3.2 Visual analysis of countries and institutions
The top ten nations and institutions contributed 5182 (97.39%) and 1974 (37.10%) articles, respectively (Table 1). The USA, Italy, England, Canada, and France rounded out the top five nations, contributing 4122 publications, accounting for 77.47%. The University of California, San Francisco, National Institute of Allergy and Infectious Diseases, Case Western Reserve University, Harvard University, and Johns Hopkins University were the top five institutions, with 1326 articles (24.92%). Figure 3 depicts a map of nations with 1601 nodes and 2849 links. The nodes of the USA, England, Canada, and other nations are colored purple, indicating their high centrality, and the map demonstrates the tight collaboration between these nations and other nations. Figure 4 has 938 nodes and 4620 connections, displaying that the National Cancer Institute works closely with other organizations.
Table 1
The top ten countries and institutions with the highest numbers of articles.
| Rank | Count | Country | Count | Institution |
| 1 | 2854 | USA | 364 | Univ Calif San Francisco |
| 2 | 363 | ITALY | 320 | NIAID |
| 3 | 335 | ENGLAND | 251 | Case Western Reserve Univ |
| 4 | 326 | CANADA | 206 | Harvard Univ |
| 5 | 244 | FRANCE | 185 | Johns Hopkins Univ |
| 6 | 236 | SPAIN | 184 | Emory Univ |
| 7 | 217 | PEOPLES R CHINA | 157 | Univ Penn |
| 8 | 207 | SOUTH AFRICA | 155 | Univ Washington |
| 9 | 205 | GERMANY | 152 | Univ Pittsburgh |
| 10 | 195 | SWEDEN | 152 | Univ Calif Los Angeles |
3.6 Visual analysis of keywords and clusters
The keywords highlight vital components of the research literature and summarize its main themes. Figure 8 shows a visual analysis of keywords with the top N set to 30. Figure 9 was created by clustering the keywords. The top 10 keywords with the highest frequency and centrality are listed in Table 4. Human immunodeficiency virus (frequency: 2451), immune activation (frequency: 2045), and antiretroviral therapy (frequency: 1343) were the top three terms that appeared most frequently. Immunodeficiency virus type 1 (centrality: 0.2), immune activation (centrality: 0.17), and infection (centrality: 0.16) were the top three keywords with the highest centrality.
The keyword map created by CiteSpace has 435 nodes and 3014 connections overall (Fig. 8). The parameter was then converted to clustering to produce 11 clusters, including those for tumor necrosis factor, infection, immune deficiency syndrome, factor alpha, neopterin, nf kappa b, viral burden, immunodeficiency virus type 1, prognostic marker, 3-dioxygenase, and risk (Fig. 9). The average contour value S and the clustering module value Q are crucial indicators to consider when assessing the significance and logic of the clustering effect. Q > 0.3 is typically thought to signify a significant cluster community structure. The clustering effect is improved by increasing the Q value. The clustering result is very trustworthy if S > 0.7. S > 0.7 and Q > 0.3 among all clusters in this map show that the clustering is effective.
Table 4
Top ten core referenced keywords related to immune activation.
| Rank | Frequency | Keywords | Centrality | Keywords |
| 1 | 2451 | human immunodeficiency virus | 0.2 | immunodeficiency virus type 1 |
| 2 | 2045 | immune activation | 0.17 | immune activation |
| 3 | 1343 | antiretroviral therapy | 0.16 | infection |
| 4 | 650 | Infection | 0.14 | factor alpha |
| 5 | 607 | Expression | 0.13 | hiv 1 infection |
| 6 | 588 | hiv infection | 0.13 | human immunodeficiency virus |
| 7 | 463 | Disease | 0.11 | immune deficiency syndrome |
| 8 | 444 | microbial translocation | 0.1 | beta 2 microglobulin |
| 9 | 422 | t cell | 0.07 | macrophage |
| 10 | 404 | Inflammation | 0.07 | central nervous system |
3.6.1 Risk
HIV-related chronic inflammation accelerates atherosclerosis and raises the risk of cardiovascular events by developing endothelial dysfunction and hypercoagulability (Arildsen et al. 2013; Hemkens et al. 2014; Martin-Iguacel et al. 2015; Reyskens et al. 2014). Freiberg et al. (2013) designed a cohort study of veterans to investigate the association between HIV infection and the risk of acute myocardial infarction (AMI). Compared to HIV-negative veterans, HIV-positive veterans were shown to have a higher risk of AMI. ART has been linked to an increased risk of AMI in an HIV-positive population, with a disproportionate risk of AMI among HIV-positive veterans with HIV-1 RNA levels < 500 copies/ml. The results may not have much meaning for women because the study's sample was primarily made up of men. According to a cross-sectional study, persons with HIV infection had twice as high risk of CVD when receiving ART than HIV-negative patients (Mathabire et al. 2018). Patients on protease inhibitors (PIs) are more likely to develop dyslipidemia (Fisher et al. 2011; Weber et al. 2013) and insulin resistance (Gibellini et al. 2012), which aid in the development of atherosclerotic plaques (Pinto et al. 2018). In Europe and North America, PIs are more often used than other antiretroviral medications, and the metabolic abnormalities in HIV-infected patients are of concern. The constituent drugs of antiretroviral regimens and their associated adverse cardiovascular effects require better understanding, with an emphasis on their multiple pharmacological interactions with other classes of drugs.
