RESUMEN
Electrical stimulation of the superior sagittal sinus in the cat activated neurones in the trigeminal nucleus caudalis. The mean latency of these responses (10.1 ms) was consistent with activation of Adelta-fibres. Microiontophoretic ejection of either the selective serotonin(1A) (5-HT(1A)) agonist (+)8-OH-DPAT or the 5-HT(1B/1D) agonist alniditan resulted in the reversible suppression of the response to superior sagittal sinus stimulation of 29/46 and 18/20 trigeminal neurones, respectively. The response to sagittal sinus stimulation was suppressed by 39+/-5% (n=46) by (+)8-OH-DPAT and 65+/-5% (n=20) by alniditan. Microiontophoretic ejection of the selective 5-HT(1A) receptor antagonist WAY-100635 significantly antagonised the effect of (+)8-OH-DPAT (effect reduced by 30%, P<0.05). The ejection of GR-127935, a selective 5-HT(1B/1D), antagonist, significantly antagonised the effect of alniditan (effect reduced by 52%, P<0.02). In eight neurones the response to convergent facial receptive field stimulation was also tested in the presence of alniditan. Only 4/8 receptive field responses were suppressed by alniditan (compared to 8/8 sagittal sinus responses) and alniditan had significantly less quantitative effect on the response to receptive field stimulation than on the response to sagittal sinus stimulation in the same neurones (mean reduction 36+/-14% and 66+/-8%, respectively, P<0.05). These results suggest that pharmacological modulation of the trigeminovascular system can occur at the first central synapse and that, in addition to 5-HT(1B/1D) receptors, 5-HT(1A) receptors may be involved in the modulation of sensory neurotransmission in the trigeminovascular system.
Asunto(s)
Receptores de Serotonina/fisiología , Núcleo Caudal del Trigémino/efectos de los fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Benzopiranos/farmacología , Gatos , Estimulación Eléctrica , Iontoforesis , Oxadiazoles/farmacología , Piperazinas/farmacología , Propilaminas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Receptores de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacología , Núcleo Caudal del Trigémino/fisiologíaRESUMEN
A method is described for fabrication of 7-barrelled microiontophoresis electrodes with a center barrel of platinum-coated tungsten. The electrodes require a minimum of expensive apparatus and can be fabricated in an hour or two. The electrodes have low recording impedance (typically 100 k omega and low resistance iontophoresis barrels (typically 20-50 M omega). Compared to electrodes with a micropipette recording barrel, these electrodes are practically noise-free and can pass ionotophoretic currents of up to 200 nA without an appreciable increase in recording noise.
Asunto(s)
Iontoforesis/instrumentación , Microelectrodos , VidrioRESUMEN
The effect of intra-carotid arterial infusions of glyceryl trinitrate (GTN), a substance known to precipitate headache, including migraine, upon the spontaneous activity of trigeminal neurons with craniovascular input was studied in cats. Second-order craniovascular neurons which received sensory input from the superior sagittal sinus were recorded in the trigeminal nucleus caudalis. Infusions of GTN were administered via a catheter inserted retrogradely into the common carotid artery through the lingual artery. Infusions of GTN (100 microg kg(-1) min(-1) in a volume of 2 ml min(-1)) increased the mean basal discharge rate of all second-order neurons to 239+/-47% of control. GTN produced a fall in mean blood pressure, but there was no correlation between this fall and the changes in discharge rate. GTN infusions sensitised neurons to the effects of electrical stimulation of the superior sagittal sinus, but not to subsequent GTN infusions. Infusions of similar volumes of vehicle did not alter the discharge rate of neurons. We conclude that GTN activates craniovascular sensory pathways at a site at, or peripheral to, the second-order neuron and that such an action may account for at least the acute-onset headache induced by GTN.
