Nef-Mediated Suppression of T Cell Activation Was Lost in a Lentiviral Lineage that Gave Rise to HIV-1

Abstract

High-level immune activation and T cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic SIV infections in natural primate hosts. The mechanisms causing these varying levels of immune activation are not understood. Here, we report that nef alleles from the great majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells, thereby blocking their responsiveness to activation. In contrast, nef alleles from HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death. Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system. This function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans.

Downregulation of the T-Cell Receptor by Human Immunodeficiency Virus Type 2 Nef Does Not Protect against Disease Progression

“…However, the conservation of highly efficient TCR downregulation after progression shows that, in vivo, TCR downregulation does not preclude disease progression in HIV-2 infection. This contrasts with the observation that the loss of TCR downregulation by Nef seems to be the cause of CD4 depletion in sooty mangabeys (22). CD4 depletion in HIV-2 infection is associated with increased viral replication, with immune activation, and, finally, with immunodeficiency, which is not the case in SIVsmm infection (21,26).…”

“…It was recently shown that HIV-1 and its simian ancestor, SIVcpz, have one distinctive characteristic that may contribute to pathogenesis. In contrast to the Nef proteins of other immunodeficiency viruses, HIV-1 and SIVcpz Nef proteins are unable to downregulate the T-cell receptor (TCR) from the surfaces of infected cells (1,22). Schindler and colleagues proposed that TCR downregulation protects the host from the impact of chronic immune activation (22), which is increasingly thought to play a major role in HIV-1 disease progression (7).…”

“…In contrast to the Nef proteins of other immunodeficiency viruses, HIV-1 and SIVcpz Nef proteins are unable to downregulate the T-cell receptor (TCR) from the surfaces of infected cells (1,22). Schindler and colleagues proposed that TCR downregulation protects the host from the impact of chronic immune activation (22), which is increasingly thought to play a major role in HIV-1 disease progression (7). In most cases, SIVsmm infection of sooty mangabeys leads to high viral loads without evidence of immunodeficiency or CD4 depletion, and this is associated with very low levels of immune activation (25).…”

“…Immunodeficiency associated with CD4 depletion was reported in only one case (18). Schindler et al discovered that in sooty mangabeys showing a loss of CD4 ϩ T cells, the Nef protein of the infecting SIVsmm was less efficient at TCR downregulation (22), suggesting that the CD4 depletion in sooty mangabeys is linked to the loss of this function, together with a loss of major histocompatibility complex class I downregulation (23). Following transmission to humans in West Africa, SIVsmm zoonosis gave rise to HIV-2 infection, identified in patients with AIDS in 1986 (10).…”

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

“…However, activation-induced cell death after TCR engagement runs the risk of limiting the life span of productively infected cells and thus the amount of viral progeny produced. Consequently, HIV-1 encodes gene products, such as Nef, to finetune activation states of infected T lymphocytes (15,16). Nef is a 25-to 34-kDa myristoylated accessory protein encoded by HIV-1, HIV-2, and SIV.…”