Quantifying antiviral effects against simian/human immunodeficiency virus induced by host immune response

Abstract

Chimeric simian and human immunodeficiency viruses (SHIVs) are appropriate animal models for the human immunodeficiency virus (HIV) because HIV has quite a narrow host range. Additionally, SHIVs that encode the HIV-1 Env protein and are infectious to macaques have many strains that show different pathogenesis, such as the highly pathogenic SHIV-KS661 and the less pathogenic SHIV-#64. Therefore, we used SHIVs to understand different aspects of AIDS pathogenesis. In a previous study, we established a mathematical model of in vivo early SHIV infection dynamics, which revealed the expected uninfected and infected dynamics in Rhesus macaques. In concrete, the number of uninfected CD4⁺ T cells in SHIV-KS661-infected Rhesus macaques decreased more significantly and rapidly than that of SHIV-#64 Rhesus macaques, and these Rhesus macaques did not any induce host immune response. In contrast, the number of uninfected CD4⁺ T cells in SHIV-#64-infected Rhesus macaques is maintained, and host immune response developed. Although we considered that the peak viral load might determine whether systemic CD4⁺ T cell depletion occurs or host immune responses develop, we could not investigate this because our model quantified only SHIV infection prior to the development of the pathogenicity or host immune responses. Therefore, we developed a new mathematical model to investigate why SHIV-#64 and SHIV-KS661 showed different long-term viral dynamics. We fitted our new model considering antibody responses to our experimental datasets that included antibody titers, CD4⁺ T cells, and viral load data. We performed a maximum likelihood estimation using a non-linear mixed effect model. From the results, we derived the basic reproduction numbers of SHIV-#64 and SHIV-KS661 from intravenous infection (IV) and SHIV-KS661 from intrarectal infection (IR), as well as the antiviral effects of antibodies against SHIV-#64(IV) and SHIV-KS661(IR). We found significant differences between the basic reproduction number of SHIV-#64(IV) or -KS661(IR) and that of SHIV-KS661(IV). We found no clear difference between the antiviral effects of SHIV-#64(IV) and SHIV-KS661(IR), and revealed that an antiviral effect more than 90% of that of maximum antibody responses was induced from initial antibody responses (i.e., antibody response just after its inducement). In conclusion, we found that the basic reproduction number, rather than SHIV strains determines whether systemic CD4⁺ T cell depletion develops, and the subsequent antibody responses occurs.

Keywords: Parameter estimation; Population dynamics model; Simian/human immunodeficiency virus; Virus dynamics.