RESUMEN
BACKGROUND: Lyme disease (LD) is an infectious multi-system illness caused by the bacterial genus Borrelia and spread by bites of infected ticks. Although most patients are successfully treated by timely antibiotic therapy, it is broadly accepted that a sizeable number of patients experience treatment failure and continue to suffer long-term, debilitating symptoms, including pain, fatigue, cognitive dysfunction and other symptoms. This is known as post-treatment LD (PTLD), for which diagnosis is not standardized and treatment remains controversial. The prevalence and societal burden of PTLD is unknown. METHODS: In an effort to help characterize the LD landscape, we estimated the number of PTLD cases in the US in 2016 and 2020 using Monte-Carlo simulation techniques, publically-available demographic datasets, uncertainty in the inputs and realistic assumptions about incidence and treatment failure rates. RESULTS: Depending on the input assumptions, PTLD prevalence estimates for 2016 ranged from 69,011 persons (95% CI 51,796 to 89,312) to 1,523,869 (CI 1,268,634 to 1,809,416). Prevalence in 2020 is predicted to be higher than 2016, and may be as high as 1,944,189 (CI 1,619,988 to 2,304,147) cases. CONCLUSIONS: The cumulative prevalence of PLTD in the United States is estimated to be high and continues to increase. These findings will be of interest to epidemiologists and health economists studying disease burden in the US and elsewhere, and justify funding to study PTLD diagnosis and treatment.
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Síndrome de la Enfermedad Post-Lyme/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Método de Montecarlo , Prevalencia , Distribución por Sexo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
We previously showed that the combination of the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 with zinc acetate (ZA) formulated in a carrageenan (CG; MZC) gel provided macaques significant protection against vaginal simian-human immunodeficiency virus-RT (SHIV-RT) challenge, better than either MIV-150/CG or ZA/CG. The MZC gel was shown to be safe in a phase 1 clinical trial. Herein, we used in vitro approaches to study the antiviral properties of ZA and the MIV-150/ZA combination, compared to other NNRTIs. Like other NNRTIs, MIV-150 has EC50 values in the subnanomolar to nanomolar range against wild type and NNRTI or RT-resistant HIVs. While less potent than NNRTIs, ZA was shown to be active in primary cells against laboratory-adapted and primary HIV-1 isolates and HIV-1 isolates/clones with NNRTI and RT resistance mutations, with EC50 values between 20 and 110 µM. The MIV-150/ZA combination had a potent and broad antiviral activity in primary cells. In vitro resistance selection studies revealed that previously described NNRTI-resistant mutations were selected by MIV-150. ZA-resistant virus retained susceptibility to MIV-150 (and other RTIs) and MIV-150-selected virus remained sensitive to ZA. Notably, resistant virus was not selected when cultured in the presence of both ZA and MIV-150. This underscores the potency and breadth of the MIV-150/ZA combination, supporting preclinical macaque studies and the advancement of MZC microbicides into clinical testing.
