Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1alphaP), a potent human immunodeficiency virus-1 (HIV-1)-suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.

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International audienceThis document outlines a set of simplified models for dark matter and its interactions with Standard Model particles. It is intended to summarize the main characteristics that these simplified models have when applied to dark matter searches at the LHC, and to provide a number of useful expressions for reference. The list of models includes both s-channel and t-channel scenarios. For s-channel, spin-0 and spin-1 mediation is discussed, and also realizations where the Higgs particle provides a portal between the dark and visible sectors. The guiding principles underpinning the proposed simplified models are spelled out, and some suggestions for implementation are presented

Light pseudoscalars interacting pre-dominantly with Standard Model gauge bosons (so-called axion-like particles or ALPs) occur frequently in extensions of the Standard Model. In this work we review and update existing constraints on ALPs in the keV to GeV mass region from colliders, beam dump experiments and astrophysics. We furthermore provide a detailed calculation of the expected sensitivity of Belle II, which can search for visibly and invisibly decaying ALPs, as well as long-lived ALPs. The Belle II sensitivity is found to be substantially better than previously estimated, covering wide ranges of relevant parameter space. In particular, Belle II can explore an interesting class of dark matter models, in which ALPs mediate the interactions between the Standard Model and dark matter. In these models, the relic abundance can be set via resonant freeze-out, leading to a highly predictive scenario consistent with all existing constraints but testable with single-photon searches at Belle II in the near future.

Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large wellcharacterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

IntroductionThe immunologic hallmark of the acquired immunodeficiency syndrome (AIDS), resulting from infection with the human immunodeficiency virus type-1 (HIV), is the depletion of CD4 ϩ T cells. 1 However, qualitative alterations of the function of circulating T cells are observed that do not appear to be related to the decline of CD4 ϩ T-cell number. [2][3][4][5] In vitro T-cell responses are impaired in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients. Thus, proliferative responses to HIV epitopes are lost early during infection, 6-8 followed by sequential impairment of T-helper cell responses to recall antigens and mitogens. 9 This progressive loss of T-cell function during the course of HIV disease is predictive for the time of onset of AIDS and death. 10 Tryptophan (Trp) catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory mechanism that limits T-cell proliferation by depletion of the essential amino acid Trp and/or accumulation of catabolites with immune-suppressive activity (kynurenines, kyn). 11 Alterations of this mechanism have been suggested to be involved in (1) development of autoimmune conditions, such as multiple sclerosis and autoimmune diabetes 12,13 ; (2) failure of immune surveillance of tumor cells 14 ; and (3) rejection of semiallogenic fetuses. 15,16 The molecular basis for T-cell hyporesponsiveness in IDO-mediated Trp depletion has been recently clarified. The consequence of reduction in available Trp in the extracellular microenvironment is the accumulation of uncharged Trp-specific transfer RNA (free-tRNA trp ) in the cytoplasm. 17 Free-tRNA trp binds to the GCN2 kinase, a key enzyme of the cellular stress-response system. 17 Once activated by ligation to free-tRNA trp , the GCN2 kinase initiates a cascade of events leading to arrest of the cell cycle, which is, in turn, the ultimate effect of tryptophan starvation. 17 Increased IDO-mediated tryptophan catabolism during HIV infection has been reported. [18][19][20][21] IDO is induced in macrophages by HIV infection, and has been suggested to be involved in the induction of HIV encephalitis and AIDS-related dementia. 20,22,23 Inhibition of HIV-induced IDO in brain macrophages enhanced HIV-specific cytotoxic T-lymphocyte (CTL) response and elimination of infected macrophages in a murine model. 24 We recently reported that IDO mRNA expression is increased in the tonsils of HIV-infected patients in whom viral replication is not controlled by effective antiretroviral therapy (ART). 25 A similar increase of IDO was found in lymphoid tissues of macaques during acute simian immunodeficiency virus (SIV) and chronic SIV/HIV infection, and correlated with reduced immune responses. 26,27 However, the functional role of IDO in HIV-associated immunosuppression is unknown.In the present study, we tested the effect of 1-methyl-tryptophan (1-mT), a competitive inhibitor of IDO, on the stimulation of The online version of this article contains a data supplement.The publication costs of this article were ...

Durable control of human immunodeficiency virus (HIV) replication and lack of disease progression in the absence of antiretroviral therapy were studied in a military cohort of 4586 subjects. We examined groups of elite controllers (ie, subjects with plasma HIV RNA levels of <50 copies/mL; prevalence, 0.55% [95% confidence interval {CI}, 0.35%-0.80%]), viremic controllers (ie, subjects with plasma HIV RNA levels of 50-2000 copies/mL; prevalence, 3.34% [95% CI, 2.83%-3.91%]), and subjects with a lack of disease progression (ie, long-term nonprogressors [LTNPs]) through 7 years of follow-up (LTNP7s; prevalence, 3.32% [95% CI, 2.70%-4.01%]) or 10 years of follow-up (LTNP10s; prevalence, 2.04% [95% CI, 1.52%-2.68%]). For elite and viremic controllers, spontaneous virologic control was established early and was typically observed when the initial viral load measurement was obtained within 1 year of estimated seroconversion. Elite controllers had favorable time to development of AIDS (P=.048), a CD4 cell count of 350 cells/microL (P= .009), and more-stable CD4 cell trends, compared with viremic controllers. LTNPs defined by 10-year versus 7-year criteria had a longer survival time (P=.001), even after adjustment for differing periods of invulnerability (P= .042). Definitions of controllers and LTNPs describe distinct populations whose differing clinical outcomes improve with the stringency of criteria, underscoring the need for comparability between study populations.