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

Abstract

Background: People with HIV are at increased risk of human papillomavirus (HPV) disease progression, given the persistence of immune activation and residual inflammation despite effective combination antiretroviral therapy (cART). Whether a low CD4:CD8 T-cell ratio, known to mirror peripheral immune dysfunction, is associated with squamous intraepithelial lesions (SILs) is unknown.

Methods: This was a 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 SILs, or high-grade SILs. Demographic and viro-immunological parameters (T-cell count, CD4:CD8 T-cell ratio, CD8+ CD38+ T-cell percentage) at the time of screening were analyzed by the chi-square test, Mann-Whitney test, and multivariate logistic regression analysis.

Results: A total of 419 cART-treated subjects were included. Half of the patients had cervical/anal SIL. Individuals with SIL were more commonly males, were men who have sex with men, were coinfected with Treponema pallidum, had been treated with integrase inhibitor (INSTI)-based cART regimens, and had a shorter time since HIV diagnosis and cART initiation than subjects with normal cytology. CD38+ CD8+ T-cell percentage, but not the CD4:CD8 T-cell ratio, correlated with SILs. HPV infection, especially with multiple and high-risk genotypes, was confirmed to be associated with SIL. In multivariate analysis, the only factors independently associated with cervical/anal dysplasia were HPV infection and harboring higher percentages of peripheral activated CD38+ CD8+ T cells.

Conclusions: HPV infection is the major driver of dysplasia in the setting of HIV infection. In this study, CD8+ CD38+ T cells were an independent predictor of dysplasia in cART-treated subjects, while CD4:CD8 T-cell ratio was not. In the setting of HIV-HPV coinfection, CD4:CD8 T-cell ratio may not fully capture the alterations of HPV-specific immunity.

Keywords: CD4:CD8 ratio; HIV infection; HPV infection; activated CD8+ CD38+ T cells; cervical–anal dysplasia.

Figure 1.

Multiple–HPV genotype infection and low/high-risk HPV genotypes according to anal/cervical dysplasia. Abbreviations: cART, combination antiretroviral therapy; HPV, human papillomavirus; HR, high-risk; LR, low-risk; SIL, squamous intraepithelial lesion.

Figure 2.

CD4+ T-cell count, CD8+ T-cell count, CD4/CD8 ratio and activated CD8+ CD38+ T-cell percentage according to anal/cervical dysplasia. CD8+ CD38+ T-cell percentage correlates with SILs. P values were calculated by Mann-Whitney test. ^∗P < .05. Abbreviation: SIL, squamous intraepithelial lesion.