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Antirretrovirales/administración & dosificación , VIH-1/efectos de los fármacos , Piridinas/administración & dosificación , Urea/análogos & derivados , Acetato de Zinc/administración & dosificación , Antirretrovirales/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Quimioterapia Combinada , VIH-1/genética , Humanos , Pruebas de Sensibilidad Microbiana , Piridinas/farmacología , Urea/administración & dosificación , Urea/farmacología , Acetato de Zinc/farmacologíaRESUMEN
When microbicides used for HIV prevention contain antiretroviral drugs, there is concern for the potential emergence of drug-resistant HIV following use in infected individuals who are either unaware of their HIV infection status or who are aware but still choose to use the microbicide. Resistant virus could ultimately impact their responsiveness to treatment and/or result in subsequent transmission of drug-resistant virus. We tested whether drug resistance mutations (DRMs) would emerge in macaques infected with simian immunodeficiency virus expressing HIV reverse transcriptase (SHIV-RT) after sustained exposure to the potent non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 delivered via an intravaginal ring (IVR). We first treated 4 SHIV-RT-infected animals with daily intramuscular injections of MIV-150 over two 21 day (d) intervals separated by a 7 d drug hiatus. In all 4 animals, NNRTI DRMs (single and combinations) were detected within 14 d and expanded in proportion and diversity with time. Knowing that we could detect in vivo emergence of NNRTI DRMs in response to MIV-150, we then tested whether a high-dose MIV-150 IVR (loaded with >10 times the amount being used in a combination microbicide IVR in development) would select for resistance in 6 infected animals, modeling use of this prevention method by an HIV-infected woman. We previously demonstrated that this MIV-150 IVR provides significant protection against vaginal SHIV-RT challenge. Wearing the MIV-150 IVR for 56 d led to only 2 single DRMs in 2 of 6 animals (430 RT sequences analyzed total, 0.46%) from plasma and lymph nodes despite MIV-150 persisting in the plasma, vaginal fluids, and genital tissues. Only wild type virus sequences were detected in the genital tissues. These findings indicate a low probability for the emergence of DRMs after topical MIV-150 exposure and support the advancement of MIV-150-containing microbicides.
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Farmacorresistencia Viral/genética , Piridinas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/genética , Urea/análogos & derivados , Administración Intravaginal , Animales , Antiinfecciosos Locales/administración & dosificación , Femenino , Inyecciones Intramusculares , Macaca mulatta , Mutación , Piridinas/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Factores de Tiempo , Urea/administración & dosificación , Urea/farmacología , Carga ViralRESUMEN
Herpes simplex virus-2 (HSV-2) infection increases HIV susceptibility. We previously established a rhesus macaque model of vaginal HSV-2 preexposure followed by cochallenge with HSV-2 and simian/human immunodeficiency virus-reverse transcriptase (SHIV-RT). Using this model, we showed that a gel containing the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 in carrageenan (CG) reduced SHIV-RT infection. To evaluate the efficacy of new generation microbicides against both viruses, we first established dual infection after single vaginal cochallenge with SHIV-RT and HSV-2 in HSV-2-naive macaques. All animals (6/6) became HSV-2 infected, with 4/6 coinfected with SHIV-RT. In a control group cochallenged with SHIV-RT and UV-inactivated HSV-2, 2/4 became SHIV-RT infected, and none had detectable HSV-2. Low-level HSV-2-specific antibody and T cell responses were detected in some HSV-2-infected animals. To test a CG gel containing MIV-150 and zinc acetate (MZC), which provided naive animals full protection from SHIV-RT for at least 8 h, MZC (vs. CG) was applied daily for 14 days followed by cochallenge 8 h later. MZC prevented SHIV-RT infection (0/9 infected, p=0.04 vs. 3/6 in CG controls), but only reduced HSV-2 infection by 20% (6/9 infected vs. 5/6 in CG, p=0.6). In HSV-2-infected animals, none of the gel-treated animals seroconverted, and only the CG controls had measurable HSV-2-specific T cell responses. This study shows the promise of MZC to prevent immunodeficiency virus infection (even in the presence of HSV-2) and reduce HSV-2 infection after exposure to a high-dose inoculum. Additionally, it demonstrates the potential of a macaque coinfection model to evaluate broad-spectrum microbicides.
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Antiinfecciosos/administración & dosificación , Quimioprevención/métodos , Herpes Genital/prevención & control , Herpesvirus Humano 2/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Cremas, Espumas y Geles Vaginales/administración & dosificación , Animales , Femenino , Transcriptasa Inversa del VIH , Macaca mulattaRESUMEN
BACKGROUND: Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non-nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application. METHODS AND FINDINGS: Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 µM MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8-24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h. CONCLUSIONS: A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans.
