Human immunodeficiency virus type 1 (HIV-1) is a member of the lentivirus genus of the
retroviridae family that causes a lethal condition known as AIDS (acquired immunodeficiency syndrome) in humans by infecting CD4
+ T lymphocytes, causing their depletion and profound immunodeficiency, leading to opportunistic infections and cancer
[41]; in addition to CD4
+ T lymphocytes, HIV-1 also infects mononuclear phagocytes that are not depleted. After infection, the viral RNA genome is retrotranscribed into DNA that is then integrated as proviral DNA in the host genome
[42]. The provirus is actively transcribed during a productive infection by the combined action of the viral protein Tat and of the cellular transcription machinery
[43]. Tat is a virus-encoded transcriptional transactivator that binds to the RNA secondary structure of the transactivation region (TAR) of the 5′ long terminal repeat (LTR) (+1 to +59)
[44][45][44,45] (
Figure 1A). Once Tat is bound to the TAR RNA, it recruits a protein complex named positive transcription elongation factor b (p-TEFb) aimed to elongate the viral transcripts. p-TEFb is formed by the regulatory subunit cyclin T1 (CyT1) and the kinase subunit cyclin-dependent kinase 9 (CDK9) that phosphorylate the RNA polymerase II (Pol II) to increase its processivity. However, Tat elongation activity requires a basal transcription that is under the control of the upstream regulatory sequences, namely, three specificity protein 1 (Sp1) and two nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) binding sites that respond to pro-inflammatory signals
[46]. The lack of NF-kB and Sp1 binding to the promoter, or the lack of recruitment of negative transcription factors to their DNA binding sites maintains a state of proviral latency
[47]. 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][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].
Figure 1. (A) Structural organization of the HIV-1 promoter. HIV-1 transcription starts at the promoter region in the 5′ LTR. Processive HIV-1 transcription is driven by the Tat protein that recruits the p-TEFb complex to the TAR RNA. pTEFb promotes the phosphorylation of the RNA Pol II, enabling the elongation of the viral transcripts. Upstream of the initiation of transcription (+1), three Sp1 and two NF-kB binding sites control the levels of basal transcription and response to inflammatory signals, respectively. (B) TRIM22 inhibits HIV-1 basal transcription by preventing Sp1 binding to the HIV-1 promoter, thus contributing to the maintenance of latent HIV-1 infection.