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Viral and Host Factors Involved in Rapid HIV-1 Disease Progression

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Viral and Host Factors Involved in Rapid HIV-1 Disease Progression Viral and host factors involved in rapid HIV-1 disease progression Judith Dalmau Moreno Institut de Recerca de la Sida – IrsiCaixa Director: Prof. Javier Martínez-Picado Universitat Autònoma de Barcelona Departament de Bioquímica i Biologia Molecular Programa de Doctorat en Bioquímica, Biologia Molecular i Biomedicina Programa de Doctorat en Bioquímica, Biologia Molecular i Biomedicina Departament de Bioquímica i Biologia Molecular Universitat Autònoma de Barcelona Viral and host factors involved in rapid HIV-1 disease progression Judith Dalmau Moreno Institut de Recerca de la Sida IrsiCaixa Hospital Universitari Germans Trias i Pujol Doctoral Thesis UAB 2014 Thesis Director: Prof. Javier Martínez-Picado Tutor: Dr. Josep Vendrell Roca El doctor Javier Martínez Picado, investigador principal i professor de recerca ICREA a l’Institut de Recerca de la Sida - IrsiCaixa (Hospital U. Germans Trias i Pujol de Badalona), Certifica: Que el treball experimental realitzat i la redacció de la memòria de la Tesi Doctoral titulada “Viral and host factors involved in rapid HIV-1 disease progression” han estat realitzats per na Judith Dalmau Moreno sota la seva direcció i considera que és apte per a ser presentat per a optar al grau de Doctor en Bioquímica, Biologia Molecular i Biomedicina per la Universitat Autònoma de Barcelona. I per tal que en quedi constància, signa aquest document a Badalona, 30 de Gener del 2014. Prof. Javier Martínez-Picado El doctor Josep Vendrell Roca, professor del Departament de Bioquímica i Biologia Molecular i degà de la Facultat de Biociències de la Universitat Autònoma de Barcelona, Certifica: Que el treball experimental realitzat i la redacció de la memòria de la Tesi Doctoral titulada “Viral and host factors involved in rapid HIV-1 disease progression” han estat realitzats per na Judith Dalmau Moreno sota la seva direcció i considera que és apte per a ser presentat per a optar al grau de Doctor en Bioquímica, Biologia Molecular i Biomedicina per la Universitat Autònoma de Barcelona. I per tal que en quedi constància, signa aquest document a Bellaterra, 30 de Gener del 2014. Dr. Josep Vendrell Roca Als meus pares, el meu germà i tota la gent que estimo "Viu com si anessis a morir demà. Aprèn com si fossis a viure per sempre". - Mahatma Gandhi SUMMARY Remarkable variation in clinical outcome can be observed following HIV-1 infection. While some HIV-1–infected individuals are able to suppress viral replication to very low levels (<2000 copies/mL) and/or maintain high CD4+ T-cell counts over many years without antiretroviral therapy (HIV controllers), others quickly progress to AIDS or meet the current criteria for antiretroviral treatment within the first 3 years after primary infection (rapid progressors, RP). Furthermore, a minority of highly viremic individuals remain asymptomatic with high CD4+ T-cell counts (viremic non-progressors, VNP), similar to those observed in the non-progressive disease model of SIV infection in natural hosts. The study of extreme phenotypes can provide important information onthe interactions established between the viral variant and the host during primary HIV infection and the subsequent clinical evolution of the infection. Indeed, the study of HIV controllers (including elite controllers, who maintain plasma viral RNA under detectable levels [<50 copies/mL]) is providing relevant data on HIV immunopathogenesis. The other extreme comprises RPs, who account for a relatively small percentage of the HIV-1-infected population. Nevertheless, the implications of their immunogenetic and immunopathogenic characteristics are remarkable. This thesis originates from the comprehensive study of 2 cases of extremely severe rapid progression that was later extended to the recruitment and study of an unprecedentedly large and well-defined cohort of RPs. The specific objective was to investigate a wide range of viral and host factors involved in rapid progression of HIV-1 infection, in contrast to other phenotypes, namely,individuals with an average progression profile (standard progressors, SP) and VNPs. The results of this study demonstrate convergence of the viral and host factors contributing to the clinical severity of rapid progression. Individuals infected with highly replicative, dual-tropic, HLA-adapted viruses were shown to be more prone to develop AIDS-defining symptoms during primary HIV-1 infection, since in many cases they are also unable to mount humoral and cellular HIV-1-specific immune responses. Concordant HLA supertypes between the source and the recipient, the presence of common and risk HLA class I alleles, and the low frequency of protective HLA alleles were also shown to further accelerate disease progression. In addition, transcriptome analysis revealed that RPs have a specific CD4+ and CD8+T-cell transcriptome profile similar to that observed in pathogenic SIV-infected rhesus macaques and characterized by higher expression of interferon-stimulated genes. VNPs, on the other hand,were characterized by a gene regulation profile similarto that of non-pathogenic SIV-infected sooty mangabeys. The present study provides important insights into the host and viral traits driving progression of HIV-1 infection, which have relevant implications for our knowledge of HIV pathogenesis and the importance of early monitoring of disease course. 