Higher risk of cytomegalovirus reactivation in human immunodeficiency virus-1-infected patients homozygous for MICA5.1.

Infection with cytomegalovirus (CMV) induces surface expression of major histocompatibility complex (MHC)-class-I-chain-related A (MICA), a ligand for NKG2D. This leads to improved recognition and elimination of infected cells by natural killer (NK) as well as CD8+ T cells. The MICA5.1 allele codes for a truncated protein. This study was performed to test whether impaired expression of a functional MICA protein would influence the susceptibility to severe CMV reactivation in immunocompromised individuals. In this study, the frequency of MICA5.1 was assessed by polymerase chain reaction in 230 Caucasian human immunodeficiency virus (HIV)-1-infected patients and in 219 healthy controls. Patients co-infected with hepatitis C virus (HCV) and GB virus-C served as controls. MICA5.1 allele was analyzed by polymerase chain reaction. Association of MICA5.1 homozygosity and risk of CMV reactivation was calculated by Pearson chi2 test. Comparison of patients with and without a history of CMV disease manifestation revealed that homozygous MICA5.1 genotype was present in a significantly higher frequency in patients with CMV reactivation (33%) than in those without (16%; p 0.032; odds ratio 0.330). The percentage was similar in HIV-1-infected patients and healthy controls. Furthermore, there was no difference in the frequency of MICA5.1 with respect to infection with HCV and GB virus-C. Our study provides the first in vivo demonstration of an association between homozygous MICA5.1 genotype and susceptibility to CMV reactivation in immunocompromised individuals.

GBV-C coinfection is negatively correlated to Fas expression and Fas-mediated apoptosis in HIV-1 infected patients.

Persistent coinfection with the apathogenic GB virus C (GBV-C) is associated with slower disease progression of human immunodeficiency virus (HIV)-1 infection. Aim of this study was to investigate whether Fas plays a role in this beneficial effect. Fas expression and susceptibility to Fas-mediated apoptosis (FMA) was analyzed in peripheral blood mononuclear cells (PBMCs) of HIV-1 patients coinfected and non-coinfected with GBV-C. Fas expression and function was evaluated in 42 GBV-C coinfected and 101 non-coinfected HIV-1 patients. Thirteen healthy and 11 Hepatitis C virus (HCV)-monoinfected individuals were analyzed as controls. Cell surface Fas expression was determined by flow cytometric analysis. Apoptosis was evaluated by staining with Annexin V and Viaprobe followed by multiparameter flow cytometry analysis. In untreated HIV-1 patients GBV-C coinfection was associated with significantly lower percentage of Fas expressing cells as compared to GBV-C non-coinfected individuals. Expression of Fas was directly correlated with sensitivity to Fas-mediated apoptosis. Sensitivity to FMA was unchanged in GBV-C coinfected patients. PBMCs of patients receiving highly active antiretroviral therapy (HAART) did not show such a difference. Untreated HIV-1 patients with GBV-C coinfection have reduced cell surface Fas expression. Lower FMA of T-cells might contribute to prolonged survival of GBV-C coinfected HIV-1 patients.

Dichotomous effects of C-C chemokines in HIV-1 pathogenesis.

Chemokines play a critical role in shaping innate and adaptive immunity. These molecules also participate in maintaining the immune balance in the body. Apart from their regulatory role, these mediators are involved in several inflammatory and autoimmune diseases including viral infection such as HIV-1/AIDS. Chemokine co-receptor CCR5 and CXCR4 and their ligands significantly contribute to HIV-1 disease progression. C-C chemokines such CCL3, CCL4 and CCL5 have been shown to possess antiviral effects by binding to HIV-1 co-receptors. CCL2, a member of the C-C chemokine family, displays a different feature instead. It is a potential enhancer rather than inhibitor of viral replication, a property exhibited by most of the C-C chemokine members. In addition, the role of CCL2 is well established in forming a Th2 type of response by directing differentiation of Th0 cells towards Th2 type, a unique feature of HIV-1 disease. We propose a hypothesis in which the chemotactic nature of CCL2 drives recruitment of target cells to the site of infection as one of the mechanisms operating in vivo that favours viral replication and eventually a high viral load in infected individuals.