Cell-Mediated Immunity in HIV-Infected Males With Human Papillomavirus–Related Anal Dysplastic Lesions

Tincati, Camilla; Rainone, Veronica; Comi, Laura; Pandolfo, Alessandro; Barco, Ambra; Bellistrì, Giusi M.; Rovati, M; Monforte, Antonella d’Arminio; Trabattoni, Daria; Marchetti, Giulia

doi:10.1093/cid/ciw590

Cited by 3 publications

(3 citation statements)

References 9 publications

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“…The reasons for this scenario are several: Next to a higher behavioral exposure of PWH to HPV [ 12 ] and a greater prevalence of cancer co-factors (eg, smoking) [ 13 , 14 ], a central role is attributable to HIV-related mucosal and systemic immune alterations, which are both key factors in hindering HPV infection and its progression. At a local level, HIV-induced mucosal damage is coupled with a significant density reduction of immune cells—CD4+ T lymphocytes [ 15 ], especially naïve CD4+ and memory CD8+ CD45R0+ T-cell pools [ 16 ], macrophages, neutrophils, and natural killer (NK) cells—an important downrepresentation of both pro- and anti-inflammatory cytokines [ 15 ], as well as increased but dysfunctional CD8+ T infiltrates [ 16–18 ]. As CD4+ T-cell count is a marker of HIV-induced immunosuppression and viral replication, it inversely correlates with HPV infection risk (especially by HR-HPV genotypes), SIL development, and progression to cancer [ 6 ].…”

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confidence: 99%

Persistence of High Percentage of Peripheral Activated CD8+ T Cells Predict Cytologic HPV-Related Dysplasia in cART-Treated, HIV-Positive Subjects

Mondatore

Bai

Augello

et al. 2022

Open Forum Infectious Diseases

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Background People with HIV are at increased risk of HPV-disease progression, given the persistence of immune activation and residual inflammation despite effective cART. Whether a low CD4:CD8 T-cell ratio, known to mirror peripheral immune dysfunction, associates with Squamous Intraepithelial Lesions (SIL) is unknown. Methods Retrospective cohort study on cART-treated HIV-positive subjects undergoing screening for HPV-related dysplasia (anal/cervical cytology and HPV genotyping). SIL was defined as the presence of either atypical squamous cells of undetermined significance (ASCUS), Low-grade SIL or High-grade SIL. Demographic and viro-immunological parameters (T-cell count, CD4:CD8 T-cell ratio, CD8+CD38+ T-cells percentage) at the time of screening were analyzed by Chi square, Mann Whitney test and multivariate logistic regression analysis. Results 419 cART-treated subjects were included. Half of the patients had cervical/anal SIL. Individuals with SIL were more commonly males, MSM, co-infected with Treponema pallidum, treated with Integrase Inhibitors (INSTI)-based cART regimens and with a shorter time since HIV diagnosis and cART initiation than subjects with normal cytology. CD38+CD8+ T-cells percentage, but not the CD4:CD8 T-cell ratio, correlated with SIL. HPV infection, especially with multiple and high-risk genotypes, was confirmed associated with SIL. In multivariate analysis, the only factors independently associated with cervical/anal dysplasia were HPV infection and harbouring higher percentages of peripheral activated CD38+CD8+ T-cells. Conclusions HPV infection is the major driver of dysplasia in the setting of HIV infection. CD8+CD38+ T-cells also resulted an independent predictor of dysplasia in cART-treated subjects, while the CD4:CD8 T-cell ratio did not. In the setting of HIV-HPV co-infection, the CD4:CD8 T-cell ratio may not fully capture the alterations of HPV-specific immunity.

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confidence: 99%

Persistence of High Percentage of Peripheral Activated CD8+ T Cells Predict Cytologic HPV-Related Dysplasia in cART-Treated, HIV-Positive Subjects

Mondatore

Bai

Augello

et al. 2022

Open Forum Infectious Diseases

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“…In MSM with HIV, we previously explored the anal microbiome as a source of diagnostic markers and identified several candidate bacteria related to HSIL 7,8 . In women, studies that have found an association between the cervical microbiome and the progression of HPV-associated lesions support the hypothesis that proinflammatory bacterial species could sustain immune disbalance and a pro-carcinogenic milieu for HPV 9,[15][16][17] . Besides the HPV and HIV fields, cumulative evidence is helping define the mechanisms by which the microbiome affects carcinogenesis 18,19 .…”