3.6.2 Viral burden
In acute HIV infection, Ndhlovu and colleagues (2015) discovered that immune activation appears soon after a detectable viral load, with CD8 + T cells activating and sharply increasing in number before the viral load reaches its peak. However, impaired long-term memory may lead to limited viral suppression owing to increased apoptosis and lack of CD127 expression, even though the majority of these early activated cells are HIV specific. Rapid induction of cytokines and chemokines, such as interferon alpha and interleukin-15, is associated with an increase in viral load during acute HIV infection (Stacey et al. 2009). Through the activation of additional effector mechanisms, the cascade of cytokine-induced reactions may aid in the regulation of viral replication. HIV nevertheless continues to exist in the body, and cytokine induction to suppress the virus only partially succeeds. Moreover, enhanced pathogenesis may be linked to the induction of cytokines and chemokines, with immune activation promoting HIV replication and potentially CD4 + T cell apoptosis. Viral load in HIV infection is a predictor of adverse disease progression. Early antiretroviral therapy reduces the latent viral reservoir size (Sáez-Cirión et al. 2013), safeguards innate and specific immunity from the damaging impacts of persistent immune activation, effectively controls viral load, and facilitates immune recovery.
3.6.3 Tumor necrosis factor-α
Tumor necrosis factor-α (TNF-α) is a crucial immune response and inflammatory mediator (Beutler et al. 1986). Even in those receiving ART who have undetectable viremia, patients with AIDS have higher levels of TNF-α than healthy people (Lu et al. 2019). TNF stimulation will facilitate the binding of the transcription factors p65/p50 NF-κB and AP-1 complexes to their respective transcription factor-binding sites found in the HIV-1 long terminal repeat (LTR) promoter in cells that are HIV-1-infected. HIV-1 production is stimulated in chronically infected T-cell lines and promonocytic cell lines by TNF-mediated nuclear translocation of nuclear factor kappa B (NF-κB) and LTR stimulation (Duh et al. 1989; Griffin et al. 1989; Okamoto et al. 1989; Osborn et al. 1989). Increased TNF expression in HIV-infected individuals may promote viral replication (Dezube et al. 1997), and impede CD4 + T cell-mediated immune control of chronic viral infection (Beyer et al. 2016). In HIV-infected individuals, a treatment strategy combining ART-assisted viral replication reduction and TNF inhibitors that have been widely used in inflammatory diseases may help to lessen immune activation (Pasquereau et al. 2017). Therefore, there is a need to develop more anti-TNF medications with low side effects to suppress inflammation and to observe the suppressive effect of a combination of ART and controlled TNF production on immune activation.
3.6.4 Neopterin
Neopterin, a GTP-derived substance, is created when the Th1-type cytokine interferon (IFN)-γ stimulates macrophages (Huber et al. 1984). Due to its elevated quantities in the blood and urine of HIV-infected people, neopterin is regarded as a reliable diagnostic of HIV-1 infection and a sign of immunological activation (Fuchs et al. 1984; Wachter et al. 1983). Neopterin concentrations in bodily fluids rise during viral infections before the development of clinical symptoms, and they seem to fluctuate in accordance with variations in viral load. The level of neopterin drops and then returns to normal as soon as the virus is eliminated (Wirleitner et al. 2005). Neopterin levels in the blood and urine of HIV-positive individuals are significantly connected with their prognosis. Neopterin and CD4 + T cell measurements are beneficial for evaluating prognosis and directing the use of combination medications (Melmed et al. 1989). Neotrophin is not a particular marker and is frequently used for blood and organ donor screening in addition to identifying pathogenic infections.
