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

Abstract

Chronic immune activation is thought to play a major role in human immunodeficiency virus (HIV) pathogenesis, but the relative contributions of multiple factors to immune activation are not known. One proposed mechanism to protect against immune activation is the ability of Nef proteins from some HIV and simian immunodeficiency virus strains to downregulate the T-cell receptor (TCR)-CD3 complex of the infected cell, thereby reducing the potential for deleterious activation. HIV type 1 (HIV-1) Nef has lost this property. In contrast to HIV-1, HIV-2 infection is characterized by a marked disparity in the disease course, with most individuals maintaining a normal life span. In this study, we examined the relationship between the ability of HIV-2 Nef proteins to downregulate the TCR and immune activation, comparing progressors and nonprogressors. Representative Nef variants were isolated from 28 HIV-2-infected individuals. We assessed their abilities to downregulate the TCR from the surfaces of CD4 T cells. In the same individuals, the activation of peripheral lymphocytes was evaluated by measurement of the expression levels of HLA-DR and CD38. We observed a striking correlation of the TCR downregulation efficiency of HIV-2 Nef variants with immune activation in individuals with a low viral load. This strongly suggests that Nef expression can influence the activation state of the immune systems of infected individuals. However, the efficiency of TCR downregulation by Nef was not reduced in progressing individuals, showing that TCR downregulation does not protect against progression in HIV-2 infection.

Efficient Nef-Mediated Downmodulation of TCR-CD3 and CD28 Is Associated with High CD4 + T Cell Counts in Viremic HIV-2 Infection

“…Viremic HIV-2-infected individuals were defined as having a plasma viral load of Ͼ500 copies per ml, and nonviremic subjects were defined as having viral loads of Ͻ500 copies per ml. The cloning and partial functional characterization of patient-representative HIV-2 nef alleles from the Guinea Bissau cohort have been described elsewhere (13). All HIV-2-infected individuals examined were seronegative for HIV-1.…”

“…Jurkat cells stably transfected with an NF-AT-dependent reporter gene vector (19) were transduced with HIV-1 Nef/eGFP constructs expressing various nef alleles or were left uninfected and subsequently treated with PHA (1 g/ml; Murex). Luciferase activity was measured and n-fold induction determined by calculating the ratio between measured relative light units of treated samples and untreated samples as described previously (13,44).…”

“…Some virological and immunological characteristics of these HIV-2-infected individuals have been described previously (4,5,13,58,60) and are summarized in Table S1 in the supplemental material. As shown in Fig.…”

“…A previous study failed to detect a protective effect of Nefmediated TCR-CD3 downmodulation against disease progression in HIV-2-infected individuals (13). However, many HIV-2 nef alleles were derived from nonprogressors with undetectable viral loads.…”

“…Thus, Nef may prevent a loss of CD4 ϩ T cells in natural SIVsmm infection by suppressing their activation-induced cell death. On the other hand, CD3 downmodulation by Nef does not prevent the progression to AIDS in some HIV-2-infected individuals (13). Notably, the characteristics of nonprogressive SIVsmm and HIV-2 infections are different.…”