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Antirretrovirales/administración & dosificación , Piridinas/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Urea/análogos & derivados , Acetato de Zinc/administración & dosificación , Administración Intravaginal , Animales , Combinación de Medicamentos , Femenino , Geles/administración & dosificación , Geles/uso terapéutico , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Humanos , Macaca , Piridinas/uso terapéutico , Virus de la Inmunodeficiencia de los Simios , Resultado del Tratamiento , Urea/administración & dosificación , Urea/uso terapéutico , Acetato de Zinc/uso terapéuticoRESUMEN
Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.
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Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Hepatocitos/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/metabolismo , Internalización del Virus/efectos de los fármacos , Secuencia de Aminoácidos , Antígenos CD/genética , Antígenos CD/metabolismo , Antivirales/aislamiento & purificación , Células Cultivadas , Farmacorresistencia Viral , Sinergismo Farmacológico , Hepacivirus/aislamiento & purificación , Hepacivirus/metabolismo , Hepatitis C/genética , Hepatitis C/virología , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Interferones/uso terapéutico , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Bibliotecas de Moléculas Pequeñas/análisis , Tetraspanina 28 , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismoRESUMEN
Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral/genética , Guanina/análogos & derivados , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Lamivudine/farmacología , Antivirales/uso terapéutico , Células Cultivadas , ADN Viral/sangre , ADN Polimerasa Dirigida por ADN/genética , Método Doble Ciego , Guanina/farmacología , Guanina/uso terapéutico , Hepatitis B/tratamiento farmacológico , Hepatitis B/virología , Humanos , Mutación , Plásmidos/genética , Resultado del Tratamiento , Replicación Viral/efectos de los fármacosRESUMEN
Comprehensive monitoring of genotypic and phenotypic antiviral resistance was performed on 673 entecavir (ETV)-treated nucleoside naïve hepatitis B virus (HBV) patients. ETV reduced HBV DNA levels to undetectable by PCR (<300 copies/mL, <57 IU/mL) in 91% of hepatitis B e antigen (HBeAg)-positive and -negative patients by Week 96. Thirteen percent (n = 88) of the comparator lamivudine (LVD)-treated patients experienced a virologic rebound (> or =1 log increase from nadir by PCR) in the first year, with 74% of these having LVD resistance (LVDr) substitutions evident. In contrast, only 3% (n = 22) of ETV-treated patients exhibited virologic rebound by Week 96. Three ETV rebounds were attributable to LVDr virus present at baseline, with one having a S202G ETV resistance (ETVr) substitution emerge at Week 48. None of the other rebounding patients had emerging genotypic resistance or loss of ETV susceptibility. Genotyping all additional ETV patients with PCR-detectable HBV DNA at Weeks 48, 96, or end of dosing identified seven additional patients with LVDr substitutions, including one with simultaneous emergence of LVDr/ETVr. Generally, ETV patients with LVDr were detectable at baseline (8/10) and most subsequently achieved undetectable HBV DNA levels on ETV therapy (7/10). No other emerging substitutions identified decreased ETV susceptibility. In conclusion, ETVr emergence in ETV-treated nucleoside naïve patients over a 2-year period is rare, occurring in two patients with LVDr variants. These findings suggest that the rapid, sustained suppression of HBV replication, combined with a requirement for multiple substitutions, creates a high genetic barrier to ETVr in nucleoside naïve patients.
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Antivirales/uso terapéutico , Farmacorresistencia Viral , Guanina/análogos & derivados , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/tratamiento farmacológico , ADN Viral/análisis , Guanina/uso terapéutico , Antígenos e de la Hepatitis B/inmunología , Humanos , Lamivudine/uso terapéutico , Nucleósidos , Resultado del TratamientoRESUMEN
We previously reported the derivation of a CCR5 (R5)-tropic pathogenic strain SHIVSF162P3. Here, we show that a simian-HIV (SHIV) molecular clone expressing the entire env gp160 of SHIVSF162P3, termed SHIV P3gp160, could fully recapitulate the in vivo replicative characteristics of the parental isolate. SHIV P3gp160 is mucosally transmissible, preferentially depletes memory CD4 T cells, and induced simian AIDS in 2 of 6 infected macaques. The availability of an infectious R5 SHIV molecular clone that can be transmitted mucosally and causes disease provides an important reagent for studies of lentiviral pathogenesis and AIDS vaccine research.
