Depletion and activation of mucosal CD4 T cells in HIV infected women with HPV-associated lesions of the cervix uteri

Abstract

Background The burden of HPV-associated premalignant and malignant cervical lesions remains high in HIV+ women even under ART treatment. In order to identify possible underlying pathophysiologic mechanisms, we studied activation and HIV co-receptor expression in cervical T-cell populations in relation to HIV, HPV and cervical lesion status. Methods Cervical cytobrush (n = 468: 253 HIV- and 215 HIV+; 71% on ART) and blood (in a subset of 39 women) was collected from women in Mbeya, Tanzania. Clinical data on HIV and HPV infection, as well as ART status was collected. T cell populations were characterized using multiparametric flow cytometry-based on their expression of markers for cellular activation (HLA-DR), and memory (CD45RO), as well as HIV co-receptors (CCR5, α 4 β 7 ). Results Cervical and blood T cells differed significantly, with higher frequencies of T cells expressing CD45RO, as well as the HIV co-receptors CCR5 and α 4 β 7 in the cervical mucosa. The skewed CD4/CD8 T cell ratio in blood of HIV+ women was mirrored in the cervical mucosa and HPV co-infection was linked to lower levels of mucosal CD4 T cells in HIV+ women (%median: 22 vs 32; p = 0.04). In addition, HIV and HPV infection, and especially HPV-associated cervical lesions were linked to significantly higher frequencies of HLA-DR+ CD4 and CD8 T cells (p-values < 0.05). Interestingly, HPV infection did not significantly alter frequencies of CCR5+ or α 4 β 7 + CD4 T cells. Conclusion The increased proportion of activated cervical T cells associated with HPV and HIV infection, as well as HPV-associated lesions, together with the HIV-induced depletion of cervical CD4 T cells, may increase the risk for HPV infection, associated premalignant lesions and cancer in HIV+ women. Further, high levels of activated CD4 T cells associated with HPV and HPV-associated lesions could contribute to a higher susceptibility to HIV in HPV infected women.

Long-term follow-up on HIV infected and non-infected women with cervical cancer from Tanzania: staging, access to cancer-directed therapies and associated survival in a real-life remote setting

“…Infection with high risk HPV subtypes is the main factor for CC oncogenicity and HIV induced immunosuppression is associated with greater HPV infection rates and persisting HPV infection leading to cancer, thus leading to early onset of cancer [ 3 , 6 , 9 ]. In line with this we recently described in HIV-infected women within our 2H cohort an increased proportion of activated cervical T cells on the mucosal level, that together with an HIV-induced depletion of cervical CD4 T cells, may increase the risk for HPV infection, associated premalignant lesions and cancer in HIV + women [ 30 ]. CC screening guidelines by the WHO and Tanzanian National Guidelines therefore recommend screening services in HIV infected women and girls, who have initiated sexual activity regardless of age, when visiting the clinic for ART every six months [ 16 , 18 ].…”

Depletion of Human Papilloma Virus E6- and E7-Oncoprotein-Specific T-Cell Responses in Women Living With HIV

“…Furthermore, we report that women living with HIV and with high-grade intraepithelial cervical lesions or cancer (HSIL/SCC) had significantly lower systemic HR HPV oncoprotein T-cell reactivity compared to those without cervical lesions. Cervical lesions (especially cancer) are associated with T-cell exhaustion, T-cell activation and inflammation (51)(52)(53). Capacity for HPV-specific IFN-g production by T cells may therefore continuously be reduced as cervical lesion progress (and more oncoproteins are being expressed).…”

HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment

“…As the study was controlled for menstrual cycle stage, our study groups had comparable progesterone levels. Limitations of the study included not controlling for HSV-2 serostatus and other sociodemographic factors that may have impacted the results [ 58 , 59 , 60 , 61 ]. Due to the low numbers of cells available in CMC samples, the study was not able to assess Treg levels in mucosal samples.…”