Herpes simplex virus-2 (HSV-2) causes a chronic infection characterized by frequent shedding episodes, the majority of which are associated with low peak viral load and are asymptomatic. Occasionally, episodes are characterized by high viral loads, last longer and results in genital ulcers. In immunocompetent subjects, all episodes are eventually controlled by the immune system, whereas in HIV-infected subjects episodes are more frequent and, after progression to AIDS, HSV-2 reactivation can result in long-lasting episodes: on rare, occasions the virus may spread to multiple organs. Although the lack of control observed in HIV-infected patients has been related to having fewer CD4+ T cells, more detailed mechanistic insights are lacking. In fact, CD4+ T cells play multiple roles in the immune response, such as helping CD8+ T cell function and guiding antibody response.
Although key for vaccine design, the identification of the defects of the immune system in such context is complicated by the need for continuous monitoring of the immune responses at sites of viral latency and lytic replication. Given the limited availability of experimental data, mathematical models represents a useful tool to reconstruct the complexity of the immune response to HSV-2 and guide further experimental studies. The expertise of bench scientists and mathematical modelers available at Fred Hutch allowed the construction of a complex model taking into account several factors: 1) seeding of new HSV-2 lesions by virus released from ganglionic latency; 2) infection of susceptible epithelial cells within a single ulcer from adjacent infected cells, 3) seeding of new ulcers by cell-free HSV-2 particles, 4) clearance of cell-free particles, 5) death of infected cells and 6) increase of T cells in response to increased burden of viral antigen.
The current model was built on experimental data obtained from a cohort of 98 HSV-2 positive HIV-1 uninfected men and 98 HSV-2 positive HIV-1 infected men. HIV-1 infected participants were further divided in three groups based on CD4+ T cell counts (<200, 200-499, and >500/μl). Experimental data showed that kinetics of shedding episodes were similar between the two groups, but episode rate was higher and episodes were longer in HIV infected as compared to uninfected subjects. Modeling these data showed that increased shedding in individual HIV-1 infected subjects was likely due to multiple rather than a single immunological defect. The rate of HSV-2 release from ganglia as well as resident T cell decay in the mucosa was higher in HIV-1 positive subjects with the largest difference detected in subjects with the lowest CD4+ T cell count, indicating a loss of T cell control of HSV-2 in men with AIDS. Moreover, a decrease in clearance of cell free virus suggested a loss of humoral immune function in HIV-infected men.
The model was then applied to mimic a continuous rather than discrete sampling. The model predicted that longer duration of episodes in subjects with CD4<200 occurred because of slower clearance of free virus that allowed secondary seeding into discrete mucosal locations allowing spatial spread, which might explain the higher percent of episodes lasting more than 10 and 20 days following progression to AIDS.
Dr. Joshua Schiffer, a modeler from the Vaccine and Infectious Disease Division at Fred Hutch and first author of a paper reporting these results published in PLOS ONE provided us with a summary statement of his work: "Our study suggests that poor immune control of HSV-2 in HIV infected patients cannot be attributed to a single deficit of immunity. Rather, multiple arms of the immune system are compromised in both sites of HSV-2 infection."
The study was supported by National Institutes of Health.
Schiffer JT, Swan DA, Magaret A, Schacker TW, Wald A, Corey L. 2016. Mathematical Modeling Predicts that Increased HSV-2 Shedding in HIV-1 Infected Persons Is Due to Poor Immunologic Control in Ganglia and Genital Mucosa. PLoS One, 11(6), e0155124.