Asunto(s)
Arteria Carótida Común/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Nitroglicerina/farmacología , Núcleos del Trigémino/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Arteria Carótida Común/fisiología , Gatos , Duramadre/efectos de los fármacos , Duramadre/fisiología , Estimulación Eléctrica , Femenino , Cefalea/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Neuronas Aferentes/fisiología , Nervio Trigémino/efectos de los fármacos , Nervio Trigémino/fisiología , Núcleos del Trigémino/fisiologíaRESUMEN
The effects of ergot alkaloids on field potentials and unit responses produced in the upper cervical spinal cord by stimulation of the superior sagittal sinus (SSS) were examined in 57 anesthetized cats. Electrical stimulation of the SSS produced field potentials and single-unit responses at latencies of 5-20 ms. Field potentials were abolished by section of the first division of the trigeminal nerve but were unaffected or increased by section of the upper cervical nerves. Field potentials were reduced or abolished by intravenous injection of ergotamine or dihydroergotamine (DHE). The evoked response of 41 units (34.4%) were suppressed by either i.v. or iontophoretic administration of ergotamine, DHE or ergometrine. The results suggest that ergot alkaloids exert an effect at a spinal cord relay centre which receives trigeminally mediated input from cranial blood vessels.
Asunto(s)
Senos Craneales/inervación , Dihidroergotamina/farmacología , Ergonovina/farmacología , Ergotamina/farmacología , Médula Espinal/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Gatos , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Vías Nerviosas/efectos de los fármacosRESUMEN
The effect of intracarotid arterial infusions of glyceryl trinitrate (GTN), a substance known to precipitate vascular headache, on the spontaneous activity of trigeminal neurons with craniovascular input was studied in cats. Cats were anaesthetised with alpha-chloralose, immobilised and artificially ventilated. The superior sagittal sinus (SSS) was isolated and stimulated electrically. Facial receptive fields (RF) were also stimulated. Single neurons were recorded from the trigeminal nucleus caudalis with a metal microelectrode equipped with six glass barrels for microiontophoresis. Infusions of GTN were administered via a catheter inserted retrogradely into the common carotid artery through the lingual artery. Infusions of GTN (mean rate 19+/-7, range 5-100 microg kg(-1) min(-1), in a volume of 2 ml min(-1)) increased the spontaneous discharge rate of second-order neurons which received dural and facial sensory input to 429+/-80% of control. Iontophoretic application of the 5-HT(1B/1D) receptor agonist eletriptan (50 nA) at the peak of the response decreased the discharge rate of neurons towards pre-GTN control levels. In the presence of continuous iontophoretic application of the 5-HT(1B/1D) receptor antagonist GR127935, the decrease in discharge rate caused by eletriptan was antagonised. We conclude (1) that GTN activates craniovascular sensory pathways at a site at, or peripheral to, the second-order neuron and that such an action may account for at least the acute-onset headache induced by GTN and (2) that the antimigraine agent eletriptan is able to selectively suppress noxious sensory information from the dura, induced by GTN, via an action at 5-HT(1B/1D) receptors.
Asunto(s)
Indoles/farmacología , Neuronas Aferentes/efectos de los fármacos , Nitroglicerina/farmacología , Pirrolidinas/farmacología , Agonistas de Receptores de Serotonina/farmacología , Núcleo Caudal del Trigémino/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Interacciones Farmacológicas , Estimulación Eléctrica , Electrofisiología , Femenino , Masculino , Trastornos Migrañosos/tratamiento farmacológico , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Receptores de Serotonina/metabolismo , Núcleo Caudal del Trigémino/citología , Triptaminas , Vasodilatación/efectos de los fármacosRESUMEN
Units in the dorsolateral area of the upper cervical cord respond to craniovascular stimulation. This study examined tooth pulp responses in this area in cats. Eleven of 21 units tested in the dorsolateral area had convergent inputs from superior sagittal sinus and tooth pulp; while 10 units had sagittal sinus, but not tooth pulp, input. Mean response latency to tooth pulp stimulation (25.8 ms) was significantly longer than to superior sagittal sinus stimulation (9.8 ms). Half of the units had cutaneous receptive fields; and in five units, action potentials could be evoked by electrical stimulation in the posterior complex of the thalamus.
Asunto(s)
Médula Espinal/fisiología , Diente/inervación , Vías Aferentes , Animales , Gatos , Plexo Cervical , Estimulación Eléctrica , Tálamo/fisiologíaRESUMEN
Units in the dorsolateral area of the upper cervical cord and the ventroposteromedial nucleus of the thalamus respond to stimulation of cranial vessels. To study the physiological role of the upper cervical cord in craniovascular transmission, we used a cryoprobe to interrupt reversibly neural transmission through the cord while recording in the thalamus. Twenty-one of 47 thalamic units tested showed reversible diminution in their response to superior sagittal sinus stimulation during cervical cord cooling. In contrast, receptive field responses and spontaneous thalamic activity were unaffected. These data suggest offt the cervical cord relays craniovascular nociceptive afferents.
