Herpes simplex virus 2 infection: molecular association with HIV and novel microbicides to prevent disease

Abstract

Infection with herpes simplex viruses is one of the most ancient diseases described to affect humans. Infection with these viruses produces vexing effects to the host, which frequently recur. Infection with herpes simplex viruses is lifelong, and currently there is no vaccine or drug to prevent or cure infection. Prevalence of herpes simplex virus 2 (HSV-2) infection varies significantly depending on the geographical region and nears 20% worldwide. Importantly, HSV-2 is the first cause of genital ulcers in the planet. HSV-2 affects approximately 500 million people around the globe and significantly increases the likelihood of acquiring the human immunodeficiency virus (HIV), as well as its shedding. Thus, controlling HSV-2 infection and spread is of public health concern. Here, we review the diseases produced by herpes simplex viruses, the factors that modulate HSV-2 infection, the relationship between HSV-2 and HIV and novel therapeutic and prophylactic microbicides/antivirals under development to prevent infection and pathological outcomes produced by this virus. We also review mutations associated with HSV-2 resistance to common antivirals.

Fig. 1

Clinical manifestations produced by herpes simplex viruses: the sites of infection by herpes simplex viruses include brain (meningitis, encephalitis), infections in the ocular area (eyes: keratitis, retinitis and conjunctivitis; mouth: lips and gingivostomatitis; facial nerves: facial paralysis), torso, limbs and genitals (neck, arms, hands, fingers, legs, genitals) and internal organs, such as lungs, kidneys and liver. The most frequent HSV serotype isolated for each pathology is indicated

Fig. 2

Relationship between HSV-2 and HIV at the site of infection. Infection with HSV-2 produces microlesions that expose the epidermis, dermis and subjacent immune cells at the site of infection to incoming viruses, such as HIV. 1. Infection of genital epithelia by HSV-2 produces the secretion of pro-inflammatory cytokines (e.g., IL-6, TNF-α, IL-1β, RANTES) in response to infection, which attracts immune cells, such as dendritic cells and T cells to the site of infection. 2. Residing and infiltrating immune cells (DCs and T cells) are infection targets for HSV-2 and HIV. 3. DC infection with HSV-2 induces the secretion of soluble molecules at the site of infection that promote the reactivation of HIV from CD4⁺ T cells in HIV⁺ individuals with subsequent replication and dissemination. 4. DCs infected with HSV-2 recruit T cells that express α₄β₇, a molecule that facilitates infection of these cells by HIV. 5. DCs accumulating at the site of infection can be used by HIV as Trojan horses to reach and infect T cells in lymph nodes