Resistance to simian immunodeficiency virus low dose rectal challenge is associated with higher constitutive TRIM5α expression in PBMC

Abstract

BackgroundAt least six host-encoded restriction factors (RFs), APOBEC3G, TRIM5α, tetherin, SAMHD1, schlafen 11, and Mx2 have now been shown to inhibit HIV and/or SIV replication in vitro. To determine their role in vivo in the resistance of macaques to mucosally-acquired SIV, we quantified both pre-exposure (basal) and post-exposure mRNA levels of these RFs, Mx1, and IFNγ in PBMC, lymph nodes, and duodenum of rhesus macaques undergoing weekly low dose rectal exposures to the primary isolate, SIV/DeltaB670.ResultsRepetitive challenge divided the monkeys into two groups with respect to their susceptibility to infection: highly susceptible (2–3 challenges, 5 monkeys) and poorly susceptible (≥6 challenges, 3 monkeys). Basal RF and Mx1 expression varied among the three tissues examined, with the lowest expression generally detected in duodenal tissues, and the highest observed in PBMC. The one exception was A3G whose basal expression was greatest in lymph nodes. Importantly, significantly higher basal expression of TRIM5α and Mx1 was observed in PBMC of animals more resistant to mucosal infection. Moreover, individual TRIM5α levels were stable throughout a year prior to infection. Post-exposure induction of these genes was also observed after virus appearance in plasma, with elevated levels in PBMC and duodenum transiently occurring 7–10 days post infection. They did not appear to have an effect on control of viremia. Interestingly, minimal to no induction was observed in the resistant animal that became an elite controller.ConclusionsThese results suggest that constitutively expressed TRIM5α appears to play a greater role in restricting mucosal transmission of SIV than that associated with type I interferon induction following virus entry. Surprisingly, this association was not observed with the other RFs. The higher basal expression of TRIM5α observed in PBMC than in duodenal tissues emphasizes the understated role of the second barrier to systemic infection involving the transport of virus from the mucosal compartment to the blood. Together, these observations provide a strong incentive for a more comprehensive examination of the intrinsic, variable control of constitutive expression of these genes in the sexual transmission of HIV.

Increased BST2 expression during simian immunodeficiency virus infection is not a determinant of disease progression in rhesus monkeys

“…One possible reason for this discrepancy is that IFN-alpha in plasma becomes undetectable by ELISA in the chronic phase of the infection and is therefore less sensitive for determining the interferon response [ 65 ] than measuring ISG like MX1 as in our work or ISG15 [ 36 ]. In agreement with results from present study, Aamer and colleagues also observed a maximum BST2 and MX1 expression during acute infection [ 66 ]. Strong induction of BST2 together with other restriction factors has also been observed in vivo after treatment of HIV/HCV-coinfected patients with pegylated IFN-alpha/ribavirin (IFN-alpha/riba) exhibiting a good correlation with ISG15 [ 36 ].…”

IFI44 suppresses HIV-1 LTR promoter activity and facilitates its latency

“…This is not unusual, since studies of other ISGs demonstrate that even basal expression of ISGs still possess certain antiviral activity. For example, the high basal expression of an ISG, TRIM5α, in peripheral blood mononuclear cells (PBMCs) dramatically restricts mucosal transmission of simian immunodeficiency virus (SIV) more efficiently than when induced with type I IFN [30]. Certain host genes, including recently discovered tyrosine kinase nonreceptor 1 (TNK1), are required for maintenance of basal ISG expression [31].…”