Asunto(s)
Nociceptores/fisiología , Médula Espinal/fisiología , Animales , Gatos , Vías Nerviosas/fisiología , Médula Espinal/citología , Tálamo/fisiología , TermodinámicaRESUMEN
[This corrects the article DOI: 10.1136/bcr.12.2010.3645.].
RESUMEN
The authors herein report the case of a 35-year-old woman undergoing adjuvant therapy for node positive breast cancer, who presented with short and rapidly progressive history of bilateral lower limb symptoms of peripheral neuropathy following therapy with paclitaxel. MRI of her neural axis revealed no leptomeningeal enhancement or focal metastatic lesions. Neurophysiological tests favoured toxic sensory axonal polyneuropathy. She remains symptomatic following discontinuation of therapy 20 months ago, and is under review with pain management.
Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Paclitaxel/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Adulto , Antineoplásicos Fitogénicos/uso terapéutico , Encéfalo/patología , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Imagen por Resonancia Magnética , Neuroimagen , Paclitaxel/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/patologíaRESUMEN
Human immunodeficiency virus type 2 (HIV-2) is generally considered capable of using a broad range of coreceptors. Since HIV-2 variants from individuals with nonprogressive infection were not studied previously, the possibility that broad coreceptor usage is a property of variants associated with progressive infection could not be excluded. To test this, we determined the coreceptor usage of 43 HIV-2 variants isolated from six long-term-infected individuals with undetectable plasma viremia. Using GHOST indicator cells, we showed for the first time that the only coreceptors efficiently used by low-pathogenic HIV-2 variants are CCR5, GPR15 (BOB), and CXCR6 (BONZO). Surprisingly, control HIV-2 variants (n = 45) isolated from seven viremic individuals also mainly used these three coreceptors, whereas use of CCR1, CCR2b, or CCR3 was rare. Nearly a quarter of all HIV-2 variants tested could infect the parental GHOST cells, which could be partially explained by CXCR4 usage. Use of CXCR4 was observed only for HIV-2 variants from viremic individuals. Thirty-eight variants from aviremic and viremic HIV-2-infected individuals were additionally tested in U87 cells. All except one were capable of infecting the parental U87 cells, often with high efficiency. When virus production in parental cells was regarded as background in the coreceptor-transduced cell lines, the results in U87 cells were largely in agreement with the findings in GHOST cells. HIV-2 isolates from aviremic individuals commonly use as coreceptors CCR5, GPR15, and CXCR6, as well as an unidentified receptor expressed by U87 cells. Broad coreceptor usage, therefore, does not appear to be associated with pathogenicity of HIV-2.
Asunto(s)
Infecciones por VIH/virología , Sobrevivientes de VIH a Largo Plazo , VIH-2/patogenicidad , Receptores del VIH/metabolismo , Viremia/virología , Línea Celular Tumoral , Variación Genética , VIH-2/clasificación , VIH-2/genética , VIH-2/metabolismo , Humanos , Receptores CCR5/metabolismo , Receptores CXCR6 , Receptores de Quimiocina , Receptores de Citocinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Péptidos/metabolismo , Receptores Virales/metabolismoRESUMEN
We have previously shown convergence of craniovascular and tooth pulp afferents in the cervical spinal cord of cats. This study looked for similar convergence in the thalamus. Fifty-four thalamic cells with input from tooth pulp, superior sagittal sinus, or both, were identified. Twenty-nine cells with tooth pulp and superior sagittal sinus input were located in the ventrobasal complex of the intralaminar nuclei. Most of these 29 cells were also excited by cooling the contralateral tooth pulp, and 21 had receptive fields on the contralateral face or forelimb. Twenty cells excited by stimulation of superior sagittal sinus, and not tooth pulp, were found in several nuclei. The 5 cells excited by stimulation of tooth pulp, but not sagittal sinus, were restricted to the ventrobasal complex. The data confirm convergence from sagittal sinus, tooth pulp, and skin in the thalamus of anaesthetized cats.
