Modulation of HIV pathogenesis and T-cell signaling by HIV-1 Nef

Abstract

HIV-1 Nef protein is an approximately 27-kDa myristoylated protein that is a virulence factor essential for efficient viral replication and infection in CD4(+) T cells. The functions of CD4(+) T cells are directly impeded after HIV infection. HIV-1 Nef plays a crucial role in manipulating host cellular machinery and in HIV pathogenesis by reducing the ability of infected lymphocytes to form immunological synapses by promoting virological synapses with APCs, and by affecting T-cell stimulation. This article reviews the current status of the efficient Nef-mediated spread of virus in the unreceptive environment of the immune system by altering CD4(+) T-lymphocyte signaling, intracellular trafficking, cell migration and apoptotic pathways.

Figure 1. Modulation of host cell signaling by HIV-1 Nef

HIV-1 Nef promotes viral replication and viral survival by hijacking host cell machinery to achieve immune evasion and anti-apoptosis. (A) HIV infection activates the two main pathways of cell death in lymphocytes: activation-induced cell death through the TNF family of death receptors; and activated T-cell autonomous death through Bcl-2-related proteins and mitochondria. Host apoptosis signals – ‘inside in’ (HIV replication initiating viral particle attack) and ‘outside in’ (FasL–Fas and membrane-bound TNF-α–TNFR2 ligations) – cause cell death before the viral lifecycle is completed. Both forms of apoptosis signaling are blocked by Nef, and in addition, Nef controls cell death in the host by phosphorylation of p53 and by promoting the upregulation of FasL and the downregulation of MHC class I (not shown) that forces the cytotoxic T lymphocyte into an apoptotic pathway and prevents the recognition of Nef-infected cells. (B) Activation of the TCR cascade by Nef requires a costimulus activation signal (through dendritic cells) to initiate a signal strong enough to stimulate viral replication. P: Phosphate; TCR: T-cell receptor.

Figure 2. HIV-1 Nef-mediated modulation of Lck and the T-cell receptor pathway

(A) TCRs and Lck molecules in resting T cells constantly traffic through early endosomes during normal physiological conditions. At the time of activation of T cells by antigen, TCR and Lck molecules are trafficked to the immunological synapse through polarized reprocessing. (B) When the cells are infected with HIV-1, Nef mediates alteration of intracellular trafficking of Lck and TCR–CD3. TCRs accumulate in recycling endosomes and their expression is slightly increased at the cell surface due to the slowing down of trafficking at both the recycling and endocytic steps. Nef stimulates the intracellular accumulation of Lck, inhibiting the process of Lck translocation from recycling endosomes to the immunological synapse to prolong signal transduction. HIV-1 particles represent all stages of the viral replicative cycle. TCR: T-cell receptor.