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Síndrome de Inmunodeficiencia Adquirida/virología , VIH/genética , Receptores CCR5/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Síndrome de Inmunodeficiencia Adquirida/fisiopatología , Síndrome de Inmunodeficiencia Adquirida/transmisión , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Recuento de Linfocito CD4 , Clonación Molecular , Modelos Animales de Enfermedad , Citometría de Flujo , Productos del Gen env/genética , VIH/inmunología , VIH/fisiología , Proteínas gp160 de Envoltorio del VIH/genética , Subgrupos Linfocitarios , Macaca mulatta , Datos de Secuencia Molecular , ARN Viral/sangre , Recombinación Genética , Síndrome de Inmunodeficiencia Adquirida del Simio/fisiopatología , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Carga ViralRESUMEN
Four successive, rapid serial passages of the nonpathogenic, CCR5-tropic simian-human immunodeficiency virus SHIV(SF162) in rhesus macaques resulted in an increase in acute plasma viremia with each passage and the emergence of a pathogenic isolate SHIV(SF162P3) in one of the passage three transfer animals (macaque T353). To explore the mechanism(s) underlying increased virulence of SHIV(SF162) upon in vivo passage, the evolution of the HIV-1 envelope gene was characterized in plasma and PBMC samples obtained from animals before (week 1) and after (week 3) the time of virus transfer. We found no evidence in support of adaptive evolution of the HIV gp120 during rapid serial passage; however, the animals which later received passage virus had more diverse quasispecies. SHIV(SF162P3)-like gp120 sequences were first detected in macaque T353 at week 6, after seroconversion. These sequence changes increased in frequency and number at later time points. The first sequence change conferred neutralization escape but not an increase in viral infectivity that could account for the apparent increase in replicative capacity of the later passage viruses. Collectively, our data argue against any host-specific adaptation of the HIV-1 envelope gp120 as the basis for the generation of more aggressive SHIV variants during rapid serial transfers in seronegative macaques, and support the model of quasispecies diversity as a predictor of pathogenesis. Envelope sequence changes accumulate principally in response to immune pressure exerted by the host, generating viral variants that can persist in the presence of a strong host immune response.
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Evolución Molecular , Variación Genética , VIH-1/clasificación , Pase Seriado , Virus de la Inmunodeficiencia de los Simios/clasificación , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/genética , Infecciones por VIH/virología , Seronegatividad para VIH , VIH-1/genética , VIH-1/patogenicidad , Humanos , Macaca mulatta/virología , Datos de Secuencia Molecular , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/patogenicidadRESUMEN
HIV pseudotypes bearing native hepatitis C virus (HCV) glycoproteins (strain H and Con1) are infectious for the human hepatoma cell lines Huh-7 and PLC/PR5. Infectivity depends on coexpression of both E1 and E2 glycoproteins, is pH-dependent, and can be neutralized by mAbs mapping to amino acids 412-447 within E2. Cell-surface expression of one or all of the candidate receptor molecules (CD81, low-density lipoprotein receptor, scavenger receptor class B type 1, and dendritic cell-specific intercellular adhesion molecule 3 grabbing nonintegrin) failed to confer permissivity to HIV-HCV pseudotype infection. However, HIV-HCV pseudotype infectivity was inhibited by a recombinant soluble form of CD81 and a mAb specific for CD81, suggesting that CD81 may be a component of a receptor complex.
