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2015 ; 4
(10
): e259
Nephropedia Template TP
gab.com Text
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Reducing IRF-1 to Levels Observed in HESN Subjects Limits HIV Replication, But
Not the Extent of Host Immune Activation
#MMPMID26506037
Su RC
; Plesniarski A
; Ao Z
; Kimani J
; Sivro A
; Jaoko W
; Plummer FA
; Yao X
; Ball TB
Mol Ther Nucleic Acids
2015[Oct]; 4
(10
): e259
PMID26506037
show ga
Cells from women who are epidemiologically deemed resistant to HIV infection
exhibit a 40-60% reduction in endogenous IRF-1 (interferon regulatory factor-1),
an essential regulator of host antiviral immunity and the early HIV replication.
This study examined the functional consequences of reducing endogenous IRF-1 on
HIV-1 replication and immune response to HIV in natural HIV target cells. IRF-1
knockdown was achieved in ex vivo CD4(+) T cells and monocytes with siRNA. IRF-1
level was assessed using flow cytometry, prior to infection with HIV-Bal,
HIV-IIIB, or HIV-VSV-G. Transactivation of HIV long terminal repeats was assessed
by p24 secretion (ELISA) and Gag expression (reverse transcription-polymerase
chain reaction (RT-PCR)). The expression of IRF-1-regulated antiviral genes was
quantitated with RT-PCR. A modest 20-40% reduction in endogenous IRF-1 was
achieved in >87% of ex vivo-derived peripheral CD4(+) T cells and monocytes,
resulted in >90% reduction in the transactivation of the HIV-1 genes (Gag, p24)
and, hence, HIV replication. Curiously, these HIV-resistant women demonstrated
normal immune responses, nor an increased susceptibility to other infection.
Similarly, modest IRF-1 knockdown had limited impact on the magnitude of
HIV-1-elicited activation of IRF-1-regulated host immunologic genes but resulted
in lessened duration of these responses. These data suggest that early expression
of HIV-1 genes requires a higher IRF-1 level, compared to the host antiviral
genes. Together, these provide one key mechanism underlying the natural
resistance against HIV infection and further suggest that modest IRF-1 reduction
could effectively limit productive HIV infection yet remain sufficient to
activate a robust but transient immune response.