The Interplay Between Host Genetic Variation, Viral Replication, and Microbial Translocation in Untreated HIV-Infected Individuals

Perkins, Molly R.; Bartha, István; Timmer, Jorinde; Liebner, Julia; Wollinsky, David; Günthard, Huldrych F.; Hauser, Christoph; Bernasconi, Enos; Hoffmann, Matthias; Calmy, Alexandra; Battegay, Manuel; Telenti, Amalio; Douek, Daniel C.; Fellay, Jacques

doi:10.1093/infdis/jiv089

Cited by 22 publications

(21 citation statements)

References 25 publications

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“…Our data are in contrast to a recent GWAS, which did not find any polymorphisms significantly associated with markers of immune activation and microbial translocation (sCD14 and i-FABP levels) [45]. However, only untreated HIV-infected individuals were included in the study, potentially making it more difficult to overcome additional variation due to (1) the extent of disease progression and (2) genetic and non-genetic contributors to viral load setpoint (factors that might confound the relationship between host genetics and sCD14).…”

Section: Discussioncontrasting

confidence: 99%

Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans

Lee

Mefford

Huang

et al. 2016

Aids

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Objective Plasma kynurenine/tryptophan (KT) ratio, a biomarker of indoleamine 2,3-dioxygenase-1 (IDO) activity, is a strong independent predictor of mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART) and may play a key role in HIV pathogenesis. We performed a genome-wide study to identify potential host genetic determinants of KT ratio in HIV-infected ART-suppressed Ugandans. Design/Methods We performed genome-wide and exome array genotyping and measured plasma KT ratio during the initial 6-12 months of suppressive ART in Ugandans. We evaluated >16 million SNPs in association with log10KT ratio using linear mixed models adjusted for cohort, gender, pregnancy, and ancestry. Results Among 597 Ugandans, 62% were female, median age was 35, median baseline CD4+ count was 135 cells/mm3, and median baseline HIV-1 RNA was 5.1 log10copies/mL. Several polymorphisms in candidate genes TNF, IFNGR1, and TLR4 were associated with log10KT ratio (P<5.0×10−5). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, while several others exhibited suggestive associations (P<5.0×10−7), including genes encoding protein tyrosine phosphatases (PTPRM, PTPRN2) and the vitamin D metabolism gene, CYP24A1. Several of these SNPs were associated with markers of inflammation, coagulation, and monocyte activation, but did not replicate in a small U.S. cohort (N=262; 33% African-American). Conclusions Our findings highlight a potentially important role of IFN-γ, TNF−α, and toll-like receptor signaling in determining IDO activity and subsequent mortality risk in HIV-infected ART-suppressed Ugandans. These results also identify potential novel pathways involved in IDO immunoregulation. Further studies are needed to confirm these findings in treated HIV-infected populations.

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Section: Discussioncontrasting

confidence: 99%

Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans

Lee

Mefford

Huang

et al. 2016

Aids

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“…Intestinal fatty acid binding protein (IFABP), a recently described marker of inflammation and damage to GALT [25], has been found to correlate significantly with microbial translocation and systemic immune activation during HIV-1 disease [26]. Here, we measured IFABP in plasma and pleural fluid from a subgroup (n = 12) of HIV/TB co-infected subjects with pleural disease, and compared it to plasma from a group of CD4 T cell matched healthy HIV-1 infected subjects with no evidence of TB (n = 13) (Fig 2).…”

Section: Resultsmentioning

confidence: 99%

Immune Activation at Sites of HIV/TB Co-Infection Contributes to the Pathogenesis of HIV-1 Disease

et al. 2016

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Systemic immune activation is critical to the pathogenesis of HIV-1 disease, and is accentuated in HIV/TB co-infected patients. The contribution of immune activation at sites of HIV/TB co-infection to viral activity, CD4 T cell count, and productive HIV-1 infection remain unclear. In this study, we measured markers of immune activation both in pleural fluid and plasma, and in T cells in pleural fluid mononuclear cell (PFMC) and peripheral blood mononuclear cell (PBMC) in HIV/TB co-infected subjects. The relationship between soluble and T cell activation markers with viral load in pleural fluid and blood CD4 T cell count were assessed. The T cell phenotype and activation status of HIV-1 p24 + T cells in PFMC and PBMC from HIV/TB patients were determined. We found that T cell and macrophage-specific and non-specific soluble markers of immune activation, sCD27, sCD163, IL1Ra, and sCD14, were higher in pleural fluid as compared to plasma from HIV/TB co-infected subjects, and higher as compared to pleural fluid from TB mono-infected subjects. Intestinal fatty acid-binding protein, a marker of intestinal tract damage, in plasma from HIV/TB co-infected patients was not different than that in HIV+ subjects. Expression of HLADR and CD38 double positive (HLADR/CD38) on CD4 T cells, and CD69+ on CD8 T cells correlated with pleural fluid viral load, and inversely with blood CD4 T cell count. Higher expression of HLADR/CD38 and CCR5 on CD4 T cells, and HLADR/CD38 and CD69 on CD8 T cells in PFMC were limited to effector memory populations. HIV-1 p24+ CD8 negative (includes CD4 + and double negative T cells) effector memory T cells in PFMC had higher expression of HLADR/CD38, Ki67, and CCR5 compared to HIV-1 p24- CD8 negative PFMC. Cumulatively, these data indicate that sites of HIV/TB co-infection are the source of intense immune activation.

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“…The recognition of the deleterious effects of HIV‐induced chronic immune activation on the arterial vasculature is yet another important justification for initiating cART early in the course of HIV infection (Aberg et al , ). Early treatment of HIV may also impact immune activation by minimizing microbial translocation due to gut mucosal damage (Perkins et al , ). The importance of therapeutic lifestyle choices to minimize arterial and venous thrombosis for PLWHA cannot be underestimated.…”

Section: Epidemiology Diagnosis and Treatment Of Haematological Abnomentioning

confidence: 99%

Haematological manifestations of human immune deficiency virus infection

Vishnu

Aboulafia

2015

Br J Haematol

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SummaryEarly in the human immunodeficiency virus (HIV) epidemic, infected patients presented to medical attention with striking abnormalities in each of the major blood cell lineages. The reasons for these derangements remain complex and multifactorial. HIV infects multipotent haematopoietic progenitor cells and establish latent cellular reservoirs, disturbs the bone marrow microenvironment and also causes immune dysregulation. These events lead to cytokine imbalances and disruption of other factors required for normal haematopoiesis. Activation of the reticulo-endothelial system can also result in increased blood cell destruction. The deleterious effects of medications, including first and second generation anti-retroviral agents, on haematopoiesis were well documented in the early years of HIV care; in the current era of HIV-care, the advent of newer and less toxic anti-retroviral drugs have had a more beneficial impact on haematopoiesis. Due to impaired regulation of the immune system and potential side effects of one or more anti-retroviral agents, there is also an increase in coagulation abnormalities such as thromboembolism, and less frequently, acquired disorders of coagulation including thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura and acquired inhibitors of coagulation. In this article we review the epidemiology and aetiology of select non-oncological haematological disorders commonly seen in people living with HIV-acquired immune deficiency syndrome.

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The Interplay Between Host Genetic Variation, Viral Replication, and Microbial Translocation in Untreated HIV-Infected Individuals

Cited by 22 publications

References 25 publications

Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans

Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans

Immune Activation at Sites of HIV/TB Co-Infection Contributes to the Pathogenesis of HIV-1 Disease

Haematological manifestations of human immune deficiency virus infection

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