Understanding viral-immune dynamics in HIV infection

by Zhang, Lei; lzhang@student.unsw.edu.au, null

The HIV epidemic has caused a health crisis globally. Using mathematical and statistical tools, we have analysed and modelled data from animal models of HIV, HSV and influenza virus, in order to understand the role of neutralising antibodies (nAbs), CD4+ T cells, CTLs and APCs in HIV infection and the implications of this for HIV vaccine design. Our analysis suggests that antibody and CTL responses confer protection at different stages of HIV infection. Passive antibodies confer protection against SHIV89.6PD infection by either neutralising the initial viral inoculum or reducing the acute viral level and growth. Consequently, CD4+ T cell preservation allows the immune system to control long-term disease progression. Therefore, vaccines that elicit high nAb levels during early infection may induce sterilising immunity or delay disease progression. By contrast, we observed that vaccine-elicited CTLs did not proliferate until day 10 following SHIV89.6P infection. More potent CTL-inducing vaccines did not reduce this delay, but further increased it and reduced CTL growth. However, more potent vaccines result in better memory CTL formation, better CD4 preservation and improved disease outcome. HIV vaccine design should aim to reduce the delay in CTL activation. To further understand the pathogenesis of HIV, we investigated the relationship between viral load and CD4+ T cell levels using simple ODE models. Our results demonstrate a positive correlation between peak viral level and the acute CD4+ T cell depletion in SHIV89.6P infection, which demonstrates how reduction of peak viral level significantly preserves CD4+ T cells. Surprisingly, this relationship between virus and CD4+ T cells was reversed in SIVmac239 infection and other CCR5 tropic infections. Future work should focus on understanding this difference between X4 and R5 infections. Regardless of viral infections, antigen presentation is essential for stimulating effective immune responses. Our study on influenza and HSV-1 infections suggests that antigen loading rate of APCs determines the magnitude of antigen presentation and the APC decay is mainly due to the degradation of pMHC, not CTL killing. The slow kinetics of HIV viral growth may be one factor that limits the level of antigen presentation and subsequent CTL response.