Asunto(s)
Vías Aferentes/fisiología , Médula Espinal/fisiología , Diente/inervación , Animales , Gatos , Plexo Cervical , Estimulación Eléctrica , Tálamo/fisiologíaRESUMEN
Several studies have demonstrated a functional role for the V1-V2 region of the human immunodeficiency virus type 1 (HIV-1) envelope surface glycoprotein gp120 in the membrane fusion processes underlying viral entry and syncytium induction. In a study with chimeric primary envelope genes, we have previously demonstrated that the exchange of V2 regions was sufficient to transfer syncytium-inducing capacity to a non-syncytium-inducing envelope protein. The exchanged V2 regions, comprising a number of variable amino acids, conferred changes to both the predicted secondary structure and to the net positive charge of the V2 loops. In a syncytium-forming assay based on transient envelope protein expression in CD4+ SupT1 cells, we have extended this observation by mutating the variable positions of the V2 region to determine the relative contribution of individual amino acids to syncytium formation. It can be shown that simultaneous mutation of multiple amino acids is needed to interfere with the V2 region-determined syncytium-inducing phenotype. Single amino acid changes either influencing charge of predicted secondary structure of the V2 loop proved to be insufficient to abolish V2 region-controlled syncytium formation. This robust V2 organization may allow the virus to accumulate mutations, while retaining its biological phenotype.
Asunto(s)
Variación Genética/genética , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/genética , Fusión de Membrana , Mutación , Secuencia de Aminoácidos , Aminoácidos/fisiología , Secuencia de Bases , Células Cultivadas , Electroquímica , Genes env/genética , Células Gigantes , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/fisiología , VIH-1/fisiología , Humanos , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Proteínas Recombinantes de Fusión/biosíntesis , Linfocitos T Reguladores/virología , TransfecciónRESUMEN
The triptans are agonists at serotonin (5-HT)1B/1D receptors; however, they are also active at 5-HT1A and 5-HT1F receptors. We conducted this series of experiments to further elucidate the site of action of naratriptan using a well-established animal model of trigeminovascular stimulation. Following electrical stimulation of the superior sagittal sinus of the cat, single cell responses (n=83) were recorded in the trigeminal nucleus caudalis. Most cells (91%) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields. The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation (response suppressed by 47 +/- 4%, P<0.001). The effect of naratriptan was significantly attenuated by application of either the 5-HT(1B/1D) receptor antagonist GR-127935 (P<0.001) or the 5-HT1A antagonist WAY-100635 (P<0.05). The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan, but by only 20 +/- 3%. Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs. receptive field responses in trigeminal neurones. These results indicate that naratriptan has a central effect in the trigeminovascular system, selectively inhibiting afferent activity in craniovascular neurones, via both 5-HT(1B/1D) and 5-HT1A receptors.
Asunto(s)
Indoles/farmacología , Trastornos Migrañosos/tratamiento farmacológico , Neuronas/efectos de los fármacos , Piperidinas/farmacología , Receptores de Serotonina 5-HT1/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Núcleo Caudal del Trigémino/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Gatos , Circulación Cerebrovascular/efectos de los fármacos , Estimulación Eléctrica , Microelectrodos , Neuronas/fisiología , Estimulación Física , Receptores de Serotonina 5-HT1/fisiología , Antagonistas de la Serotonina/farmacología , Núcleo Caudal del Trigémino/irrigación sanguínea , Núcleo Caudal del Trigémino/fisiología , TriptaminasRESUMEN
The antiviral activity of a CD8(+) cytotoxic T-lymphocyte (CTL) clone (TCC108) directed against a newly identified HLA-B14-restricted epitope, human immunodeficiency virus type 1 (HIV-1) Rev(67-75) SAEPVPLQL, was analyzed with respect to its kinetics of target cell lysis and inhibition of HIV-1 production. Addition of TCC108 cells or CD8(+) reverse transcriptase-specific CTLs to HLA-matched CD4(+) T cells at different times after infection with HIV-1 IIIB showed that infected cells became susceptible to CTL-mediated lysis before peak virus production but after the onset of progeny virus release. When either of these CTLs were added to part of the infected cells immediately after infection, p55 expression and virus production were significantly suppressed. These data support a model in which CTLs, apart from exerting cytolytic activity which may prevent continued virus release, can interfere with viral protein expression during the eclipse phase via noncytolytic mechanisms. TCC108-mediated inhibition of virus replication in peripheral blood mononuclear cells caused rapid selection of a virus with a mutation (69E-->K) in the Rev(67-75) CTL epitope which abolished recognition by TCC108 cells. Taken together, these data suggest that both cytolytic and noncytolytic antiviral mechanisms of CTLs can be specifically targeted to HIV-1-infected cells.
