RESUMEN
Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.
Asunto(s)
Aptitud Genética , Infecciones por VIH/diagnóstico , VIH-1/genética , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Linfocitos T/inmunología , Adulto , Secuencia de Aminoácidos , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Evolución Molecular , Femenino , Células HEK293 , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , Interacciones Huésped-Patógeno/genética , Humanos , Evasión Inmune/genética , Masculino , Datos de Secuencia Molecular , Filogenia , Pronóstico , Carga Viral/genética , Replicación Viral/genéticaRESUMEN
Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57-restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus-infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences.
Asunto(s)
Presentación de Antígeno , Antígenos VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , VIH-1/inmunología , Linfocitos T Citotóxicos/inmunología , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Células Clonales , ADN Viral/genética , Epítopos/genética , Productos del Gen gag/genética , Productos del Gen gag/inmunología , Variación Genética , Infecciones por VIH/genética , Antígenos HLA-B/genética , Humanos , Datos de Secuencia Molecular , Mutación , Homología de Secuencia de AminoácidoRESUMEN
The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.
Asunto(s)
Evolución Biológica , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/fisiología , Antígenos HLA-B/inmunología , África Austral , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/inmunología , Femenino , Frecuencia de los Genes , Productos del Gen nef/química , VIH-1/genética , Antígenos HLA-A/genética , Antígenos HLA-A/inmunología , Antígenos HLA-B/genética , Humanos , Lactante , Masculino , Polimorfismo Genético/genética , Carga Viral , Productos del Gen nef del Virus de la Inmunodeficiencia HumanaRESUMEN
The hypothesis that the intrapatient emergence of cytotoxic T-lymphocyte escape variants contributes to the evolution of human immunodeficiency virus type 1 at the population (interpatient) level was tested using the HLA-A*0201-restricted gag p17 epitope SLYNTVATL. Using a simple experimental design, we investigated the evolutionary processes operating within this epitope among patients while compensating for the confounding influence of intrapatient natural selection. Using this approach, we revealed a pattern of A*0201-driven escape within patients, followed by the sustained transmission of these escape variants among patients irrespective of their HLA type.