Biological Determinants of Immune Reconstitution in HIV‐Infected Patients Receiving Antiretroviral Therapy: The Role of Interleukin 7 and Interleukin 7 Receptor α and Microbial Translocation

Rajasuriar, Reena; Booth, David R.; Solomon, Ajantha; Chua, Kyra; Spelman, Tim; Gouillou, Maëlenn; Schlub, Timothy E.; Davenport, Miles P.; Crowe, Suzanne; Elliott, Julian; Hoy, Jennifer; Fairley, Christopher K.; Stewart, Graeme J.; Cameron, Paul; Lewin, Sharon R.

doi:10.1086/656369

Cited by 109 publications

(126 citation statements)

References 48 publications

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“…[25][26][27][28][29][30][31] We recently demonstrated by using a multivariable model that IL-7Ra haplotype-2 was a significant predictor of more rapid CD4 T-cell recovery following suppressive cART in an Australian-based largely Caucasian HIVinfected cohort. 22 Consistent with observations in haplotype-2 carriers in HIV-uninfected cohorts, 9,11,32,33 we found that HIV-infected patients who were homozygous for haplotype-2 had significantly lower concentrations of sIL-7Ra compared with non-haplotype-2 carriers. 22 We therefore proposed that the reduced sIL-7Ra levels in haplotype-2 carriers may increase the availability of IL-7 to bind to membrane-bound IL-7Ra on T-cells, leading to faster CD4 T-cell recovery.…”

Section: Introductionsupporting

confidence: 90%

“…22 Consistent with observations in haplotype-2 carriers in HIV-uninfected cohorts, 9,11,32,33 we found that HIV-infected patients who were homozygous for haplotype-2 had significantly lower concentrations of sIL-7Ra compared with non-haplotype-2 carriers. 22 We therefore proposed that the reduced sIL-7Ra levels in haplotype-2 carriers may increase the availability of IL-7 to bind to membrane-bound IL-7Ra on T-cells, leading to faster CD4 T-cell recovery.…”

Section: Introductionsupporting

confidence: 90%

“…Given the lack of an association between IL-7Ra haplotype-2 and faster CD4 T-cell recovery in this study, which was in contrast to our prior findings in a Caucasian cohort, 22 and given that Africans are known to have shorter and more varied haplotypes, 35 we next determined whether other IL-7Ra SNPs or their haplotypes were associated with rate of recovery of CD4 T-cells in the UARTO cohort. The role of SNPs in the a-chain of the IL-7Ra in CD4 þ T-cell recovery R Rajasuriar et al…”

Section: Il-7ra Haplotypes Are Different In Africans and Caucasiansmentioning

confidence: 58%

“…This was the same analysis approach that we had previously used in our study of Caucasian patients. 22 In the UARTO cohort, the median duration of follow up was 2.3 years (inter-quartile range 1.2-2.9). At 3 years, an estimated 6.4% (95% confidence interval (CI): 5.2-7.8%) of participants had achieved two successive CD4 T-cell counts 4500 cells ml À1 .…”

Section: Resultsmentioning

confidence: 99%

“…14,15 Various clinical factors have been associated with impaired CD4 T-cell reconstitution following cART, including lower CD4 T-cell counts at initiation of cART, [16][17][18][19] being older at cART initiation 1,17,19,20 and higher levels of immune activation both before and while on cART as measured by T-cell activation markers (such as human leukocyte antigen (HLA)-DR þ CD38 þ expression). [21][22][23][24] Multiple host genetic factors have also been found to influence CD4 T-cell recovery. [25][26][27][28][29][30][31] We recently demonstrated by using a multivariable model that IL-7Ra haplotype-2 was a significant predictor of more rapid CD4 T-cell recovery following suppressive cART in an Australian-based largely Caucasian HIVinfected cohort.…”

Section: Introductionmentioning

confidence: 99%

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The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

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We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

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Section: Introductionsupporting

confidence: 90%

Section: Introductionsupporting

confidence: 90%

Section: Il-7ra Haplotypes Are Different In Africans and Caucasiansmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

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Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Yang

Zhang

et al. 2020

Journal of Leukocyte Biology

191

214

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The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

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HIV replication is associated with increased severity of liver biopsy changes in HIV‐HBV and HIV‐HCV co‐infection

Audsley

Cros

Goodman

et al. 2012

Journal of Medical Virology

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Histological parameters were assessed in liver biopsies (n = 48) performed in patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in order to evaluate factors which were associated with significant liver disease. Necroinflammation and fibrosis was scored by the Ishak classification system, and binary logistic regression analysis was used to assess HIV and antiretroviral-related determinants of necroinflammation and fibrosis. A total of 46 biopsies were included; 33 were from HIV-positive patients co-infected with HCV and 15 biopsies were from HIV-positive patients co-infected with HBV. One HIV-positive patient was co-infected with HBV and HCV. Median biopsy inflammatory grade for the cohort was 8.5 (IQR 6-10), the median fibrosis Stage 2 (IQR 1.8-4), and the median steatosis score was 1 (IQR 0-2). At the univariate level, HIV-related variables that were significantly associated with more severe biopsy changes were higher HIV RNA at the time of biopsy (associated with inflammatory Grade 10+; P = 0.018) and any exposure to didanasine (ddI) or stavudine (D4T; associated with fibrosis Stage 3+; P = 0.022). HIV RNA at the time of biopsy remained significant at the multivariate level. Patients with HIV hepatitis co-infection in this cohort had surprisingly mild changes in liver histology, and there were no statistically significant differences between biopsy results in HBV compared to HCV co-infection. The association between HIV RNA and necroinflammation supports current recommendations for earlier initiation of HAART in patients with HIV-hepatitis co-infection.

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Biological Determinants of Immune Reconstitution in HIV‐Infected Patients Receiving Antiretroviral Therapy: The Role of Interleukin 7 and Interleukin 7 Receptor α and Microbial Translocation

Abstract: Both the extent of immune depletion prior to ART and IL-7Rα haplotype 2 are important determinants of time to CD4(+) T cell recovery to counts of >500 cells/μL.

Cited by 109 publications

References 48 publications

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

HIV replication is associated with increased severity of liver biopsy changes in HIV‐HBV and HIV‐HCV co‐infection

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