No abstract

Naturally SIV-infected sooty mangabeys (SMs) remain asymptomatic despite high virus replication. Elucidating the mechanisms underlying AIDS resistance of SIV-infected SMs may provide crucial information to better understand AIDS pathogenesis. In this study, we assessed the determinants of set-point viremia in naturally SIV-infected SMs, i.e., immune control of SIV replication versus target cell limitation. We depleted CD4 + T cells in 6 naturally SIV-infected SMs by treating with humanized anti-CD4 mAb (Cdr-OKT4A-huIgG1). CD4 + T cells were depleted almost completely in blood and BM and at variable levels in mucosal tissues and LNs. No marked depletion of CD14 + monocytes was observed. Importantly, CD4 + T cell depletion was associated with a rapid, significant decline in viral load, which returned to baseline level at day 30-45, coincident with an increased fraction of proliferating and activated CD4 + T cells. Throughout the study, virus replication correlated with the level of proliferating CD4 + T cells. CD4 + T cell depletion did not induce any changes in the fraction of Tregs or the level of SIV-specific CD8 + T cells. Our results suggest that the availability of activated CD4 + T cells, rather than immune control of SIV replication, is the main determinant of set-point viral load during natural SIV infection of SMs.

NK cells have been established as an important effector of innate immunity in a variety of viral infections. In HIV-1 infection in humans, alterations of NK cell function, frequency, and expression of various NK receptors have been reported to be associated with differential dynamics of disease progression. Expression of certain alleles of KIR3DL and KIR3DS receptors on NK cells was shown to correlate with levels of virus replication. In the SIV-infected rhesus macaque (RM) model of AIDS, several families of killer inhibitory Ig-related receptors (KIR receptors) corresponding to their human counterparts have been characterized, but only at the level of individual sequence variants. Here we define 14 different alleles of KIR3DL expressed among 38 SIV-infected RM, characterized by either high or low levels of SIV replication, by analyzing multiple sequences from individual animals and show an unequal distribution of certain alleles in these cohorts. High levels of SIV replication were associated with significant increases in KIR3DL mRNA levels in addition to decreases in both the frequency and function of NK cells in these animals. The higher frequency of inheritance of two KIR3DL alleles characterized by a single nucleotide polymorphism 159 H/Q was associated with RM that exhibited high plasma viral load. This data for the first time defines multiple alleles of KIR3DL in RM and shows an association between virus control, NK cell function and genetic polymorphisms of KIR receptors.

Strong antimicrobial activity of xanthohumol and other derivatives from hops (Humulus lupulus L.) on gut anaerobic bacteria. APMIS 2017; 125: 1033-1038.Anaerobic bacteria, such as Bacteroides fragilis or Clostridium perfringens, are part of indigenous human flora. However, Clostridium difficile represents also an important causative agent of nosocomial infectious antibiotic-associated diarrhoea. Treatment of C. difficile infection is problematic, making it imperative to search for new compounds with antimicrobial properties. Hops (Humulus lupulus L.) contain substances with antibacterial properties. We tested antimicrobial activity of purified hop constituents humulone, lupulone and xanthohumol against anaerobic bacteria. The antimicrobial activity was established against B. fragilis, C. perfringens and C. difficile strains according to standard testing protocols (CLSI, EUCAST), and the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBC) were calculated. All C. difficile strains were toxigenic and clinically relevant, as they were isolated from patients with diarrhoea. Strongest antimicrobial effects were observed with xanthohumol showing MIC and MBC values of 15-107 lg/mL, which are close to those of conventional antibiotics in the strains of bacteria with increased resistance. Slightly higher MIC and MBC values were obtained with lupulone followed by higher values of humulone.Our study, thus, shows a potential of purified hop compounds, especially xanthohumol, as alternatives for treatment of infections caused by select anaerobic bacteria, namely nosocomial diarrhoea caused by resistant strains.

IntroductionAlthough highly active antiretroviral therapy (HAART) has a major beneficial effect on HIV-1-infected individuals, 1,2 it is clear that the next major therapeutic breakthrough requires a better definition of strategies for full immune reconstitution. 3 One of the challenges in achieving this goal is our lack of understanding of the precise spectrum or kinetics of the development of immune dysfunction in individual HIV-infected patients and strategies best suited to reconstitute such immune defects. Although virus-specific cytotoxic T lymphocytes (CTLs) clearly play a major role in eliminating virus-infected cells, 4-6 development and maintenance of such CTL pools require CD4 ϩ T helper cell function and an appropriate balance of cytokines. 3,7,8 It is also clear that innate immune mechanisms play a major role particularly during the initial stages of infection, 9,10 influencing the viral load set point, and that virus-neutralizing antibodies contribute to the containment of cell-free virus infection of naive cells. 11,12 Thus, a variety of immune reconstitution strategies need to be explored, some of which may be of benefit to those patients who were initiated on HAART during acute infection, whereas others may be more appropriate to patients with chronic infection. Since the primary target of HIV-1 infection is the CD4 ϩ T cells and the depletion of those cells is one of the major consequences of infection, our laboratory has initially focused on seeking methodologies for the replenishment of this cell lineage.Several studies aimed at immune reconstitution have previously been performed utilizing autologous unfractionated and in vitro expanded CD8 ϩ T cells from HIV-1-infected patients. [13][14][15] Transient decreases in viral load and increases in CD4 ϩ T-cell counts have been achieved utilizing such immune reconstitution therapies. However, these studies used autologous cells collected after HIV infection. Thus, lack of a more profound effect could be due to either an abnormal microenvironment for the adoptively transferred cells to home, survive, and/or execute immune function, or an intrinsic defect in the transferred T cells, as a direct and/or indirect effect of the virus infection. Clearly, a number of defects ranging from loss of lymphocyte specificities and subsets to signaling defects of CD4 ϩ T cells from HIV-1-infected patients have been documented. [16][17][18][19][20] Yet definitive proof for such defects cannot be obtained from the study of humans infected with HIV-1, since it would involve the use of autologous cells obtained prior For personal use only. on May 10, 2018. by guest www.bloodjournal.org From to infection. Hence, such mechanistic questions require the use of an animal model, which provides infection-induced immune dysfunction within an immune system comparable to humans. Simian immunodeficiency virus (SIV)-infected nonhuman primates provide such a model, in which we may attempt to distinguish among the above-mentioned 2 possibilities since the CD4 ϩ T cells can be colle...