaluation of preexposure prophylaxis methods to inhibit HIV transmission. Human hematopoiesis is reconstituted in NOD-scid mice by implantation of human fetal liver and thymus tissue to generate human T cells plus intravenous injection of autologous liver-derived CD34+ hematopoietic stem cells

Research paper thumbnail of R5 strains of human immunodeficiency virus type 1 from rapid proegressors lacking X4 strains do not possess X4-type pathogenicity in human thymus

Thrombosis and Haemostasis, 1999

Some individuals infected with only R5 strains of human immunodeficiency virus type 1 progress to... more Some individuals infected with only R5 strains of human immunodeficiency virus type 1 progress to AIDS as quickly as individuals harboring X4 strains. We determined that three R5 viruses were much less pathogenic than an X4 virus in SCID-hu Thy/Liv mice, suggesting that R5 virus-mediated rapid disease progression is associated with host, not viral, factors.

Research paper thumbnail of Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals

PLOS One, 2007

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclin... more BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/Principal FindingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection

Research paper thumbnail of Inhibition of Human Immunodeficiency Virus Type 1 Infection in SCID-hu Thy/Liv Mice by the G-Quartet-Forming Oligonucleotide, ISIS 5320

Viral replication was inhibited in a dose-dependent manner after administration of the phosphorot... more Viral replication was inhibited in a dose-dependent manner after administration of the phosphorothioate oligonucleotide TTGGGGTT (ISIS 5320) to human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu Thy/Liv mice. Potent in vivo antiviral activity was observed against the T-cell-tropic molecular clone NL4-3; the agent was found to have weak activity against one primary HIV-1 isolate, and the agent was inactive against a

Research paper thumbnail of Efficacy of broadly neutralizing monoclonal antibody PG16 in HIV-infected humanized mice

Virology, 2014

Highly potent broadly neutralizing human monoclonal antibodies hold promise for HIV prophylaxis a... more Highly potent broadly neutralizing human monoclonal antibodies hold promise for HIV prophylaxis and treatment. We used the SCID-hu Thy/Liv and BLT humanized mouse models to study the efficacy of these antibodies, primarily PG16, against HIV-1 clades A, B, and C. PG16 targets a conserved epitope in the V1/V2 region of gp120 common to 70-80% of HIV-1 isolates from multiple clades and has extremely potent in vitro activity against HIVJR-CSF. PG16 was highly efficacious in SCID-hu mice as a single intraperitoneal administration the day before inoculation of R5-tropic HIV directly into their Thy/Liv implants and demonstrated even greater efficacy if PG16 administration was continued after Thy/Liv implant HIV inoculation. However, PG16 as monotherapy had no activity in humanized mice with established R5-tropic HIV infection. These results provide evidence of tissue penetration of the antibodies, which could aid in their ability to prevent infection if virus crosses the mucosal barrier.

Research paper thumbnail of Superior human leukocyte reconstitution and susceptibility to vaginal HIV transmission in humanized NOD-scid IL-2Rγ−/− (NSG) BLT mice

Virology, 2011

Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permi... more Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permitting study of early events in HIV pathogenesis and evaluation of preexposure prophylaxis methods to inhibit HIV transmission. Human hematopoiesis is reconstituted in NOD-scid mice by implantation of human fetal liver and thymus tissue to generate human T cells plus intravenous injection of autologous liver-derived CD34(+) hematopoietic stem cells to engraft the mouse bone marrow. In side-by-side comparisons, we show that NOD-scid mice homozygous for a deletion of the IL-2Rγ-chain (NOD-scid IL-2Rγ(-/-)) are far superior to NOD-scid mice in both their peripheral blood reconstitution with multiple classes of human leukocytes (e.g., a mean of 182 versus 14 CD4(+) T cells per μl 12 weeks after CD34(+) injection) and their susceptibility to intravaginal HIV exposure (84% versus 11% viremic mice at 4 weeks). These results should speed efforts to obtain preclinical animal efficacy data for new HIV drugs and microbicides.

Research paper thumbnail of Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals

PLoS ONE, 2007

Background. The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the precl... more Background. The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals. Methodology/Principal Findings. Endpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drugresistance substitutions. Conclusion. Given the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans. Citation: Stoddart CA, Bales CA, Bare JC, Chkhenkeli G, Galkina SA, et al (2007) Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals. PLoS ONE 2(8): e655.

Research paper thumbnail of The social impacts of payments for environmental services in Costa Rica. A quantitative field survey and analysis of the Virilla watershed

Research paper thumbnail of Valoración económica del uso de tecnologías de saneamiento ecológico para aguas residuales domiciliares

In Costa Rica only 4% of the population has Sanitary Sewage System (SSS) with treatment plant in ... more In Costa Rica only 4% of the population has Sanitary Sewage System (SSS) with treatment plant in operation. This has contributed to generate very high environmental costs, not only by the deterioration in quality and quantity of a vital natural resource like water, but also because this deterioration causes additional costs like the diseases and the diminution in the productivity of some economic activities that depend on this natural resources. If technologies of ecological sanitation are implemented, the environmental costs caused by traditional technologies are reduced significantly and their costs of implementation are relatively low for families. In the present work two models were specified in which each family of the Metropolitan area of San José (Costa Rica) incurs in an environmental cost of between U$305 (with Sanitary Sewage System - SSS) and US$ 509 (with septic tank and no treatment of served water - NTSW). Considering that 400,000 families live in this area the total a...

