Cellular Factors Targeting HIV-1 Transcription and Viral RNA Transcripts

Abstract

Restriction factors are structurally and functionally diverse cellular proteins that constitute a first line of defense against viral pathogens. Exceptions exist, but typically these proteins are upregulated by interferons (IFNs), target viral components, and are rapidly evolving due to the continuous virus–host arms race. Restriction factors may target HIV replication at essentially each step of the retroviral replication cycle, and the suppression of viral transcription and the degradation of viral RNA transcripts are emerging as major innate immune defense mechanisms. Recent data show that some antiviral factors, such as the tripartite motif-containing protein 22 (TRIM22) and the γ-IFN-inducible protein 16 (IFI16), do not target HIV-1 itself but limit the availability of the cellular transcription factor specificity protein 1 (Sp1), which is critical for effective viral gene expression. In addition, several RNA-interacting cellular factors including RNAse L, the NEDD4-binding protein 1 (N4BP1), and the zinc finger antiviral protein (ZAP) have been identified as important immune effectors against HIV-1 that may be involved in the maintenance of the latent viral reservoirs, representing the major obstacle against viral elimination and cure. Here, we review recent findings on specific cellular antiviral factors targeting HIV-1 transcription or viral RNA transcripts and discuss their potential role in viral latency.

Inhibition of miR-155 Promotes TGF-β Mediated Suppression of HIV Release in the Cervical Epithelial Cells

“…We next analyzed the probable role of miR-155 in HIV release by the cervical epithelial cells and found that while TGF-β neutralization increased the HIV shedding, inhibition of miR-155 prior to TGF-β neutralization restricted the virus release as well as viral gene expression by the cervical epithelial cells. Further, since host restriction factors interfere with the HIV replication and its release, we examined whether inhibition of miR-155 alters the gene expression of the cellular restriction factors affecting, HIV-1 viral protein synthesis (IFITM-1 and IFITM-3) [43], reverse transcription (APOBEC-3G) [44][45][46] and HIV gene expression (IFI-16) [47,48]. We found that except IFITM-1, the expression of IFITM-3, APOBEC-3G and IFI-16 genes were increased in the presence miR-155 inhibitor.…”

“…Since, host restriction factors hamper the HIV replication and its release, we further examined whether miR-155 inhibition alters the gene expression of the HIV-1 viral protein synthesis (IFITM-1 and IFITM-3) [43], reverse transcription (APOBEC-3G) [44][45][46] and HIV gene expression (IFI-16) [47,48]. While there was no significant change in the expression of IFITM-1 mRNA (Figure 3b) as a result of miR-155 inhibition, we found a significant increase in the expression of IFITM-3 gene at days 1 (11-fold; p = 0.03) and 3 (31-fold; p = 0.01) post infection in the ME-180 cells transfected with miR-155 inhibitor as compared to the mock cells (Figure 3c).…”

TRIM22. A Multitasking Antiviral Factor

“…In this regard, latently infected cells (mostly CD4 + T cells) are considered the main obstacle to virus eradication in that they are not affected by combination antiretroviral therapy (cART) [48,49]. The accomplishment of a full HIV-1 life cycle is essential for viral spreading, and it is counteracted by numerous host determinants collectively defined as restriction factors that are constitutively expressed prior to infection and/or are rapidly induced upon pathogen exposure [50]. Among these, other members of the TRIM family have been shown to play a significant role in preventing or containing HIV-1 replication, including TRIM5α [51], TRIM11 [52], TRIM28 [53], TRIM33 [54], TRIM34 [55] and TRIM37 [56].…”

Innate immune regulation in HIV latency models

“…Many ISGs specifically function as HIV restriction factors including APOBEC3G [ 14 ], IFITM1 [ 15 ], MX2 [ 16 , 17 ], ISG15 [ 18 ], BST2 (tetherin) [ 19 ], and others [ 4 , 20 – 22 ]. HIV has evolved a myriad of mechanisms to block and/or evade these restriction factors, largely through the actions of viral protein products including the HIV protease, Vif, Nef, and Vpu [ 4 , 23 , 24 ].…”