Asunto(s)
Infecciones por VIH/inmunología , VIH-1/inmunología , Linfocitos T Citotóxicos/inmunología , Secuencia de Aminoácidos , Línea Celular , Pruebas Inmunológicas de Citotoxicidad , Productos del Gen rev/inmunología , Infecciones por VIH/sangre , Transcriptasa Inversa del VIH/inmunología , VIH-1/crecimiento & desarrollo , VIH-1/fisiología , Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Humanos , Cinética , Datos de Secuencia Molecular , Replicación Viral , Productos del Gen rev del Virus de la Inmunodeficiencia HumanaRESUMEN
Entry of human immunodeficiency virus type 1 (HIV-1) into target cells is mediated by binding of the surface envelope glycoprotein to the CD4 molecule. Interaction of the resulting CD4-glycoprotein complex with alpha- or beta-chemokine receptors, depending on the biological phenotype of the virus, then initiates the fusion process. Here, we show that primary HIV-2 isolates and biological clones, in contrast to those of HIV-1, may use a broad range of coreceptors, including CCR-1, CCR-3, CCR-5, and CXCR-4. The syncytium-inducing capacity of these viruses did not correlate with the ability to infect via CXCR-4 or any other coreceptor. One cell-free passage of the intermediate isolates in mitogen-stimulated, CD8+ cell-depleted peripheral blood mononuclear cells resulted in the outgrowth of variants with CCR-5 only, whereas the coreceptor usage of late and early isolates did not change. Since HIV-2 is less pathogenic in vivo than HIV-1, these data suggest that HIV pathogenicity in vivo is not directly related to the spectrum of coreceptors used in in vitro systems.
Asunto(s)
VIH-2/fisiología , Receptores CCR5/fisiología , Receptores CXCR4/fisiología , Receptores del VIH/fisiología , HumanosRESUMEN
Intravenous infusions of serotonin (5-hydroxtryptamine creatinine sulphate, 5HT, 50-300 microg/kg/min) in cats reversibly inhibited the responses of cervical spinal cord neurons to electrical stimulation of the superior sagittal sinus. Inhibition developed over 20-30 min and resolved over the same time course, suggesting a dependence on accumulation of 5HT in the central nervous system. Inhibition was suppressed by prior intravenous injection of the 5HT antagonists methysergide (1 mg/kg) and methiothepin (1 mg/kg). Infusions of 5HT (50 microg/kg/min) caused a rise in whole blood levels of 5HT by a factor of 1.5 of control values. 5HT levels in platelet-free plasma rose by a factor of 50. Levels of 5HT and 5 hydroxyindole acetic acid released into the cerebrospinal fluid rose significantly. The results suggest that earlier clinical observations that 5HT infusions can ameliorate the pain of migraine may not have been due to cranial vasoconstriction alone, but could have involved a central action of 5HT.
Asunto(s)
Duramadre/irrigación sanguínea , Hemodinámica/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Serotonina/farmacología , Médula Espinal/fisiopatología , Potenciales de Acción/efectos de los fármacos , Animales , Gatos , Cromatografía Líquida de Alta Presión , Senos Craneales , Estimulación Eléctrica , Ácido Hidroxiindolacético/sangre , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Infusiones Intravenosas , Metiotepina/farmacología , Metisergida/farmacología , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/fisiopatología , Neuronas Aferentes/fisiología , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Receptores de Serotonina/efectos de los fármacos , Serotonina/administración & dosificación , Serotonina/sangre , Serotonina/líquido cefalorraquídeo , Serotonina/uso terapéutico , Antagonistas de la Serotonina/farmacología , Sístole/efectos de los fármacos , Núcleos del Trigémino/fisiopatologíaRESUMEN
The pathogenic properties of four primary human immunodeficiency virus type 2 (HIV-2) isolates and two primary HIV-2 biological clones were studied in an in vivo human-to-mouse chimeric model. The cell-associated viral load and the ability to reduce the severity of the induced graft-versus-host disease symptoms, the CD4/CD8 ratio and the level of repopulation of the mouse tissues by the graft, were determined. All HIV-2 strains, irrespective of their in vitro biological phenotype, replicated to high titres and significantly reduced graft-versus-host disease symptoms as well as the CD4/CD8 ratios. Reduction of graft repopulation caused by infection with the respective HIV-2 strains showed that the in vitro replication rate, syncytium-inducing capacity and ability to infect human macrophages did influence the in vivo pathogenic potential whereas broadening of coreceptor usage did not.
