RESUMO
HIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses.
Assuntos
HIV-1/patogenicidade , Especificidade de Hospedeiro , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Lentivirus de Primatas/crescimento & desenvolvimento , Vírus da Imunodeficiência Símia/patogenicidade , Proteínas Virais Reguladoras e Acessórias/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Sequência de Aminoácidos , Animais , Antígeno 2 do Estroma da Médula Óssea/genética , Antígeno 2 do Estroma da Médula Óssea/imunologia , Complexo CD3/genética , Complexo CD3/imunologia , Chlorocebus aethiops , Feminino , Regulação da Expressão Gênica , HIV-1/crescimento & desenvolvimento , Proteínas do Vírus da Imunodeficiência Humana/genética , Humanos , Lentivirus de Primatas/patogenicidade , Ativação Linfocitária , NF-kappa B/genética , NF-kappa B/imunologia , Alinhamento de Sequência , Transdução de Sinais , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Transcrição Gênica , Carga Viral , Proteínas Virais Reguladoras e Acessórias/genética , Virulência , Replicação Viral , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genéticaRESUMO
Defining the virus-host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses. Here, we generated infectious molecular clones of transmitted founder (TF; n = 27) and chronic control (CC; n = 14) viruses of subtypes B (n = 18) and C (n = 23) and compared their phenotypic properties in assays specifically designed to probe the earliest stages of HIV-1 infection. We found that TF virions were 1.7-fold more infectious (P = 0.049) and contained 1.9-fold more Env per particle (P = 0.048) compared with CC viruses. TF viruses were also captured by monocyte-derived dendritic cells 1.7-fold more efficiently (P = 0.035) and more readily transferred to CD4+ T cells (P = 0.025). In primary CD4+ T cells, TF and CC viruses replicated with comparable kinetics; however, when propagated in the presence of IFN-α, TF viruses replicated to higher titers than CC viruses. This difference was significant for subtype B (P = 0.000013) but not subtype C (P = 0.53) viruses, possibly reflecting demographic differences of the respective patient cohorts. Together, these data indicate that TF viruses are enriched for higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN-α resistance. These viral properties, which likely act in concert, should be considered in the development and testing of AIDS vaccines.