3.6.5 Nuclear factor kappa B
Nuclear factor kappa B is a family of transcription factors that selectively bind to B cell κ-light chain enhancers to regulate the expression of many genes and play an essential role in inflammation and immune responses. NF-κB attracts innate and adaptive immune cells to the infection site in response to foreign stimuli, which also causes inflammation (Wong et al. 2021). The long terminal repeat section of the HIV-1 viral genome is where transcription begins (Jeeninga et al. 2000). Viral proteins and host factors, such as NF-κB, activated in virally infected cells, regulate the LTR (Brass et al. 2008; Nabel et al. 1987; Siekevitz et al. 1987; Weissman et al. 1996). The two tandem NF-κB binding sites are some of the most conserved elements in the HIV-1 genome, and NF-κB is recognized to have regulatory activity in the LTR (Stroud et al. 2009). Canonical and noncanonical NF-κB signaling are the two NF-κB pathways. In canonical NF-κB (cNF-κB) signaling, when IκB kinase is phosphorylated, p65/p50 is released from the cytoplasm for nuclear translocation. It is then bound to the gene promoter for transcription through ubiquitination and proteasomal degradation of IκBα (Deng et al. 2018). As HIV is transcribed, IκBα degradation creates a series of cNF-κB signaling events that translocate p65/p50 to the nucleus and begin transcription (Wong and Jiang 2021). HIV latency is linked to low cNF-κB expression or impaired cNF-κB translocation to the nucleus (Jiang et al. 2015). Latent HIV is reactivated when IκB is pulled down, indicating that the pathway can be controlled to disrupt latency (Khan et al. 2019). Protein kinase C agonists (PKCa) control the expression of HIV by phosphorylating and deactivating IκB (Jiang and Dandekar 2015). However, the use of PKCa to disrupt latency is still plagued by toxicity issues and a lack of efficient and secure PKCa.
3.6.6 Prognostic marker
CCL2, also recognized as monocyte chemoattractant protein-1 (MCP-1), is a member of the C-C chemokine family and has a modest molecular weight. In memory CD4 + T cells and macrophages, the CCL2 receptor (CCR2) is highly expressed, and CCL2 attracts these target cells to areas of inflammation caused by tissue damage or infection (Ansari et al. 2011). With increased production and release during HIV infection, CCL2 facilitates viral infection of the target cells it recruits by being activated by viral proteins (Fantuzzi et al. 2001; Mengozzi et al. 1999). HIV-associated neurological disorders, such as HIV-associated dementia (Cinque et al. 1998; Zink et al. 2001), are linked to altered CCL2/CCR2 expression. A correlation between the CCR2 rs1799864_814 AG genotype and the chance of inadequate immunological reconstitution after undergoing ART was discovered by Yeregui et al. (2020) after analyzing circulating baseline and 48-week follow-up concentrations of MCP-1/CCL2. High linkage disequilibrium exists for CCR2 rs1799864, and numerous single nucleotide polymorphisms have been linked to the boost and promotion of histone markers.
The HIV coreceptor C-C chemokine receptor type 5 (CCR5) (Lusso 2015) offers novel approaches for the management and prevention of HIV infection and is viewed as a potential therapeutic target for a number of complex diseases (Fantuzzi et al. 2019). The CCR5 rs1800024 CT polymorphism is markedly correlated with immunological nonresponders that fail to normalize their CD4 + T cell counts even after the most effective treatment and complete suppression of viral replication (Yeregui 2020). It has also been shown that the CCR5Δ32 homozygous genotype is associated with inferior immune recovery. CD4 + cells count, anemia, CD4/CD8 ratio, etc., are also closely associated with HIV infection and are valuable in clinical studies as prognostic markers of clinical disease progression
3.6.7 Indoleamine 2,3-dioxygenase
It is thought that the intracellular enzyme indoleamine 2,3-dioxygenase (IDO), which catalyzes the conversion of tryptophan to tyrosine, has a tolerance-inducing effect on T cells that require tryptophan for proliferation. IDO enhances tryptophan catabolism and reduces the ability of T cells to resist different illnesses, including viral infection (Fuchs et al. 1991). Increased IDO expression will result in CD4 + T cells differentiating into T regulatory cells rather than CD4 + T helper cells, which will adversely affect T cells' ability to respond to HIV infection (Favre et al. 2010). IDO activity rises during HIV infection, and ART can lower it but not normalize it (Chen et al. 2014). IDO activity was linked to total HIV DNA instead of immune activation, according to Chen et al.'s (Chen et al. 2019) analysis of the connection between IDO activity and total HIV DNA in the peripheral blood of HIV-infected patients undergoing ART. However, due to the small sample size, more studies are required to increase the number of participants and improve the generalizability of the findings. According to the research above, it is reasonable to assume that a persistent HIV infection impacts IDO activity and that inhibition of the immune system by increasing IDO activity may also cause HIV storage to increase. Increasing attention is being paid to the prevention of HIV infection by reducing IDO activity. The role of IDO as an immunotherapy target in lowering the HIV reservoir requires more investigation. Some researchers (Favre 2010) hold the view that CD4 + T helper cell loss and an increase in IDO activity occur as a result of acute inflammation during HIV infection. Immunosuppression results from the differentiation of CD4 + T cells affected by IDO enhanced activity. More studies are still needed on the potential feedback loop between immune activation and IDO expression.
