Research ArticleHIV

Exposure to SIV in utero results in reduced viral loads and altered responsiveness to postnatal challenge

Science Translational Medicine  12 Aug 2015:
Vol. 7, Issue 300, pp. 300ra125
DOI: 10.1126/scitranslmed.aac5547

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Getting an early start in HIV protection

HIV disease is characterized by a state of chronic immune activation that appears to contribute to the dysfunction of the immune system. Control of immune activation in infected patients may help to protect against immune dysfunction and delay the progression of the disease. In a new study, Baker et al. exposed fetal rhesus macaques to simian immunodeficiency virus (SIV), a close relative of HIV, during a prenatal period, hypothesizing that this would cause the macaque’s immune system to become less reactive to, or tolerant of, material derived from SIV. When experimentally infected after birth, the authors hypothesized that exposed macaques might mount less aggressive immune responses against the virus, have lower immune activation, and may have less severe disease than unexposed animals. They found that macaques exposed to SIV in utero did not display any direct evidence of tolerance to SIV; however, the animals did have significantly lower viral loads after infection and altered immune responses that were associated with the control of viral replication. This study supports a new avenue for HIV vaccine design.

Abstract

HIV disease progression appears to be driven by increased immune activation. Given observations that fetal exposure to infectious pathogens in utero can result in reduced immune responses, or tolerance, to those pathogens postnatally, we hypothesized that fetal exposure to HIV may render the fetus tolerant to the virus, thus reducing damage caused by immune activation during infection later in life. To test this hypothesis, fetal rhesus macaques (Macaca mulatta) were injected with the attenuated virus SIVmac1A11 in utero and challenged with pathogenic SIVmac239 1 year after birth. SIVmac1A11-injected animals had significantly reduced plasma RNA viral loads (P < 0.02) up to 35 weeks after infection. Generalized estimating equations analysis was performed to identify immunologic and clinical measurements associated with plasma RNA viral load. A positive association with plasma RNA viral load was observed with the proportion of CD8+ T cells expressing the transcription factor, FoxP3, and the proportion of CD4+ T cells producing the lymphoproliferative cytokine, IL-2. In contrast, an inverse relationship was found with the frequencies of circulating CD4+ and CD8+ T cells displaying intermediate expression of the proliferation marker, Ki-67. Animals exposed to simian immunodeficiency virus (SIV) in utero appeared to have enhanced SIV-specific immune responses, a lower proportion of CD8+ T cells expressing the exhaustion marker PD-1, and more circulating TH17 cells than controls. Although the development of tolerance was not demonstrated, these data suggest that rhesus monkeys exposed to SIVmac1A11 in utero had distinct immune responses associated with the control of viral replication after postnatal challenge.

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