Research paper thumbnail of Propuesta metodológica para valorar el impacto de las actividades económicas en áreas costeras

The coastal areas are very important for the economic and social development of the countries; ne... more The coastal areas are very important for the economic and social development of the countries; nevertheless, they received negative impacts over their natural and environmental resources not only from those activities developed in these areas but also from others realized in the medium and high river basins. At the moment, some methodological frameworks allows the valuation of the services bring for the coastal ecosystems, nevertheless there are lack of some fundamental aspects like the incorporation, from the beginning of the process, of social aspects, the validation of results and the generation of recommendations that can be including in the management of the RENAs and that previously are validated by the involved actors. The methodology starts from the identification of the negative effect on the coastal RENAs, the identification of the main origins of the problem (Economic activities/population); the generation of physical, social and economic indicators; the economic valuatio...

Research paper thumbnail of Costa Rica: Building a Democratic Environmental Organizational Structure

Research paper thumbnail of Contributions of the Existence of National Parks and Biological Reserves in Costa Rica

Research paper thumbnail of Protected Areas-Not just for Biodiversity Conservation. The Contributions of Protected Areas to the Economic and Social Development in Bhutan, Costa Rica and Benin

Research paper thumbnail of The social impacts of carbon markets in Costa Rica

Research paper thumbnail of The social impacts of carbon markets in Costa Rica: A case study of the Huetar Norte region. Los impactos sociales de los mercados del carbono en Costa Rica: …

orton.catie.ac.cr

Resumen: This study assesses the impacts of the payments for environmental services (PES) program... more Resumen: This study assesses the impacts of the payments for environmental services (PES) programme in Costa Rica in relation to reforestation activities for the establishment of carbon sinks. The methodology used is the Sustainable Livelihoods Approach (SLA) ...

Research paper thumbnail of The social impacts of payments for environmental services in Costa Rica. A quantitative field survey and analysis of the Virilla watershed

International Institute for …, 2003

... Gross power generation by hydroelectric plants in the Virilla Watershed, CNFL (MWh) .11 Table... more ... Gross power generation by hydroelectric plants in the Virilla Watershed, CNFL (MWh) .11 Table 2.4 ... While no information was collected in this field survey from poorer households, the authors ... areas of the upper slopes to make way for dairy farms, ornamental plant production ...

Research paper thumbnail of Oral Administration of the Nucleoside EFdA (4’ -Ethynyl-2-Fluoro-2’ -Deoxyadenosine) Provides Rapid Suppression of HIV Viremia in Humanized Mice and Favorable Pharmacokinetic Properties in Mice and the Rhesus Macaque

Antimicrobial Agents and Chemotherapy, 2015

Like normal cellular nucleosides, the nucleoside reverse transcriptase (RT) inhibitor 22

Research paper thumbnail of Human immunodeficiency virus type 1 Nef-mediated downregulation of CD4 correlates with Nef enhancement of viral pathogenesis

Journal of virology, 2003

The nef gene products encoded by human immunodeficiency virus type 1 (HIV-1) and simian immunodef... more The nef gene products encoded by human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus type 1 (SIV-1) increase viral loads in infected hosts and accelerate clinical progression to AIDS. Nef exhibits a spectrum of biological activities, including the ability to downregulate surface expression of CD4 and major histocompatibility complex (MHC) class I antigens, to alter the state of T-cell activation, and to enhance the infectivity of viral particles. To determine which of these in vitro functions most closely correlates with the pathogenic effects of Nef in vivo, we constructed recombinant HIV-1 NL4-3 viruses carrying mutations within the nef gene that selectively impair these functions. These mutant viruses were evaluated for pathogenic potential in severe combined immunodeficiency (SCID) mice implanted with human fetal thymus and liver (SCID-hu Thy/Liv mice), in which virus-mediated depletion of thymocytes is known to be Nef dependent. Disruption of the polyp...

Research paper thumbnail of CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo

Journal of virology, 1998

CCR5-utilizing (R5) and CXCR4-utilizing (X4) strains of human immunodeficiency virus type 1 (HIV-... more CCR5-utilizing (R5) and CXCR4-utilizing (X4) strains of human immunodeficiency virus type 1 (HIV-1) have been studied intensively in vitro, but the pathologic correlates of such differential tropism in vivo remain incompletely defined. In this study, X4 and R5 strains of HIV-1 were compared for tropism and pathogenesis in SCID-hu Thy/Liv mice, an in vivo model of human thymopoiesis. The X4 strain NL4-3 replicates quickly and extensively in thymocytes in the cortex and medulla, causing significant depletion. In contrast, the R5 strain Ba-L initially infects stromal cells including macrophages in the thymic medulla, without any obvious pathologic consequence. After a period of 3 to 4 weeks, Ba-L infection slowly spreads through the thymocyte populations, occasionally culminating in thymocyte depletion after week 6 of infection. During the entire time of infection, Ba-L did not mutate into variants capable of utilizing CXCR4. Therefore, X4 strains are highly cytopathic after infection ...

