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Defensin gene variation and HIV/AIDS: a comprehensive perspective needed.

ABSTRACT: Both ?- and ?-defensins have anti-human immunodeficiency virus activity. These defensins achieve human immunodeficiency virus inhibition through a variety of mechanisms, including direct binding with virions, binding to and modulation of host cell-surface receptors with disruption of intracellular signaling, and functioning as chemokines or cytokines to augment and alter adaptive immune responses. Polymorphisms in the defensin genes have been associated with susceptibility to human immunodeficiency virus infection and disease progression. However, the roles that these defensins and their genetic polymorphisms have in influencing human immunodeficiency virus/acquired immunodeficiency syndrome outcomes are not straightforward and, at times, appear contradictory. Differences in populations, study designs, and techniques for genotyping defensin gene polymorphisms may have contributed to this lack of clarity. In addition, a comprehensive approach, where both subfamilies of defensins and their all-inclusive genetic polymorphism profiles are analyzed, is lacking. Such an approach may reveal whether the human immunodeficiency virus inhibitory activities of ?- and ?-defensins are based on parallel or divergent mechanisms and may provide further insights into how the genetic predisposition for susceptibility or resistance to human immunodeficiency virus/acquired immunodeficiency syndrome is orchestrated between these molecules.

SUBMITTER: Mehlotra RK

PROVIDER: S-EPMC6608511 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Defensin gene variation and HIV/AIDS: a comprehensive perspective needed.

Mehlotra Rajeev K RK Zimmerman Peter A PA Weinberg Aaron A

Journal of leukocyte biology 20160308 5

Both α- and β-defensins have anti-human immunodeficiency virus activity. These defensins achieve human immunodeficiency virus inhibition through a variety of mechanisms, including direct binding with virions, binding to and modulation of host cell-surface receptors with disruption of intracellular signaling, and functioning as chemokines or cytokines to augment and alter adaptive immune responses. Polymorphisms in the defensin genes have been associated with susceptibility to human immunodeficie ...[more]

PMID: 26957215

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Project description:CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies <0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03). Second, seven highly correlated SNPs spanning 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (P = .01-.02). These results reiterate the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.

Project description:BackgroundSince the advent of combination antiretroviral therapy, in developed countries HIV increasingly is perceived as a long-term illness. Individuals may experience health-related consequences of HIV and its associated treatments, a concept that may be termed disability. To date, a comprehensive framework for understanding the health-related consequences experienced by people living with HIV has not been developed. The purpose of this research was to develop a conceptual framework of disability from the perspective of adults living with HIV.MethodsWe conducted four focus groups and 15 face-to-face interviews with 38 adults living with HIV. We asked participants to describe their health-related challenges, their physical, social and psychological areas of life affected, and impact on their overall health. We analyzed data using grounded theory techniques. We also conducted two validity check focus groups with seven returning participants.ResultsDisability was conceptualized by participants as multi-dimensional and episodic characterized by unpredictable periods of wellness and illness. The Episodic Disability Framework consisted of three main components: a) dimensions of disability that included symptoms and impairments, difficulties carrying out day-to-day activities, challenges to social inclusion, and uncertainty that may fluctuate on a daily basis and over the course of living with HIV, b) contextual factors that included extrinsic factors (social support and stigma) and intrinsic factors (living strategies and personal attributes) that may exacerbate or alleviate disability, and c) triggers that initiate momentous or major episodes of disability such as receiving an HIV diagnosis, starting or changing medications, experiencing a serious illness, and suffering a loss of others.ConclusionThe Episodic Disability Framework considers the variable nature of disability, acknowledges uncertainty as a key component, describes contextual factors that influence experiences of disability, and considers life events that may initiate a major or momentous episode. This framework presents a new way to conceptualize disability based on the experience of living with HIV.

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Defensin gene variation and HIV/AIDS: a comprehensive perspective needed.

Publications

Defensin gene variation and HIV/AIDS: a comprehensive perspective needed.

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