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Hepacivirus/patogenicidad , Proteínas del Envoltorio Viral/fisiología , Anticuerpos Monoclonales , Antígenos CD/fisiología , Línea Celular , Quimera/genética , Quimera/inmunología , VIH/genética , VIH/patogenicidad , VIH/fisiología , Células HeLa , Hepacivirus/genética , Hepacivirus/fisiología , Anticuerpos contra la Hepatitis C , Hepatocitos/virología , Humanos , Concentración de Iones de Hidrógeno , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/fisiología , Pruebas de Neutralización , Receptores Virales/antagonistas & inhibidores , Receptores Virales/fisiología , Tetraspanina 28 , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
Through rapid serial transfer in vivo, the chimeric CCR5-tropic simian/human immunodeficiency virus SHIV(SF162) evolved from a virus that is nonpathogenic and poorly transmissible across the vaginal mucosa to a variant that still maintains CCR5 usage but which is now pathogenic and establishes intravaginal infection efficiently. To determine whether envelope glycoprotein gp120 is responsible for increased pathogenesis and transmissibility of the variant SHIV(SF162P3), we cloned and sequenced the dominant envelope gene (encoding P3 gp120) and characterized its functions in vitro. Chimeric SHIV(SF162) virus expressing P3 gp120 of the pathogenic variant, designated SHIV(SF162PC), was also constructed and assessed for its pathogenicity and mucosal transmissibility in vivo. We found that, compared to wild-type SHIV(SF162) gp120, P3 gp120 conferred in vitro neutralization resistance and increased entry efficiency of the virus but was compromised in its fusion-inducing capacity. In vivo, SHIV(SF162PC) infected two of two and two of three rhesus macaques by the intravenous and intravaginal routes, respectively. Nevertheless, although peak viremia reached 10(6) to 10(7) RNA copies per ml of plasma in some infected animals and was associated with depletion of gut-associated CD4(+) lymphocytes, none of the animals maintained a viral set point that would be predictive of progression to disease. Together, the data from this study suggest a lack of correlation between entry efficiency and cytopathic properties of envelope glycoproteins with viral pathogenicity. Furthermore, whereas env gp120 contains the determinant for enhanced mucosal transmissibility of SHIV(SF162P3), the determinant(s) of its increased virulence may require additional sequence changes in env gp41 and/or maps to other viral genes.
Asunto(s)
Proteína gp120 de Envoltorio del VIH/fisiología , VIH/fisiología , Membrana Mucosa/virología , Receptores CCR5/fisiología , Virus de la Inmunodeficiencia de los Simios/fisiología , Secuencia de Aminoácidos , Animales , Quimera , Clonación Molecular , VIH/patogenicidad , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/genética , Humanos , Macaca mulatta , Datos de Secuencia Molecular , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Células Tumorales CultivadasRESUMEN
The potential role of dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) binding in human immunodeficiency virus transmission across the mucosal barrier was investigated by assessing the ability of simian-human immunodeficiency chimeric viruses (SHIVs) showing varying degrees of mucosal transmissibility to bind the DC-SIGN expressed on the surface of transfected cells. We found that gp120 of the highly transmissible, pathogenic CCR5-tropic SHIV(SF162P3) bound human and rhesus DC-SIGN with an efficiency threefold or greater than that of gp120 of the nonpathogenic, poorly transmissible parental SHIV(SF162), and this increase in binding to the DC-SIGN of the SHIV(SF162P3) envelope gp120 translated into an enhancement of T-cell infection in trans. The presence of an additional glycan at the N-terminal base of the V2 loop of SHIV(SF162P3) gp120 compared to that of the parental virus was shown to be responsible for the increase in binding to DC-SIGN. Interestingly, this glycan also conferred escape from autologous neutralization, raising the possibility that the modification occurred as a result of immune selection. Our data suggest that more-efficient binding of envelope gp120 to DC-SIGN could be relevant to the enhanced mucosal transmissibility of SHIV(SF162P3) compared to that of parental SHIV(SF162).