Background: Herpes simplex virus type 2 (HSV-2), the mostfrequent cause of genital ulcer disease (GUD), has been shown to play a moreimportant role than any other sexually transmitted infections (STIs) in drivingHIV prevalence in Africa. In turn, HIV-1 infection leads to more frequent HSV-2reactivations and shedding. The exact immune mechanisms involved in thisvirological negative immuno-synergy are unknown. In the present study we soughtto assess whether HIV co-infection would affects HSV-specific T cell immunity.Methods: Nineteen HSV peptides, derived from HSV-2glycoproteins gB and gD, were used to analyze the frequency and the magnitudeof HSV-2-specific IFN-γ-producing CD4⁺ and CD8⁺ T cellresponses in 30 HSV-2 seropositive patients and 17 HSV-2 seronegativeindividuals in a cohort of heterosexual Senegalese HIV-discordant couples,using ELISpot assay. HIV RNA viral load has been run for HIV infected subjects and CD4 count ran for all subjects using a flow cytometry method..Results: The magnitude and frequency HSV-2-specific Tcell responses was compared between 21 HSV-2 co-infected with HIV-1 and 9 HSV-2mono-infected individuals. A significantly higher magnitude of IFN-γ-producingT cell responses were observed in HSV-2 infected patients compared toseronegative individuals (median, 61 vs. 0 spots/10⁶ PBMC, P= 0.001). Moreover, twenty-four (80%) out of 30 HSV-2 seropositive patientsshowed significant HSV-2-specific IFN-γ-producing T cell responses comparedwith only 6 (35%) out of 17 HSV-2 negative subjects (P < 0.001). TheHSV-2 mono-infected patients showed significantly higher magnitude ofHSV-2-specific T cell responses compared to HSV/HIV co-infected patients(median, 140 vs. 42 spots/10⁶ PBMC, P = 0.024).Conclusions: Our finding suggest that co-infection with HIV-1 inHSV-2-infected patients might be associated with reduced HSV-2 cellular immuneresponses. However, the interaction between HIV and HSV-2 appears complex, andprecise longitudinal studies will be required to dissect their exact temporalrelationship.

Advanced basal cell carcinomas (BCCs) are driven by the Hedgehog (HH) pathway and often possess inherent resistance to SMO inhibitors. Identifying and targeting pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify an MTOR expression signature in BCC. Pharmacological inhibition of MTOR activity in BCC cells significantly reduces cell proliferation without affecting HH signalling. Similarly, treatment of the Ptch1 ^fl/fl ; Gli1-Cre^ERT2 mouse BCC tumor model with everolimus reduces tumor growth. aPKC, a downstream target of MTOR, shows reduced activity, suggesting that MTOR promotes tumor growth by activating aPKC and demonstrating that suppressing MTOR could be a promising target for BCC patients.

Basal cell carcinoma (BCC) is a locally invasive epithelial cancer that is primarily driven by the Hedgehog (HH) pathway. Advanced BCCs are a critical subset of BCCs that frequently acquire resistance to Smoothened (SMO) inhibitors and identifying pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify a PI3K pathway expression signature in BCC. Pharmacological inhibition of PI3K activity in BCC cells significantly reduces cell proliferation and HH signaling. However, treatment of Ptch1^fl/fl ; Gli1-Cre^ERT2 mouse BCCs with the PI3K inhibitor BKM120 results in a reduction of tumor cell growth with no significant effect on HH signaling. Downstream PI3K components aPKC and Akt1 showed a reduction in active protein, whereas their substrate, cyclin-dependent kinase inhibitor p21, showed a concomitant increase in protein stability. Our results suggest that PI3K promotes BCC tumor growth by kinase-induced p21 degradation without altering HH signaling.

Tumour cells adapt to nutrient deprivation in vivo, yet strategies targeting the nutrient poor microenvironment remain unexplored. In melanoma, tumour cells often experience low glutamine levels, which promote cell dedifferentiation. Here, we show that dietary glutamine supplementation significantly inhibits melanoma tumour growth, prolongs survival in a transgenic melanoma mouse model, and increases sensitivity to a BRAF inhibitor. Metabolomic analysis reveals that dietary uptake of glutamine effectively increases the concentration of glutamine in tumours and its downstream metabolite, αKG, without increasing biosynthetic intermediates necessary for cell proliferation. Mechanistically, we find that glutamine supplementation uniformly alters the transcriptome in tumours. Our data further demonstrate that increase in intra-tumoural αKG concentration drives hypomethylation of H3K4me3, thereby suppressing epigenetically-activated oncogenic pathways in melanoma. Therefore, our findings provide evidence that glutamine supplementation can serve as a potential dietary intervention to block melanoma tumour growth and sensitize tumours to targeted therapy via epigenetic reprogramming.