Determinants in HIV1 Nef for enhancement of virus replication and depletion of CD4+ T lymphocytes in human lymphoid tissue ex vivo (original) (raw)
Related papers
Journal of virology, 1999
The nef gene is important for the pathogenicity associated with simian immunodeficiency virus infection in rhesus monkeys and with human immunodeficiency virus type 1 (HIV-1) infection in humans. The mechanisms by which nef contributes to pathogenesis in vivo remain unclear. We investigated the contribution of nef to HIV-1 replication in human lymphoid tissue ex vivo by studying infection with parental HIV-1 strain NL4-3 and with a nef mutant (DeltanefNL4-3). In human tonsillar histocultures, NL4-3 replicated to higher levels than DeltanefNL4-3 did. Increased virus production with NL4-3 infection was associated with increased numbers of productively infected cells and greater loss of CD4(+) T cells over time. While the numbers of productively infected T cells were increased in the presence of nef, the levels of viral expression and production per infected T cell were similar whether the nef gene was present or not. Exogenous interleukin-2 (IL-2) increased HIV-1 production in NL4-3-i...
Journal of virology, 2003
The nef gene products encoded by human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus type 1 (SIV-1) increase viral loads in infected hosts and accelerate clinical progression to AIDS. Nef exhibits a spectrum of biological activities, including the ability to downregulate surface expression of CD4 and major histocompatibility complex (MHC) class I antigens, to alter the state of T-cell activation, and to enhance the infectivity of viral particles. To determine which of these in vitro functions most closely correlates with the pathogenic effects of Nef in vivo, we constructed recombinant HIV-1 NL4-3 viruses carrying mutations within the nef gene that selectively impair these functions. These mutant viruses were evaluated for pathogenic potential in severe combined immunodeficiency (SCID) mice implanted with human fetal thymus and liver (SCID-hu Thy/Liv mice), in which virus-mediated depletion of thymocytes is known to be Nef dependent. Disruption of the polyp...
Nef functions in BLT mice to enhance HIV-1 replication and deplete CD4+CD8+ thymocytes
Retrovirology, 2012
Background: The outcome of untreated HIV-1 infection is progression to AIDS and death in nearly all cases. Some important exceptions are the small number of patients infected with HIV-1 deleted for the accessory gene, nef. With these infections, disease progression is entirely suppressed or greatly delayed. Whether Nef is critical for high levels of replication or is directly cytotoxic remains controversial. The major problem in determining the role of Nef in HIV/AIDS has been the lack of tractable in vivo models where Nef's complex pathogenic phenotype can be recapitulated.
International Journal of Drug Development and Research, 2016
Background: Humans infected with HIV-1 containing nef gene deletions show very slow or non-progression to AIDS. Therefore, a nef-deleted HIV-1 may be useful in generating a pathogenically-attenuated candidate therapeutic HIV-1 vaccine. We have created a mutant of HIV-1eli lacking a functional nef gene. In this study we have characterized the pathogenic phenotype of this mutant in an animal model of HIV-1 disease. Methods and findings: We determined the contribution of the nef gene to replication and infectivity in cell culture and to pathogenesis in humanized BLT mice after infection with HIV-1eli, a CXCR4-tropic subtype D virus. We constructed a nef-null virus to create HIV-1eliΔnef. Human peripheral blood mononuclear cell cultures from 13 different donors were infected and viral growth was monitored for 14 days. HIV-1eli produced higher p24 levels compared to HIV-1eliΔnef, indicating lower viral replication. HIV-1eli and HIV-1eliΔnef were then used to infect humanized BLT mice. Vi...
HIV-1 Nef impairs multiple T-cell functions in antigen-specific immune response in mice
International Immunology, 2011
The viral protein Nef is a key element for the progression of HIV disease. Previous in vitro studies suggested that Nef expression in T-cell lines enhanced TCR signaling pathways upon stimulation with TCR cross-linking, leading to the proposal that Nef lowers the threshold of T-cell activation, thus increasing susceptibility to viral replication in immune response. Likewise, the in vivo effects of Nef transgenic mouse models supported T-cell hyperresponse by Nef. However, the interpretation is complicated by Nef expression early in the development of T cells in these animal models. Here, we analyzed the consequence of Nef expression in ovalbumin-specific/CD4 1 peripheral T cells by using a novel mouse model and demonstrate that Nef inhibits antigen-specific T-cell proliferation and multiple functions required for immune response in vivo, which includes T-cell helper activity for the primary and memory B-cell response. However, Nef does not completely abrogate T-cell activity, as defined by low levels of cytokine production, which may afford the virus a replicative advantage. These results support a model, in which Nef expression does not cause T-cell hyperresponse in immune reaction, but instead reduces the T-cell activity, that may contribute to a low level of virus spread without viral cytopathic effects.
HIV: A new role for Nef in the spread of HIV
Current Biology, 1999
The HIV Nef protein downregulates the cell-surface expression of the HIV receptor glycoprotein CD4, but the significance of this event has remained obscure. Recent data suggest that Nef reduces cell-surface CD4 to promote the efficient spread of the virus.
Effects of the exogenous Nef protein on HIV-1 target cells
Cell Biochemistry and Function, 1999
Nef is a multifunctional gene of HIV which can increase virus replication either directly or by modulating the target cell's metabolism. Nevertheless the role of the exogenous Nef protein is not yet well understood. To investigate it, we studied the eects of the recombinant Nef protein on the expression of some antigens of lymphoid T-cells permissive to HIV-1 replication, and on their proliferation and on apoptosis induction. For this purpose, we utilised MT-4 and H9 T-cell lines. We evaluated FN ( ®bronectin), CD4 and CD71 expression in uninfected and acutely or chronically infected cells, both untreated and treated with Nef. Our studies showed a signi®cant up-regulation of FN especially in uninfected cells, with a dose of 2 . 5 mg ml À1 ; in contrast, a signi®cant down-modulation of CD4 and CD71 both in uninfected and in acutely or chronically infected cells, was detected. The proliferation of H9 uninfected cells was signi®cantly reduced 24 h after treatment with Nef protein in a dose-dependent manner (ranging from 0 . 02 to 2 . 5 mg ml À1 ); likewise a signi®cant inhibition of proliferation of acutely and chronically infected cells was evident with 2 . 5 mg ml À1 . Moreover, we demonstrated a dose-dependent activity of Nef on inducing apoptosis in H9 uninfected cells and no eects of this protein on modulation of INF a and g production in peripheral blood mononucleated cells of health donors. Nef appeared to be able to increase the eect of apoptotic stimuli. In conclusion, our data suggest that in our experimental system, the exogenous Nef protein can inhibit cellular synthesis facilitating the metabolic pathway involved in virus replication. In addition it modulates the susceptibility to the HIV-1 infection and ®nally, that apoptosis induction or enhancement can facilitate the release of neoformed virions.