3.7 Keywords with the strongest citation bursts
Citations with rapid increases in keyword usage indicate a sudden surge in the short-term frequency of the words. By detecting and analyzing burst keywords, it is possible to predict future research trends and directions and gain insight into the research frontiers of a particular era and their development and history over time. Figure 10 displays the top 25 keywords with the highest number of citation bursts, with the red line representing the cycle of keyword bursts and the blue line representing the time interval. The keyword "inflammation," which surged in 2015, has the highest intensity and has remained so through 2022, indicating that it is one of the key mechanisms underlying HIV infection and that there is a great deal of interest in both its negative effects and the potential it presents for curing the infection. Recent years have seen many studies on the phrases “inflammation”, “risk”, “mortality”, "cardiovascular disease", "persistence", and "biomarker", which are regarded as the cutting edge of immune activation in HIV infection.
3.7.1 Inflammation
Due to multiple viral infections, some tissue cells become less sensitive to antiretroviral medications while receiving ART, which aids in HIV cell-to-cell transmission in high CD4 + T cell density areas. A decrease in cell-free viral infections and an increase in HIV cell-to-cell transmission are the effects of long-term antiretroviral therapy (Sigal et al. 2011). HIV can expand the viral reservoir in lymphoid tissues by causing T cells to express specific activation markers, which develops new targets for infection (Biancotto et al. 2008). Cell populations infected with HIV with replication ability are known as HIV viral reservoirs (Lau et al. 2021). Only a small portion of the population is replication-capable reservoirs, while the majority have an HIV infection with incomplete replication. Resting CD4 + T cells exhibit the accumulation of partial reverse transcripts, which activate defense mechanisms, cause apoptosis, and cause inflammation that can reawaken additional latently infected cells (Doitsh et al. 2010). This inflammatory response leads to the activation of more latently infected CD4 + T cells, triggering programmed cell death and releasing inflammatory signals to maintain inflammation, resulting in a vicious cycle.
In addition to the activation-induced cell death that results from persistent immune activation, the niche hypothesis for damaged lymphoid tissues (Zeng et al. 2012) is another crucial mechanism. HIV infection causes a chronic inflammatory response that increases collagen deposition in lymphoid tissues, disrupts the fibroblastic reticular cell network, and restricts the availability of interleukin-7, which leads to preferential depletion of naive T cells.
3.7.2 Mortality and biomarkers
Inflammation is a significant factor in higher mortality in HIV infection, as evidenced by the fact that inflammatory markers such as soluble tumor necrosis factor receptor 1, IDO, and fibrinogen predict mortality during HIV infection (Byakwaga et al. 2014; Hunt et al. 2016; Tien et al. 2010). It is believed that some inflammatory factors, including D-dimer, are linked to accelerated atherosclerosis, an increased risk of CVD, and an increased risk of death (Ford et al. 2010). Neurocognitive disorders, type 2 diabetes, and other conditions have also been linked to chronic immune activation and chronic inflammation. Indicators related to adaptive immunodeficiency, such as the CD4/CD8 ratio, CD4 + T-cell count, and T-cell activation, are still used to predict mortality, especially in areas with limited medical resources. In studies of HIV infection treated by a combination of interleukin-2 and ART (Group et al. 2009), CD4 + T-cell counts increased. However, the risk of morbidity and mortality was not significantly reduced compared with antiretroviral therapy alone, suggesting that some biomarkers may not be reliable.