Asunto(s)
Infecciones por VIH/etiología , VIH-2/patogenicidad , Receptores del VIH/fisiología , Enfermedad Aguda , Animales , Relación CD4-CD8 , Quimera , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-2/fisiología , Humanos , Inmunohistoquímica , Leucocitos Mononucleares/trasplante , Ratones , Trasplante Heterólogo , Replicación ViralRESUMEN
OBJECTIVE: To study phenotypic and genotypic resistance of HIV-2 against nucleoside reverse transcriptase inhibitors (NRTI). METHODS: Biologic HIV-2 clones were generated from 3 patients before and after initiation of antiretroviral therapy with zidovudine (AZT) in patient RH2-7, AZT and didanosine (ddI) in patient PH2-1, and after addition of lamivudine (3TC) to AZT monotherapy in patient RH2-5. The sensitivity to NRTI of the virus clones, as defined by the 50% inhibitory concentration (IC(50)), was determined in vitro. The predicted amino acid sequences of the reverse transcriptase proteins from these clones were determined. RESULTS: Comparing the sensitivity of the biologic HIV-2 clones obtained after start of therapy with those from antiviral naive patients, resistance had developed to AZT (patients RH2-7 and RH2-5) and 3TC (patient PH2-1 and RH2-5). No resistance to AZT was observed in the biologic clone from PH2-1 obtained after start of therapy. The resistant clones from RH2-5 and PH2-1, but not RH2-7, contained amino acid mutations at positions where HIV-1 has been shown to mutate after AZT and 3TC treatment. CONCLUSIONS: Phenotypic resistance of HIV-2 to nucleoside analogues, which developed in HIV-2-infected patients treated with NRTIs, was associated with genotypic changes. Some of the mutations at amino acid positions in the HIV-2 reverse transcriptase gene corresponded with those involved in HIV-1 resistance, although no conventional mutations associated with resistance to AZT were observed.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , VIH-2/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto , Secuencia de Aminoácidos , Secuencia de Consenso , Didanosina/farmacología , Didanosina/uso terapéutico , Farmacorresistencia Microbiana , Quimioterapia Combinada , Femenino , Genes Virales , Genotipo , Infecciones por VIH/virología , VIH-2/enzimología , VIH-2/genética , Humanos , Lamivudine/farmacología , Lamivudine/uso terapéutico , Masculino , Datos de Secuencia Molecular , Fenotipo , ADN Polimerasa Dirigida por ARN/genética , Zidovudina/farmacología , Zidovudina/uso terapéuticoRESUMEN
Early after seroconversion, macrophage-tropic human immunodeficiency virus type 1 (HIV-1) variants are predominantly found, even when a mixture of macrophage-tropic and non-macrophage-tropic variants was transmitted. For virus contracted by sexual transmission, this is presently explained by selection at the port of entry, where macrophages are infected and T cells are relatively rare. Here we explore an additional mechanism to explain the selection of macrophage-tropic variants in cases where the mucosa is bypassed during transmission, such as blood transfusion, needle-stick accidents, or intravenous drug abuse. With molecularly cloned primary isolates of HIV-1 in irradiated mice that had been reconstituted with a high dose of human peripheral blood mononuclear cells, we found that a macrophage-tropic HIV-1 clone escaped more efficiently from specific cytotoxic T-lymphocyte (CTL) pressure than its non-macrophage-tropic counterpart. We propose that CTLs favor the selective outgrowth of macrophage-tropic HIV-1 variants because infected macrophages are less susceptible to CTL activity than infected T cells.