Abstract
We previously showed intravaginal inoculation with SHIVsf162p3 results in transient viremia followed by undetectable viremia in most macaques, and some displayed subsequent immunity to superinfection with pathogenic SIVmac251. Here we compare early T cell activation, proliferation, and plasma cytokine/chemokine responses in macaques intravaginally infected with either SHIVsf162p3 or SIVmac251 to determine whether distinct differences in host responses may be associated with early viral containment. The data show SIVmac251 infection results in significantly higher levels of T cell activation, proliferation, and a mixed cytokine/chemokine “storm” in plasma in primary infection, whereas infection with SHIVsf162p3 resulted in significantly lower levels of T cell activation, proliferation, and better preservation of memory CD4+ T cells in early infection which immediately preceded control of viremia. These results support the hypothesis that early systemic immune activation, T cell proliferation, and a more prominent and broader array of cytokine/chemokine responses facilitate SIV replication, and may play a key role in persistence of infection, and the progression to AIDS. In contrast, immune unresponsiveness may be associated with eventual clearance of virus, a concept that may have key significance for therapy and vaccine design.
Highlights
Rhesus macaques are the premier animal model for studying the pathogenesis and immunology of Human immunodeficiency virus (HIV) infection
SHIVsf162P3 was originally described as a pathogenic simian/human immunodeficiency viruses (SHIVs), and some rhesus macaques clearly develop AIDS when infected with this virus [1], yet while most SHIV-infected macaques have marked peak viremia, and often similar to those infected with more pathogenic viruses, the majority fail to sustain viremia, and most clear infection, at least to undetectable levels in plasma within a few weeks of infection
The reasons for these disparate outcomes are unknown, few studies have directly compared the host responses in identical cohorts of macaques inoculated with a pathogenic virus (SIVmac251) with those infected with a virus that results in early high viremia, but is eventually cleared to undetectable levels in plasma, such as SHIVsf162P3
Summary
Rhesus macaques are the premier animal model for studying the pathogenesis and immunology of HIV infection. Most SHIVs are transmissible and initially highly infectious, yet most SHIVinfected macaques fail to maintain plasma viremia for more than a few weeks/months, making these viruses less useful for pathogenesis or vaccine studies. SHIVsf162P3 was originally described as a pathogenic SHIV, and some rhesus macaques clearly develop AIDS when infected with this virus [1], yet while most SHIV-infected macaques have marked peak viremia, and often similar to those infected with more pathogenic viruses, the majority fail to sustain viremia, and most clear infection, at least to undetectable levels in plasma within a few weeks of infection. SIVmac251 is among the most widely used virus for examining the immunology and pathogenesis of HIV infection in humans, largely due to its high infectivity, persistent and stable post peak (set point) viremia, and high rate of progression to AIDS within 1–3 years. Since most SHIV-infected animals ‘‘clear’’ or control infection to undetectable levels, we hypothesized there would be detectable differences in immune responses between macaques infected with SIV mac251, which may yield correlates of a protective immune response that prevents animals from progressing to AIDS
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