Research paper thumbnail of Class I in the HIV1Infected Thymus MHC Predendritic Cells Up-Regulates IFN{alpha} Secretion by Type 2

Research paper thumbnail of Superior human leukocyte reconstitution and susceptibility to vaginal HIV transmission in humanized NOD scid IL2Rγ −/− (NSG) BLT mice

Virology, 2011

Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permi... more Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permitting study of early events in HIV pathogenesis and evaluation of preexposure prophylaxis methods to inhibit HIV transmission. Human hematopoiesis is reconstituted in NOD-scid mice by implantation of human fetal liver and thymus tissue to generate human T cells plus intravenous injection of autologous liver-derived CD34+ hematopoietic stem cells

Research paper thumbnail of R5 strains of human immunodeficiency virus type 1 from rapid proegressors lacking X4 strains do not possess X4-type pathogenicity in human thymus

Thrombosis and Haemostasis, 1999

Some individuals infected with only R5 strains of human immunodeficiency virus type 1 progress to... more Some individuals infected with only R5 strains of human immunodeficiency virus type 1 progress to AIDS as quickly as individuals harboring X4 strains. We determined that three R5 viruses were much less pathogenic than an X4 virus in SCID-hu Thy/Liv mice, suggesting that R5 virus-mediated rapid disease progression is associated with host, not viral, factors.

Research paper thumbnail of Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals

PLOS One, 2007

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclin... more BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/Principal FindingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection

Research paper thumbnail of Inhibition of Human Immunodeficiency Virus Type 1 Infection in SCID-hu Thy/Liv Mice by the G-Quartet-Forming Oligonucleotide, ISIS 5320

Viral replication was inhibited in a dose-dependent manner after administration of the phosphorot... more Viral replication was inhibited in a dose-dependent manner after administration of the phosphorothioate oligonucleotide TTGGGGTT (ISIS 5320) to human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu Thy/Liv mice. Potent in vivo antiviral activity was observed against the T-cell-tropic molecular clone NL4-3; the agent was found to have weak activity against one primary HIV-1 isolate, and the agent was inactive against a

Research paper thumbnail of Efficacy of broadly neutralizing monoclonal antibody PG16 in HIV-infected humanized mice

Virology, 2014

Highly potent broadly neutralizing human monoclonal antibodies hold promise for HIV prophylaxis a... more Highly potent broadly neutralizing human monoclonal antibodies hold promise for HIV prophylaxis and treatment. We used the SCID-hu Thy/Liv and BLT humanized mouse models to study the efficacy of these antibodies, primarily PG16, against HIV-1 clades A, B, and C. PG16 targets a conserved epitope in the V1/V2 region of gp120 common to 70-80% of HIV-1 isolates from multiple clades and has extremely potent in vitro activity against HIVJR-CSF. PG16 was highly efficacious in SCID-hu mice as a single intraperitoneal administration the day before inoculation of R5-tropic HIV directly into their Thy/Liv implants and demonstrated even greater efficacy if PG16 administration was continued after Thy/Liv implant HIV inoculation. However, PG16 as monotherapy had no activity in humanized mice with established R5-tropic HIV infection. These results provide evidence of tissue penetration of the antibodies, which could aid in their ability to prevent infection if virus crosses the mucosal barrier.

Research paper thumbnail of Superior human leukocyte reconstitution and susceptibility to vaginal HIV transmission in humanized NOD-scid IL-2Rγ−/− (NSG) BLT mice

Virology, 2011

Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permi... more Humanized Bone marrow/Liver/Thymus (BLT) mice recapitulate the mucosal transmission of HIV, permitting study of early events in HIV pathogenesis and evaluation of preexposure prophylaxis methods to inhibit HIV transmission. Human hematopoiesis is reconstituted in NOD-scid mice by implantation of human fetal liver and thymus tissue to generate human T cells plus intravenous injection of autologous liver-derived CD34(+) hematopoietic stem cells to engraft the mouse bone marrow. In side-by-side comparisons, we show that NOD-scid mice homozygous for a deletion of the IL-2Rγ-chain (NOD-scid IL-2Rγ(-/-)) are far superior to NOD-scid mice in both their peripheral blood reconstitution with multiple classes of human leukocytes (e.g., a mean of 182 versus 14 CD4(+) T cells per μl 12 weeks after CD34(+) injection) and their susceptibility to intravaginal HIV exposure (84% versus 11% viremic mice at 4 weeks). These results should speed efforts to obtain preclinical animal efficacy data for new HIV drugs and microbicides.

Research paper thumbnail of Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals

PLoS ONE, 2007

Background. The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the precl... more Background. The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals. Methodology/Principal Findings. Endpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drugresistance substitutions. Conclusion. Given the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans. Citation: Stoddart CA, Bales CA, Bare JC, Chkhenkeli G, Galkina SA, et al (2007) Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals. PLoS ONE 2(8): e655.