RESUMO
BACKGROUND: Elite non-progressors (plasma viral load < 50 copies/ml while antiretroviral naive) constitute a tiny fraction of HIV-infected individuals. After 12 years follow-up of a cohort of 13 long-term non-progressors (LTNP) identified from 135 individuals with transfusion-acquired HIV infection, 5 remained LTNP after 23 to 26 years infection, but only 3 retained elite LTNP status. We examined the mechanisms that differentiated delayed progressors from LTNP in this cohort. RESULTS: A survival advantage was conferred on 12 of 13 subjects, who had at least one host genetic factor (HLA, chemokine receptor or TLR polymorphisms) or viral attenuating factor (defective nef) associated with slow progression. However, antiviral immune responses differentiated the course of disease into and beyond the second decade of infection. A stable p24-specific proliferative response was associated with control of viraemia and retention of non-progressor status, but this p24 response was absent or declined in viraemic subjects. Strong Gag-dominant cytotoxic T lymphocyte (CTL) responses were identified in most LTNP, or Pol dominant-CTL in those with nef-defective HIV infection. CTL were associated with control of viraemia when combined with p24 proliferative responses. However, CTL did not prevent late disease progression. Individuals with sustained viral suppression had CTL recognising numerous Gag epitopes, while strong but restricted responses to one or two immunodominant epitopes was effective for some time, but failed to contain viraemia over the course of this study. Viral escape mutants at a HLA B27-restricted Gag-p24 epitope were detected in only 1 of 3 individuals, whereas declining or negative p24 proliferative responses occurred in all 3 concurrent with an increase in viraemia. CONCLUSION: Detectable viraemia at study entry was predictive of loss of LTNP status and/or disease progression in 6 of 8, and differentiated slow progressors from elite LTNP who retained potent virological control. Sustained immunological suppression of viraemia was independently associated with preserved p24 proliferative responses, regardless of the strength and breadth of the CTL response. A decline in this protective p24 response preceded or correlated with loss of non-progressor status and/or signs of disease progression.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteína do Núcleo p24 do HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , Reação Transfusional , Viremia/imunologia , Sequência de Aminoácidos , Estudos de Coortes , Progressão da Doença , Produtos do Gene gag/química , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Ativação Linfocitária/imunologia , RNA Viral/sangue , Carga Viral , Viremia/virologiaRESUMO
BACKGROUND: The Sydney blood bank cohort (SBBC) of long-term survivors consists of multiple individuals infected with attenuated, nef-deleted variants of human immunodeficiency virus type 1 (HIV-1) acquired from a single source. Long-term prospective studies have demonstrated that the SBBC now comprises slow progressors (SP) as well as long-term nonprogressors (LTNP). Convergent evolution of nef sequences in SBBC SP and LTNP indicates the in vivo pathogenicity of HIV-1 in SBBC members is dictated by factors other than nef. To better understand mechanisms underlying the pathogenicity of nef-deleted HIV-1, we examined the phenotype and env sequence diversity of sequentially isolated viruses (n = 2) from 3 SBBC members. RESULTS: The viruses characterized here were isolated from two SP spanning a three or six year period during progressive HIV-1 infection (subjects D36 and C98, respectively) and from a LTNP spanning a two year period during asymptomatic, nonprogressive infection (subject C18). Both isolates from D36 were R5X4 phenotype and, compared to control HIV-1 strains, replicated to low levels in peripheral blood mononuclear cells (PBMC). In contrast, both isolates from C98 and C18 were CCR5-restricted. Both viruses isolated from C98 replicated to barely detectable levels in PBMC, whereas both viruses isolated from C18 replicated to low levels, similar to those isolated from D36. Analysis of env by V1V2 and V3 heteroduplex tracking assay, V1V2 length polymorphisms, sequencing and phylogenetic analysis showed distinct intra- and inter-patient env evolution. CONCLUSION: Independent evolution of env despite convergent evolution of nef may contribute to the in vivo pathogenicity of nef-deleted HIV-1 in SBBC members, which may not necessarily be associated with changes in replication capacity or viral coreceptor specificity.
Assuntos
Produtos do Gene nef/genética , Infecções por HIV/genética , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , HIV-1/fisiologia , Sequência de Aminoácidos , Sequência de Bases , Proteína gp120 do Envelope de HIV/genética , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Dados de Sequência Molecular , Fragmentos de Peptídeos/genética , Fenótipo , Filogenia , Polimorfismo Genético , Replicação Viral/genética , Produtos do Gene nef do Vírus da Imunodeficiência HumanaRESUMO
We studied the evolution of human immunodeficiency virus type 1 (HIV-1) in a cohort of long-term survivors infected with an attenuated strain of HIV-1 acquired from a single source. Although the cohort members experienced differing clinical courses, we demonstrate similar evolution of HIV-1 nef/long-terminal repeat (LTR) sequences, characterized by progressive sequence deletions tending toward a minimal nef/LTR structure that retains only sequence elements required for viral replication. The in vivo pathogenicity of attenuated HIV-1 is therefore dictated by viral and/or host factors other than those that impose a unidirectional selection pressure on the nef/LTR region of the HIV-1 genome.
Assuntos
Produtos do Gene nef/genética , Infecções por HIV/virologia , Repetição Terminal Longa de HIV/genética , HIV-1/genética , Adaptação Fisiológica , Idoso , Estudos de Coortes , Feminino , Deleção de Genes , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise de Sequência , Produtos do Gene nef do Vírus da Imunodeficiência HumanaAssuntos
Infecções por HIV/epidemiologia , Sobreviventes de Longo Prazo ao HIV , HIV-1 , Reação Transfusional , Idoso , Idoso de 80 Anos ou mais , Contagem de Linfócito CD4 , Estudos de Coortes , Progressão da Doença , Infecções por HIV/transmissão , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales/epidemiologia , Carga Viral , Viremia/epidemiologia , Viremia/transmissãoRESUMO
This article describes the methods used by the New South Wales Division of the Australian Red Cross Blood Service (ARCBS-NSW) to conduct human immunodeficiency virus (HIV) lookback, assesses the success and limitations of the different methods used, and discusses the results obtained. This article shows that an important outcome of the HIV lookback undertaken by the ARCBS-NSW was the establishment and maintenance of an observational database. This database became an integral part of several research projects that contributed significantly to understanding factors influencing the rate of progression of HIV to acquired immunodeficiency virus and knowledge of HIV pathogenesis in general. This article argues that if lookback is extended beyond its original function of identifying transfusion-infected recipients and the implicated donors to create and maintain a linked register of these recipients and donors, the information obtained in such an observational database can be used to describe the natural history of transfusion-transmitted infectious diseases and can contribute to the research necessary to the understanding of disease pathogenesis.