A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells

Abstract

Herpes simplex virus type 2 (HSV-2) is highly prevalent in the human population producing significant morbidity, mainly because of the generation of genital ulcers and neonatal encephalitis. Additionally, HSV-2 infection significantly increases the susceptibility of the host to acquire HIV and promotes the shedding of the latter in the coinfected. Despite numerous efforts to create a vaccine against HSV-2, no licensed vaccines are currently available. A long-standing strategy, based on few viral glycoproteins combined with adjuvants, recently displayed poor results in a Phase III clinical study fueling exploration on the development of mutant HSV viruses that are attenuated in vivo and elicit protective adaptive immune components, such as antiviral antibodies and T cells. Importantly, such specialized antiviral immune components are likely induced and modulated by dendritic cells, professional antigen presenting cells that process viral antigens and present them to T cells. However, HSV interferes with several functions of DCs and ultimately induces their death. Here, we propose that for an attenuated mutant virus to confer protective immunity against HSV in vivo based on adaptive immune components, such virus should also be attenuated in dendritic cells to promote a robust and effective antiviral response. We provide a background framework for this idea, considerations, as well as the means to assess this hypothesis. Addressing this hypothesis may provide valuable insights for the development of novel, safe, and effective vaccines against herpes simplex viruses.

The Role of Dendritic Cells During Infections Caused by Highly Prevalent Viruses

“…Once matured, DCs will be able to internalize the virus, either as a free particle or by phagocyting other infected cells -even infected DCs-, degrade it, and eventually cross-present it to the adaptive immune system, which will initiate a new response (321,324). Furthermore, depletion of the IgD glycoprotein in HVS-2 has been found to promote efficient activation of DCs and effective activation of CD4 + and CD8 + T cells (325).…”

Intramuscular vaccination of mice with the human herpes simplex virus type-1(HSV-1) VC2 vaccine, but not its parental strain HSV-1(F) confers full protection against lethal ocular HSV-1 (McKrae) pathogenesis

“…Although a number of vaccine approaches are being currently investigated, currently there is no HSV vaccine that has been approved by FDA for human use. Current approaches include subunit, multivalent and live vaccine with partial or complete deletion of HSV proteins [15][16][17][18][19]. Because there is a significant homology between HSV-1 and HSV-2 [20], a vaccine that generates cross reactive immunity may have significant benefit over a type-specific vaccine.…”

HIV-Related Immune Activation and Inflammation: Current Understanding and Strategies

“…Active HSV infection, regardless of symptoms, involves the recruitment of activated CD4 + T cells to the genital area and can lead to breaks in the mucosal layer through which HIV can enter [ 45 , 46 ]. HIV-1 infection also impairs HSV-specific CD4 + and CD8 + T cell response by reducing Th1 cytokines and CCR5 ligand secretion [ 47 ], while HSV-2 infection significantly increases the susceptibility of the host to acquire HIV and promotes the shedding of the latter during the coinfection [ 48 ]. In addition, in patients coinfected with HIV and HCV, the inflammatory response, platelet activation, and oxidative stress are more intense, indicating its enhanced immune activation [ 49 , 50 ].…”