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

Abstract

HIV disease progression appears to be driven by high levels of 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 tolerize the fetus to the virus, thus reducing damage caused by immune activation if infected later in life. To test this hypothesis, fetal rhesus macaques (Macaca mulatta) were injected with the attenuated virus SIVmac1A11 in utero and then challenged with pathogenic SIVmac239 one year after birth. SIVmac1A11-injected animals had significantly reduced plasma RNA viral loads (p<0.02) up to 35 weeks post-infection. Generalized estimating equations (GEE) analysis was performed to identify immunologic and clinical measurements significantly associated with plasma RNA viral load. A positive association 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, while an inverse relationship was found with the levels of circulating CD4+ and CD8+ T cells expressing intermediate levels of the proliferation marker, Ki-67. Further analyses demonstrated that animals exposed to SIV in utero appeared to have enhanced SIV-specific cellular immune responses, expressed lower levels of the exhaustion marker, PD-1, on CD8+ T cells, and had more circulating Th17 cells when compared to controls. While 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.

Prenatal Exposure to Respiratory Syncytial Virus Alters Postnatal Immunity and Airway Smooth Muscle Contractility during Early-Life Reinfections

“…Among several aspects requiring additional investigation, the influence of maternal RSV infection on postnatal offspring immunity, neurotrophins expression, and mechanism of airway smooth muscle contractility during postnatal RSV LRTI remains largely unknown. Recently, vertical transmission of viral antigens was reported to impact postnatal immunity whereby macaques exposed to viral epitopes in utero displayed altered immunity after postnatal virus challenge [ 17 ]. Regarding RSV, the concept of maternal-to-fetal transmission during pregnancy is not unrealistic as evidenced by the documentation of multiple sites of extrapulmonary RSV infection [ 18 – 25 ].…”

Development and Evaluation of mini-EXPLORER: A Long Axial Field-of-View PET Scanner for Nonhuman Primate Imaging

“…In this work, we describe the development and performance of a long axial FOV PET scanner for imaging nonhuman primates. The physiologic and evolutionary relatedness between humans and nonhuman primates supports rhesus monkeys as a suitable animal model in several areas of biomedical research, including neuroscience, immunology, infectious disease, health across the life span (fetal to aged), regenerative medicine, and drug discovery (20)(21)(22)(23)(24)(25)(26).…”

Gag-Specific CD8 T-Cell Proliferation Is Associated With Higher Peripheral Blood Levels of Transforming Growth Factor-β and Gut-Homing T Cells in Youths Perinatally Infected With Human Immunodeficiency Virus-1: The ANRS-EP38-IMMIP Study

“…After long-term highly-active antiretroviral therapy, efficient gut-associated lymphoid tissue (GALT) CD4 T restoration is associated with both higher polyfunctionality of HIV-specific CD4 and CD8 T cells and an increased number of GALT CD4 T cells producing IL-17 in response to mitogens [ 24 ]. In simian immunodeficiency virus (SIV)-infected macaques, enhanced SIV-specific T-cell responses and higher levels of Th17 cells were concomitantly observed [ 25 , 26 ].…”