The Impact of Methamphetamine on Genital Herpes Disease Pathogenesis and Host Immune Responses to Herpes Simplex Virus Type 2 in Mouse and Guinea Pig Models

Use of the stimulant methamphetamine (METH) is increasingly common, with over 35 million users worldwide. There is a known association between stimulant use and an increased incidence of HIV and other sexually transmitted infections (STI). Although behavioral disinhibition is an important component of this association, there is increasing evidence that METH use can alter immune responses, suggesting that it may have direct biological effects. However, the extent of these effects on disease pathogenesis and the mechanisms by which the alterations occur, have not yet been fully elucidated. The purpose of the studies in this dissertation was to investigate the impact of METH use on disease using an STI pathogen of public health importance, Herpes Simplex Virus type 2 (HSV-2), the primary cause of genital herpes worldwide. The central hypothesis of this dissertation is that METH alters the innate and adaptive immune response, increasing susceptibility to infection and altering genital herpes disease. In these studies a well characterized murine model of HSV-2 infection was used to determine the impact of METH use on host immune responses, susceptibility to infection, and pathogenesis of disease. Additionally, a well characterized guinea pig model of HSV-2 infection was employed to determine the impact of METH on parameters that cannot be measured in the mouse model including severity of primary genital disease, frequency of recurrent lesions, and viral shedding during latency. STI infections are more prevalent in females and stimulants such as METH have different effects in male and female users. Consequently the majority of the studies are in female animals. We were able to show that METH accelerates disease pathogenesis in both the mouse and guinea pig models. Further, using the mouse we found that METH treatment causes cytokine dysregulation at the site of infection. We were also able to show that there is a significantly reduced number in IFNγ secreting CD4+ T cells in the genital tract of METH-treated mice compared to controls. This result may be associated with an increase in regulatory T cells in the vagina. Using the guinea pig we were able to show that METH-treatment increased that amount of virus shed at the vagina as well as the frequency of recurrences. The results obtained from these studies provide important new information about the interaction between drugs of abuse and infectious disease, an area which has been little studied but which is of significant clinical relevance. The findings may contribute to the treatment of at risk populations and importantly may be of broader relevance to other important diseases such as HIV.