HIV accessory genes are known to extensively alter the internal composition of infected cells by hijacking normal phosphorylation and ubiquitin processes, mediating viral gene transcription, and suppressing immune surveillance and detection . These data suggest that the presence of genes associated with these pathways may be associated with HIV-infected cells.
The TP63 gene belongs to a P53 family of transcription factors that also includes P73 and the tumor suppressor gene P53 , which share a high degree of homology and are important for cell homeostasis . TP63 is an important marker for the development of basic tumor biology by regulating genetic processes [11, 12, 13]. TP63 can be synthesized from two different start sites, leading to two different N-terminal protein domains, the TA (transactivation) domain and DN domain. Both the TAp63 and DNp63 isoforms have α, β and γ splice variants in the carboxyl terminal region, which leads to multiple TP63 isoforms . These isoforms play a corresponding role in regulating tumor development and other physiological and pathological processes . DNp63 can act as a sequence-specific transcription activator or suppressor. DNp63α isomers, in detail, can activate specific target genes via a second transcription activation domain . In addition, DNp63 interacts with a variety of epigenetic factors to effectively repress transcription . TP63 is considered a transcriptional regulator of the basal gene program and is upregulated in basal subtypes of bladder, breast and ovarian cancers . The enrichment of immune pathways in TAp63-expressing tumors suggests a link between TAp63 and tumor immune infiltrates . An aggressive basal subtype of bladder cancer can be identified by the activation of TP63-driven genetic programs, which share the same molecular characteristics as squamous tumors occurring in other organs . The superenhancer-driven long noncoding RNA LINC01503, regulated by TP63, is overexpressed and oncogenic in squamous cell carcinoma .
LMO4 belongs to the LIM-only family of transcriptional coregulatory proteins and consists of two LIM protein-protein interaction domains that act as connexins in multiprotein complexes . Sequence analysis of the mouse LMO4 gene revealed that it spans approximately 18 kb and consists of at least six exons, including two alternatively spliced 5′ exons. SLK (Ste20-like kinase) is a kinase that plays a key role in cell migration and focal adhesion turnover . Mechanistically, SLK functions through complex phosphorylation regulation . LMO4 can directly bind to SLK in vivo and in vitro and activate its kinase activity . LMO4 can also interact with Ldb1 (LIM domain-binding protein) and play a role in cell proliferation and motility ; for example, LMO4 is overexpressed in samples of patient tissue and oral squamous cell carcinomas . Deletion of LMO4 impairs Ldb1 and SLK recruitment in migratory cells . LMO4 is closely related to the occurrence of many malignant tumors, such as pancreatic cancer, non-small cell lung cancer, and head and neck cancer [27, 28], and can affect the differentiation of T cells, leading to acute leukemia .
The above results demonstrate that the TP63 and LMO4 genes may change the internal composition of HIV-infected cells by mediating viral gene transcription and phosphorylation pathways. Moreover, HIV-encoded proteins may interact with the TP63 and LMO4 proteins and modulate their function in different ways. TP63 and LMO4 have been intensively studied as transcriptional targets in squamous cell carcinoma. They can regulate the expression of diverse tumor-related proteins and are involved in extracellular matrix and tumor microenvironment remodeling as well as in growth factor-mediated signal transduction [30, 31, 32]. Pathological specimens of HIV-related penile squamous cell carcinoma are very rare, so our sample size is relatively small, but the results obtained still have certain reference value. First of all, the heterogeneity between the included cases was very low, including the pathological types and stages of penile squamous cell carcinoma in the experimental group and the control group, as well as the surgical and chemoradiotherapy methods adopted. Secondly, we carried out quality control of RNA and raw data, and found that the differentially expressed genes were significant (absolute value of logFc > 1.0 and p value < 0.05 FDR < 0.05). Our small sample size made it difficult to compare the genomic locations of TP63 and LMO4 mutations, and whether these differences in presentation and prognosis are related to the systemic effects of HIV-mediated immunosuppression or to specific biological characteristics of the primary tumor is still unclear. Additional studies with larger sample sizes are needed to validate our experimental results. Genetic studies on NADCs provide another possibility and opportunity to explore the relationship between HIV and tumors in regards to biological processes and molecular pathways. Whether the inhibition of related pathways or genes can induce immune reconstruction to combat early penile cancer and prevent the occurrence of NADCs is worthy of further study.