1 RESUM Els éssers humans mostren una notable variació en el desenvolupament clínic rere la infecció per VIH-1. Si bé algunes persones amb VIH-1 són capaces de suprimir la replicació viral del VIH a nivells molt baixos (<2000 còpies/ml) i/o mantenir els recomptes de CD4 alts durant molts anys en absència de teràpia antiretroviral (Controladors), altres progressen ràpidament a sida o compleixen els criteris actuals per a iniciar tractament antiretroviral en els 3 primers anys rere la infecció primària (Progressors ràpids, RP). D'altra banda, una minoria d'individus amb alts nivells de virèmia roman asimptomàtica i manté els recomptes de cèl·lules T CD4+ elevats (Virèmics no progressors, VNP), similars als observats en el model no progressiu d’infecció per SIV en l’hoste natural. L'estudi de fenotips extrems pot donar informació rellevant en termes de les interaccions que s'estableixen entre el virus i l'hoste durant la infecció primària pel VIH, així com de l'evolució clínica posterior a la infecció. De fet, l'estudi dels controladors (incloent els controladors d’elit, que mantenen l’ARN viral a nivells indetectables) està proporcionant dades rellevants de la immunopatogènesi de la infecció. L'extrem oposat són els RPs, els quals representen un percentatge relativament petit de la població infectada per VIH-1.No obstant això, les implicacions de les seves característiques immunogenètiques i immunopatogèniques són notables . Aquesta tesi té el seu origen en l’estudi exhaustiu de 2 casos de progressió extremadament severa i ràpida, que posteriorment es va estendre a la creació i l'estudi d'una cohort gran i ben definida de RPs sense precedents. L'objectiu específic va ser investigar una àmplia gamma de factors virals i de l'hoste implicats en la progressió ràpida de la infecció per VIH-1, en comparació amb altres fenotips, incloent individus amb un perfil estàndard de progressió (progressors estàndard, SP) i VNPs. Els resultats d'aquest estudi demostren la convergència de factors virals i de l'hoste que contribueixen a la gravetat clínica de la progressió ràpida. Les persones infectades amb virus altament replicatius, dual-tròpics i HLA-adaptats van mostrar ser més propenses a desenvolupar símptomes definitoris de SIDA durant la infecció primària per VIH-1, donat que en molts casos tampoc no són capaces de produir respostes immunitàrieshumorals i cel·lulars específiques contra VIH-1. La concordança de supertipus d’HLA, la presència d'al·lels d’HLA comuns i d’al·lels de risc, i la baixa freqüència d’al·lels protectius, també van mostrar associació amb l’acceleració de la malaltia. A més, l'anàlisi del transcriptoma va revelar que els RPs tenen un perfil transcriptòmic específic a les cèl·lules T CD4+ i CD8+, similar a l'observat en la infecció patogènica per SIV en rhesus macacs, i caracteritzat per una major expressió de gens estimulats per l'interferó. Els VNPs, en canvi,es caracteritzen per un perfil de regulació de gens similar a la infecció no patogènica per SIV dels sooty mangabeys. El present estudi proporciona informació rellevant sobre les característiques virals i de l’hoste implicades en la progressió ràpida de la infecció per VIH-1, la qual té implicacions destacables en el nostre coneixement de la patogènesi del VIH-1 i en la importància de la monitorització primerenca de l'evolució de la malaltia. 3 RESUMEN Los seres humanos muestran una notable variación en el desarrollo clínico tras la infección por VIH-1. Si bien algunas personas son capaces de suprimir la replicación viral del VIH a niveles muy bajos (<2.000 copias/ml) y/o mantener los recuentos de CD4 altos durante varios años en ausencia de terapia antirretroviral (Controladores), otras progresan rápidamente a SIDA o cumplen los criterios de inicio de tratamiento antirretroviral en los 3 primeros años tras la infección primaria (Progresores rápidos, RP). Por otra parte, una minoría de individuos con altos niveles de viremia permanece asintomática y mantiene los recuentos de células T CD4+ elevados (Virémicos no progresores, VNP), similares a los observados en el modelo no progresivo de infección por SIV en el huésped natural. El estudio de fenotipos extremos puede dar información relevante en términos de las interacciones que se establecen entre el virus y el huésped durante la infección primaria por el VIH, así como de la evolución clínica posterior a la infección. De hecho, el estudio de los controladores (incluyendo los controladores de élite, que mantienen el ARN viral a niveles indetectables) está proporcionando datos relevantes de la inmunopatogénesis de la infección. El extremo opuesto son los RPs, los cuales representan un porcentaje relativamente pequeño de la población infectada por VIH-1.
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