HLA-C and HIV-1: friends or foes?

The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins

Positioning of APOBEC3G/F Mutational Hotspots in the Human Immunodeficiency Virus Genome Favors Reduced Recognition by CD8+ T Cells

Due to constitutive expression in cells targeted by human immunodeficiency virus (HIV), and immediate mode of viral restriction upon HIV entry into the host cell, APOBEC3G (A3G) and APOBEC3F (A3F) have been considered primarily as agents of innate immunity. Recent bioinformatic and mouse model studies hint at the possibility that mutation of the HIV genome by these enzymes may also affect adaptive immunity but whether this occurs in HIV-infected individuals has not been examined. We evaluated whether APOBEC-mediated mutations within common HIV CD8+ T cell epitopes can potentially enhance or diminish activation of HIV-specific CD8+ T cells from infected individuals. We compared ex vivo activation of CD8+ T lymphocytes from HIV-infected individuals by wild type HIV peptide epitopes and synthetic variants bearing simulated A3G/F-induced mutations by measuring interferon-c (IFN-c) production. We found that A3G/F-induced mutations consistently diminished HIV-specific CD8+ T cell responses against the common epitopes we tested. If this reflects a significant trend in vivo, then adaptation by HIV to enrich sequences that are favored for mutation by A3G/F (A3G/F hotspots) in portions of its genome that encode immunogenic CD8+ T cell epitopes would favor CTL escape. Indeed, we found the most frequently mutated A3G motif (CCC) is enriched up to 6-fold within viral genomic sequences encoding immunodominant CD8+ T cell epitopes in Gag, Pol and Nef. Within each gene, A3G/F hotspots are more abundant in sequences encoding epitopes that are commonly recognized due to their HLA restriction. Thus, in our system, mutations of the HIV genome, mimicking A3G/F activity, appeared to abrogate or severely reduce CTL recognition. We suggest that the physiological significance of this potential effect in facilitating CTL escape is echoed in the adaptation of the HIV genome to enrich A3G/F hotspots in sequences encoding CTL epitopes that are more immunogenic at the population level

Determination of soluble ICAM-1 and TNFalphaR in the cerebrospinal fluid and serum levels in a population of Brazilian patients with relapsing-remitting multiple sclerosis Determinação dos níveis de ICAM-1 e TNFalfaR solúvel no líquido cefalorraqueano e soro numa população de pacientes brasileiros com esclerose múltipla forma surto-remissão

Cytokines and adhesion molecules have been implicated in the pathogenesis of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. In this study we analyzed intrathecal (CSF) and serum levels of soluble intercellular adhesion molecule (ICAM-1) and TNFalphaR (60kD) from 20 patients with clinically definite MS during acute relapse or stable disease. Comparing to control groups of healthy individuals and patients with intervertebral herniated disc, MS patients showed increased levels (p< 0.001) of sICAM-1 and TNFalphaR in both serum and CSF samples. Regardless stage of disease there was no significant difference in the levels of sICAM-1 during acute relapse (657±124.9 ng/ml) or remission (627±36.2 ng/ml). A steady increase of TNFalphaR (60kD) in both serum and CSF, indicate the existence of a continuous inflammatory process within the brain tissue of MS patients despite absence of clinical signs of disease activity.<br>Citocinas e moléculas de adesão estão implicadas na patogênese da esclerose múltipla (EM), uma doença inflamatória crônica do sistema nervoso central. Neste estudo, nós determinamos os níveis solúveis da molécula de adesão intercelular (sICAM-1) e TNFalfaR (60kD) no soro e líquido cefalorraqueano (LCR) de 20 pacientes com EM clinicamente definida durante surto ou remissão. Os pacientes com EM apresentaram, em comparação com os grupos controle formados por indivíduos sadios e com hérnia de disco intervertebral submetidos a mielografia, níveis significativamente (p< 0.001) elevados de sICAM-1 e TNFalfaR tanto no soro como no LCR. Independente do estágio da doença, nenhuma diferença significativa foi encontrada entre os pacientes durante o surto (657±124.9 ng/ml) ou na remissão (627±36.2 ng/ml). Um aumento consistente dos níveis de TNFalfaR no soro e LCR, apontam para a existência de processo inflamatório continuado no tecido cerebral dos pacientes com EM, a despeito da ausência de sinais clínicos de doença em atividade