RNA viruses, in pursuit of genome miniaturization, tend to employ cellular proteins to facilitate their replication. HIV-1, one of the most well-studied retroviruses, is not an exception. There is numerous evidence that the exploitation of cellular machinery relies on nucleic acid-protein and protein-protein interactions. Apart from Vpr, Vif, and Nef proteins that are known to regulate cellular functioning via interaction with cell components, another viral protein, integrase, appears to be crucial for proper virus-cell dialog at different stages of the viral life cycle. The goal of this review is to summarize and systematize existing data on known cellular partners of HIV-1 integrase and their role in the HIV-1 life cycle.

The structural organization of HIV-1 integrase is based on a tetramer formed by two protein dimers. Within this tetramer, the catalytic domain of one subunit of the first dimer interacts with the N-terminal domain of a subunit of the second dimer. It is the tetrameric structure that allows both ends of viral DNA to be correctly positioned relative to cellular DNA and to implement the catalytic functions of integrase, namely 3′-processing and strand transfer. However, during the HIV-1 replicative cycle, integrase is responsible not only for the integration stage, it is also involved in reverse transcription and is necessary at the stage of capsid formation of newly formed virions. HIV-1 integrase is proposed to be a structurally dynamic protein and its biological functions depend on its structure. Accordingly, studying the interactions between the domains of integrase that provide its tetrameric structure is important for understanding its multiple functions. In this work, we investigated the role of three amino acids of the catalytic domain I182, R187 and K188, located in the contact region of two integrase dimers in the tetramer structure, in reverse transcription and integration. It has been shown that the R187 residue is extremely important for the formation of the correct integrase structure, which is necessary at all stages of its functional activity. The I182 residue is necessary for successful integration and is not important for reverse transcription, while the K188 residue, on the contrary, is involved in the formation of the integrase structure, which is important for effective reverse transcription.

The SFPQ (Splicing Factor Proline and Glutamine rich) protein, initially identified as a splicing factor, is a multifunctional nuclear protein involved in various cellular processes. Its main cellular partner is NONO (Non-POU domain-containing octamer-binding protein), with which SFPQ forms a heterodimer that is a crucial component of subnuclear structures called paraspeckles and located near nuclear speckles. However, SFPQ can also function independently in certain cellular processes and is essential for cell viability. There is substantial evidence of the involvement of SFPQ in the repair of double-strand DNA breaks (DSBs), but a definitive understanding of the mechanism of its participation in this critical cellular process is still lacking. In this review, we aim to summarize and systematize the existing data on the role of SFPQ and its complex with NONO in the repair of double-strand DNA breaks.

Upstream open reading frames (uORFs) are widespread regulatory elements located in the 5′-untranslated regions of eukaryotic and viral mRNAs. Once considered rare exceptions to the canonical scanning model, uORFs are now recognized as actively translated features present in approximately half of human transcripts, frequently initiating at non-canonical start codons. In eukaryotes, uORFs fine-tune protein synthesis in response to cellular stress by modulating ribosome reinitiation, as exemplified by the stress-dependent regulation of ATF4 and GCN4. In viral genomes, uORFs serve as compact, evolutionarily conserved modules that optimize protein stoichiometry, coordinate expression with the host cell state, and support persistent infection across diverse viral families through cis-regulation of translation. Beyond this, uORF-encoded peptides (uPeptides) can possess independent biological activities, influencing virulence, tissue tropism, and immune modulation. In this review, we systematize the available data on the dual functionality of uORFs as cis-regulatory elements of translation and as sources of bioactive uPeptides in viruses. Deciphering the full spectrum of uORF-mediated mechanisms may reveal novel layers of viral replication control and uncover potential targets for antiviral development, although, as discussed here, the available evidence for such applications is still largely limited to proof-of-principle mutagenesis.

Structural organization of HIV-1 integrase is based on a tetramer formed by two protein dimers. Within this tetramer, the catalytic domain of one subunit of the first dimer interacts with the N-terminal domain of the second dimer subunit. It is the tetrameric structure that allows both ends of the viral DNA to be correctly positioned relative to the cellular DNA and to realize catalytic functions of integrase, namely 3′-processing and strand transfer. However, during the HIV-1 replicative cycle, integrase is responsible not only for the integration stage, it is also involved in reverse transcription and is necessary at the stage of capsid formation of the newly formed virions. It has been suggested that HIV-1 integrase is a structurally dynamic protein and its biological functions depend on its structure. Accordingly, studying interactions between the domains of integrase that provide its tetrameric structure is important for understanding its multiple functions. In this work, we investigated the role of three amino acids of the catalytic domain, I182, R187, and K188, located in the contact region of two integrase dimers in the tetramer structure, in reverse transcription and integration. It has been shown that the R187 residue is extremely important for formation of the correct integrase structure, which is necessary at all stages of its functional activity. The I182 residue is necessary for successful integration and is not important for reverse transcription, while the K188 residue, on the contrary, is involved in formation of the integrase structure, which is important for the effective reverse transcription.