RESUMO
The predictability of virus-host interactions and disease progression in rapidly evolving human viral infections has been difficult to assess because of host and genetic viral diversity. Here we examined adaptive HIV-specific cellular and humoral immune responses and viral evolution in adult monozygotic twins simultaneously infected with the same virus. CD4 T cell counts and viral loads followed similar trajectories over three years of follow up. The initial CD8 T cell response targeted 17 epitopes, 15 of which were identical in each twin, including two immunodominant responses. By 36 months after infection, 14 of 15 initial responses were still detectable in both, whereas all new responses were subdominant and remained so. Of four responses that declined in both twins, three demonstrated mutations at the same residue. In addition, the evolving antibody responses cross-neutralized the other twin's virus, with similar changes in the pattern of evolution in the envelope gene. These results reveal considerable concordance of adaptive cellular and humoral immune responses and HIV evolution in the same genetic environment, suggesting constraints on mutational pathways to HIV immune escape.
Assuntos
Substituição de Aminoácidos , Epitopos de Linfócito T/genética , Evolução Molecular , Produtos do Gene env/genética , Soropositividade para HIV/genética , HIV-1/genética , Mutação Puntual , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Contagem de Linfócito CD4/métodos , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Feminino , Seguimentos , Produtos do Gene env/imunologia , Soropositividade para HIV/sangue , Soropositividade para HIV/imunologia , HIV-1/imunologia , Humanos , Imunidade Celular/genética , Imunidade Celular/imunologia , MasculinoRESUMO
Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.
Assuntos
Antígenos HIV , Infecções por HIV/imunologia , HIV-1/imunologia , HIV-1/fisiologia , Linfócitos T Citotóxicos/imunologia , Replicação Viral/imunologia , Vacinas contra a AIDS/imunologia , Sequência de Aminoácidos , Estudos de Coortes , Mapeamento de Epitopos , Epitopos/genética , Variação Genética , Antígenos HIV/genética , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , Antígenos HLA-B/genética , Antígeno HLA-B15 , Humanos , Epitopos Imunodominantes/genética , Técnicas In Vitro , Dados de Sequência MolecularRESUMO
The sequence diversity of human immunodeficiency virus type 1 (HIV-1) represents a major obstacle to the development of an effective vaccine, yet the forces impacting the evolution of this pathogen remain unclear. To address this issue we assessed the relationship between genome-wide viral evolution and adaptive CD8+ T-cell responses in four clade B virus-infected patients studied longitudinally for as long as 5 years after acute infection. Of the 98 amino acid mutations identified in nonenvelope antigens, 53% were associated with detectable CD8+ T-cell responses, indicative of positive selective immune pressures. An additional 18% of amino acid mutations represented substitutions toward common clade B consensus sequence residues, nine of which were strongly associated with HLA class I alleles not expressed by the subjects and thus indicative of reversions of transmitted CD8 escape mutations. Thus, nearly two-thirds of all mutations were attributable to CD8+ T-cell selective pressures. A closer examination of CD8 escape mutations in additional persons with chronic disease indicated that not only did immune pressures frequently result in selection of identical amino acid substitutions in mutating epitopes, but mutating residues also correlated with highly polymorphic sites in both clade B and C viruses. These data indicate a dominant role for cellular immune selective pressures in driving both individual and global HIV-1 evolution. The stereotypic nature of acquired mutations provides support for biochemical constraints limiting HIV-1 evolution and for the impact of CD8 escape mutations on viral fitness.