Section: Introductionmentioning

confidence: 77%

Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer

Serrano‐Villar

Tincati

Raju

et al. 2023

Nat Med

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Anal cancer is a leading neoplasia in people with immune impairment, but the lack of an accurate screening test challenges its prevention. Bacteria living in the anal epithelium -the anal microbiome-seem to influence cancer development, and so detecting specific microbial components could help diagnose precancerous anal lesions.Here, we aimed to discover microbial biomarkers of anal precancer in high-risk populations. We discovered twelve proteins, previously reported to be associated with cancer progression, that are more abundant in anal bacteria from subjects with precancerous lesions. Because these proteins contribute to succinyl-CoA and cobalamin production, we measured their intracellular bacterial concentrations. We found that cobalamin and succinyl-CoA were dramatically increased in the anal microbiome of patients with anal precancer and exhibited excellent diagnostic power. Furthermore, the metabolites were clearly superior to anal cytology when we compared their ability to differentiate persons with or without anal precancer.Therefore, we discovered two powerful biomarkers of anal precancer that could improve anal cancer prevention.

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Section: Introductionmentioning

confidence: 77%

Microbiome-Derived Cobalamin and Succinyl-CoA are Powerful Biomarkers for Improved Screening of Anal Cancer

Serrano‐Villar

Sáenz

Tincati

et al. 2022

Preprint

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Background. People with HIV (PWH) exhibit a markedly increased risk of anal cancer, especially men who have sex with men (MSM), with specific microbiota signatures possibly contributing to greater human papillomavirus (HPV) oncogenic potential. Low specificity of the current screening strategy for detecting high-grade squamous intraepithelial lesions (HSIL) hinders anal cancer prevention. We investigated microbiome derivatives associated with HSIL in anal cytology samples. Methods. We recruited a discovery and a validation cohort at four clinical sites in Spain and Italy. Study participants were mostly MSM undergoing HSIL screening with high-resolution anoscopy and anal biopsies to confirm HSIL. We extracted the bacterial DNA, proteins, and metabolites from anal cytology samples, and we performed 16SrRNA gene sequencing, mass spectrometry, and targeted metabolite quantification. Results. We included 213 participants, 167 in the discovery cohort (70 with confirmed HSIL) and 46 in the validation cohort (25 with confirmed HSIL). While we did not find clear microbiome composition signatures associated with HSIL, the microbiome associated with HSIL overexpressed proteins involved in the production of succinyl-CoA and cobalamin, with levels consistently increased in subjects with HSIL in the discovery and validation cohorts. Combined measurement of succinyl-CoA and cobalamin overperformed anal cytology, improving sensitivity from 91.2% to 96.6%, specificity from 34.1% to 81.8%, positive predictive value from 48.1% to 77.8%, and negative predictive value from 85.3% to 97.3%. While anal cytology correctly classified only 59.9% of individuals, combined measurement of both metabolites improved the classification to 87.7%. This test overcame internal (adjusted AUC 0.877) and external validation. From 98 false-positive cytologic results, succinyl-CoA and cobalamin level measurement reclassified 49 (50%) to true negatives. Finally, we demonstrate greater in vitro production of succinyl-CoA and cobalamin in bacteria associated with HSIL or cancer vs. those presumably protective. Conclusions. Cobalamin and succinyl-CoA are overexpressed in the anal microbiome of patients with HSIL and show excellent diagnostic capacity. Their measurement overperforms anal cytology to screen for patients with HSIL. Hence, we discovered two powerful biomarkers for which detection methods can readily be established, that could improve the current strategy of anal cancer screening.

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Cell-Mediated Immunity in HIV-Infected Males With Human Papillomavirus–Related Anal Dysplastic Lesions

Cited by 3 publications

References 9 publications

Persistence of High Percentage of Peripheral Activated CD8+ T Cells Predict Cytologic HPV-Related Dysplasia in cART-Treated, HIV-Positive Subjects

Persistence of High Percentage of Peripheral Activated CD8+ T Cells Predict Cytologic HPV-Related Dysplasia in cART-Treated, HIV-Positive Subjects

Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer

Microbiome-Derived Cobalamin and Succinyl-CoA are Powerful Biomarkers for Improved Screening of Anal Cancer

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