Among the KEGG pathways, two terms linked to the regulation of cell proliferation and survival, including DNA replication and cell adhesion molecule metabolism, were identified. This suggests that HIV integration may promote the proliferation and persistence of infected cells. Although HIV has not been shown to directly cause carcinogenic transformation, the incidence of cancer in HIVIIs is higher than that in patients without HIV. HIV can persist and permanently insert itself into selected chromosomal locations within infected cells; it can also reverse transcribe its genome, like all retroviruses. Once HIV successfully integrates into a chromosomal site, all subsequent cells generated by cell division contain the same viral integration site . Approximately 80% of the integration sites have viral integration within gene transcripts, and approximately 12.5% of these genes are related to cancer development. It is unclear whether a link exists between the HIV site selection and potential oncogenic development, but Wagner TA et al. found that HIV preferentially integrates into cancer-related genes and other genes that promote cell proliferation . There is also the idea that HIV DNA is undetectable in the cancer cells of most HIVIIs; however, experiments supporting this idea are not well documented in the literature, and many HIV proviruses may have been missed by testing only a small fraction of the HIV genome .
After HIV infection, the virus can have a synergistic effect on tumorigenesis, and HIV-1 (human immunodeficiency virus type 1) is among the most common synergistic oncogenes . HIV-1 is a terrible pathogen that can cause persistent infections and evolve rapidly by integrating the original viral genome into chronically infected cells . During viral replication, HIV-1 can mutate and recombine at a high frequency, promoting viral persistence and regulating HIV replication while usurping the cellular mechanisms of HIV replication during gene expression . Further research on HIV-1 replication may help to identify new targets for antiretroviral therapy that will enable continued viral inhibition in patients with treatment failure . The TAT (transactivator of transcription) proteins produced by the HIV-1 gene, regardless of their immune status, are widely associated with the increases in angiogenesis and other functions in ADCs and have become the research target for a treatment strategy. G Saraga et al prepared HIV-1 moderators, which have potential as mediators and have been used in clinical gene therapies for pancreatic cancer . HIV-based lentiviral vectors and many other gene delivery strategies have been used to evaluate cell culture, small and large animal models, and HIV treatment methods in patients .
Genome-wide techniques have been used in the field of HIV research to achieve the goal of understanding the complex interactions between host and pathogen . The expression and transcription of HIV-1 gene is a key step in the viral replication cycle and is considered as a potential target for inhibition of HIV-1 . Liang Shan et al. found that in the analysis of the regulation of HIV-1 gene expression, it was important to consider the nature of HIV-1 integration sites. Reactivation of latent HIV-1 might be a strategy to eliminate the HIV-1 latent reservoir in resting memory CD4(+) T cells. By compared viral integration sites and the levels of expression of the host gene, they had identified new features of the integration sites of latent HIV-1, which might provide a better understanding of the mechanism of HIV-1 latency .
In recent years, the use of transgenic T cells to treat previously incurable diseases such as cancer has multiplied. This success is now driving the use of the same technology to treat HIV infection [45, 46]. While antiretroviral combination therapy can significantly reduce the circulating viral loads in HIV-infected patients, highly replicable viruses remain. Thor A Wagner et al noted that mechanisms allowing the persistence of HIV include long-term latent infection of cells, low levels of HIV replication, and proliferation of HIV-infected cells. Integrating HIV into specific genes may promote the proliferation of HIV-infected cells and slow the decay of the virus in antiretroviral therapeutic processes . Of all the methods currently being studied to treat HIV, the effectiveness of gene therapy is supported by most data. Gene therapy has the advantages of specificity and persistence and has the potential to protect patients from subsequent infections. A patient in Berlin that was positive for both HIV and AML (acute myeloid leukemia) received two stem cell transplants from a donor homozygous for a CCR5delta32 mutation. Eight years after his second transplant, he still had no HIV or AML infection. This case provides a strong proof-of-principle that a cure for HIV is possible and can be achieved through gene therapy . Some articles have pointed out that in genome-wide studies, HIV integration is beneficial for the transcription sites of active genes and for the establishment of HIV replication and latency [49, 35], thus promoting pathways related to tumorigenesis . Understanding the relationship between HIV and tumors may provide a method for reducing the risk of HIV tumors or even a genetic pathway for treating HIV. As the principle suggests, gene therapy can cure HIV, and the improvement of current methods may lead to the optimization of transduction efficiency and persistence in vivo. Gene therapy strategies are linked to human pathology at a fundamental level to correct and improve the underlying genetic factors of any disease by delivering DNA and RNA molecules. The history of HIV gene therapy is particularly interesting, as targeted viruses are quickly chosen together as part of targeted strategies. It is generally accepted that the combination approach is the most promising for the functional treatment of HIV infection.