Large extracellular vesicle (EV) miR-155 copies, according to a recent study, may serve as indicators of immune activation (Bazié et al. 2022). Since EVs mirror their secretory cells in terms of molecular composition, they can identify immune cells' functional status. miR-155 has pleiotropic effects on some immune cells. EVs loaded with miR-155 may aid in maintaining immune activation and inflammation, as shown by HIV-infected individuals receiving ART (Hsin et al. 2018). MiR-155 has a variety of effects on immune activation in HIV infection, but the quantitative link and the mechanism are not well known.
3.7.3 Cardiovascular disease
HIV infection causes chronic inflammation, which raises the levels of circulating pro-inflammatory cytokines and pro-fibrotic factors. This increases the risk of CVD by causing endothelial dysfunction, a hypercoagulable state, and myocardial fibrosis (Arildsen et al. 2013; Hemkens and Bucher 2014; Martin-Iguacel et al. 2015; Reyskens and Essop 2014; Thiara et al. 2015). There are two types of macrophages: M1 and M2. M1 macrophages secrete proinflammatory cytokines, whereas M2 macrophages are linked to the activation of the fibrotic pathway and can release profibrotic factors (Hulsmans et al. 2016; Wynn et al. 2010). Mast cell density is elevated in diseases associated with myocardial fibrotic processes (Engels et al. 1995), but the mechanism of mast cell involvement in myocardial fibrosis is not fully understood. Chyme and histamine, which are released by mast cells, play a role in the fibrotic process (Levick et al. 2011). Histamine promotes fibroblast growth (Jordana et al. 1988). Histamine H2 receptor inhibitors aid in lowering the production of cyclic adenosine monophosphate, which lowers oxygen consumption and safeguards cardiac function, improving ventricular remodeling (Kim et al. 2006). Chymase can modify fibrotic signaling pathways by boosting the levels of transforming growth factor-β and angiotensin II (Liu et al. 2017). Platelets and lymphocytes could also play a direct or indirect role in the progression of myocardial fibrosis. In HIV infection, activation of the renin-angiotensin aldosterone system, inflammatory, and profibrotic cytokines increases the profibrotic pathway with enhanced deposition of collagen I and III and inhibits collagen degradation, which promotes cardiac fibrosis (Teer et al. 2022). Myocardial fibrosis is closely linked to cardiovascular diseases such as heart failure and sudden cardiac death and is a major contributor to cardiac remodeling (Heusch et al. 2014). Currently, the gold standard techniques for the diagnosis of cardiac fibrosis are expensive and invasive, such as endomyocardial biopsy. Therefore, noninvasive, inexpensive, and specific screening techniques should receive attention in future studies.
3.7.4 Persistence
Effective antiretroviral therapy prevents new HIV replication cycles and HIV molecular evolution by suppressing ongoing HIV replication. The provirus-carrying cells, however, survive and create latent viral reservoirs, particularly in lymph nodes and lymphoid tissue of the intestine (Lau et al. 2021). Clonal expansion maintains the majority of the latent reservoir (Bui et al. 2017), which is a significant barrier to cure. When exposed to an antigen, naive CD4 + T cells become activated, develop into memory T cells, and multiply into numerous cells. When stimulated with a homologous antigen, HIV-infected memory CD4 + T cells undergo clonal expansion and can multiply into numerous infected cells (Yeh et al. 2021). Cytotoxic effects are removed through clearing, but many infected cells survive. Memory CD4 + T cells return to a transcriptionally inactive quiescent state, and HIV does not produce viral antigens, allowing it to evade immune clearance if the cognate antigen is removed. HIV may become active when T cells do, making infected cells susceptible to immunological destruction. The activation level has a gradient and is not entirely active (Yeh et al. 2021). As a result, HIV-infected cells continue to exist in a dormant state.
Therefore, the existence of a latent viral reservoir, where latently infected cells can multiply in the body without causing viral expression and evade immune clearance, is the main barrier to the treatment of HIV. The widely accepted "shock-and-kill" (Deeks 2012) strategy employs ART in conjunction with a viral transcriptional inducer to reverse the latent state and activate the infected cells so that the immune system can eliminate them. However, it is difficult to induce full activation of each T-cell with this option. A cure might not necessitate the activation of all latently infected cells, according to one study that gives hope for a cure for HIV infection (Hill et al. 2014). Better techniques are required to induce the majority of latently infected cells due to the low induction of latent provirus. PKC agonists have been identified as potential HIV activators by targeting NF-κB signaling to induce latent HIV expression in the viral reservoir. Non-cytotoxic medicines capable of altering HIV latency may be identified if PKC agonists are less toxic.