Flaviviruses are in >100 countries across the globe and in areas with endemic HIV. Despite the occurrence of large flavivirus outbreaks and geographic overlap in countries with high HIV prevalence, there is insufficient research to determine the risks of flavivirus co-infection in people living with HIV and impact on co-morbidities. Here, in SIV-infected pigtail macaques, we investigated the hypothesis that enhanced ZIKV pathogenesis occurs in people living with HIV.
Pigtail macaques (n=7) were infected with SIVmac239M and co-infected with ZIKV at 9 weeks post-SIV infection (SIV+/ZIKV+). Animals were compared to control animals (n=7) only infected with ZIKV (SIV-/ZIKV+). SIV and ZIKV viral loads in plasma and peripheral tissues were measured by qRT-PCR. Blood/peripheral blood mononuclear cells (PBMCs), lymph node, and rectal tissues collected pre- and post-SIV and/or ZIKV infection were evaluated for innate and adaptive immune responses by flow cytometry. Alterations in host responses were measured in PBMC using NanoString gene analysis.
At the time of ZIKV co-infection, SIV+ animals had severe CD4 depletion and an average viral setpoint of 5.6 log10 SIV copies/ml of plasma. ZIKV viremia was detected on average for 2 days longer in SIV+/ZIKV+ animals in comparison to SIV-/ZIKV+ control animals and peak viremia was shifted on average 1.67 days later in SIV+/ZIKV+ animals. Post-ZIKV infection, peripheral recruitment of CD16+ monocytes, the in vivo blood target of ZIKV infection, was dampened and delayed in SIV+/ZIKV+ vs SIV-/ZIKV+ animals, and corresponded to the delayed ZIKV viremia in SIV+/ZIKV+ animals. Despite lower levels of CD16+ monocyte recruitment, SIV infection induced sustained activation of CD16+ monocytes during ZIKV co-infection. Furthermore, PBMC gene expression analysis post-ZIKV infection revealed hyperactivation of the innate immune response, including interferon alpha signaling, in SIV+/ZIKV+ animals.
Here, we provide evidence that ZIKV viremia is delayed in SIV-infected macaques, demonstrating a prolonged window of viral transmission. Characterization of the immune response revealed chronic activation of innate signaling pathways and innate immune activation, but impaired innate cellular recruitment responses during SIV-ZIKV co-infection. Collectively, these findings suggest that untreated SIV/HIV infection could create an environment of immunological tolerance that may lead to poor ZIKV viral clearance and promote pathogenesis.