Pathogenesis Of HIV Infection Research Articles

Immunosenescence and its related comorbidities in older people living with HIV

Abstract With the aging of the global population, older people living with HIV (OPLWH) have emerged as a focal point in HIV/AIDS research. Although antiretroviral therapy has demonstrated positive effects in OPLWH, concerns persist regarding overall poor immune reconstitution and elevated rates of age-related comorbidities, such as cardiovascular disease, bone disease, and cognitive impairment. This review aims to elucidate the mechanisms underlying immunosenescence and the interaction of immunosenescence with HIV infection, further exploring its role in the pathogenesis of HIV infection during aging. Aging-induced involution of the immune system, along with chronic inflammation and infection, can induce immunosenescence, leading to immune dysfunction that impairs the effective control of HIV infection. In addition, HIV infection induces immunosenescence through persistent inflammation and immune activation, even under treatment. The combined effects of aging and HIV infection accelerate the progression of immunosenescence in OPLWH, increasing their susceptibility to multiple age-related diseases. The unfavorable prognosis observed among OPLWH is largely attributed to increased levels of immunosenescence. A comprehensive understanding of the relationship between immunosenescence and HIV infection is crucial for developing targeted therapeutic strategies for this vulnerable population.

ROS Chronicles in HIV Infection: Genesis of Oxidative Stress, Associated Pathologies, and Therapeutic Strategies.

Reactive oxygen species (ROS) are widely regarded as signaling molecules and play essential roles in various cellular processes, but when present in excess, they can lead to oxidative stress (OS). Growing evidence suggests that the OS plays a critical role in the pathogenesis of HIV infection and is associated with several comorbidities in HIV-infected individuals. ROS, generated both naturally during mitochondrial oxidative metabolism and as a response to various cellular processes, can trigger host antiviral responses but can also promote viral replication. While the multifaceted roles of ROS in HIV pathophysiology clearly need more investigation, this review paper unravels the mechanisms of OS generation in the context of HIV infections, offering insights into HIV viral protein-mediated and antiretroviral therapy-generated OS. Though the viral protein Tat is significantly attributed to the endogenous cellular increase in ROS post HIV infection, this paper sums up the contribution of other viral proteins in HIV-mediated elicitation of ROS. Given the investigations recognizing the significant role of ROS in the onset and progression of diverse pathologies, the paper also explores the critical function of ROS in the mediation of an of array of pathologies associated with HIV infection and retroviral therapy. HIV patients are observed with disruption to the antioxidant defense system, the antioxidant therapy is gaining focus as a potential therapeutic intervention and is well discussed. While ROS play a significant role in the HIV scenario, further exploratory studies are imperative to identifying alternative therapeutic strategies that could mitigate the toxicities and pathologies associated with ART-induced OS.

Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen.

The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.

Induction of the antiviral factors APOBEC3A and RSAD2 upon CCL2 neutralization in primary human macrophages involves NF-κB, JAK/STAT, and gp130 signaling.

The CCL2/CC chemokine receptor 2 axis plays key roles in the pathogenesis of HIV-1 infection. We previously reported that exposure of monocyte-derived macrophages to CCL2 neutralizing antibody (αCCL2 Ab) restricted HIV-1 replication at postentry steps of the viral life cycle. This effect was associated with induction of transcripts coding for innate antiviral proteins, including APOBEC3A and RSAD2. This study aimed at identifying the signaling pathways involved in induction of these factors by CCL2 blocking in monocyte-derived macrophages. Through a combination of pharmacologic inhibition, quantitative reverse transcription polymerase chain reaction, Western blotting, and confocal laser-scanning microscopy, we demonstrated that CCL2 neutralization activates the canonical NF-κB and JAK/STAT pathways, as assessed by time-dependent phosphorylation of IκB, STAT1, and STAT3 and p65 nuclear translocation. Furthermore, pharmacologic inhibition of IκB kinase and JAKs strongly reduced APOBEC3A and RSAD2 transcript accumulation elicited by αCCL2 Ab treatment. Interestingly, exposure of monocyte-derived macrophages to αCCL2 Ab resulted in induction of IL-6 family cytokines, and interference with glycoprotein 130, the common signal-transducing receptor subunit shared by these cytokines, inhibited APOBEC3A and RSAD2 upregulation triggered by CCL2 neutralization. These results provide novel insights into the signal transduction pathways underlying the activation of innate responses triggered by CCL2 neutralization in macrophages. Since this response was found to be associated with protective antiviral effects, the new findings may help design innovative therapeutic approaches targeting CCL2 to strengthen host innate immunity.

Rev Protein Diversity in HIV-1 Group M Clades.

The HIV-1 Rev protein expressed in the early stage of virus replication is involved in the nuclear export of some forms of virus RNA. Naturally occurring polymorphisms in the Rev protein could influence its activity. The association between the genetic features of different virus variants and HIV infection pathogenesis has been discussed for many years. In this study, Rev diversity among HIV-1 group M clades was analyzed to note the signatures that could influence Rev activity and, subsequently, clinical characteristics. From the Los Alamos HIV Sequence Database, 4962 Rev sequences were downloaded and 26 clades in HIV-1 group M were analyzed for amino acid changes, conservation in consensus sequences, and the presence of clade-specific amino acid substitutions (CSSs) and the Wu-Kabat protein variability coefficient (WK). Subtypes G, CRF 02_AG, B, and A1 showed the largest amino acid changes and diversity. The mean conservation of the Rev protein was 80.8%. In consensus sequences, signatures that could influence Rev activity were detected. In 15 out of 26 consensus sequences, an insertion associated with the reduced export activity of the Rev protein, 95QSQGTET96, was identified. A total of 32 CSSs were found in 16 clades, wherein A6 had the 41Q substitution in the functionally significant region of Rev. The high values of WK coefficient in sites 51 and 82, located on the Rev interaction surface, indicate the susceptibility of these positions to evolutionary replacements. Thus, the noted signatures require further investigation.

The ecto-enzyme CD38 modulates CD4T cell immunometabolic responses and participates in HIV pathogenesis.

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after T cell receptor (TCR)-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular nicotinamide adenine dinucleotide and nicotinamide mononucleotide concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the oxygen consumption rate/extracellular acidification rate ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ecto-CD38 catalytic activity in TM cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous proinflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morphofunctionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.

HIV-1-Host Interaction in Gut-Associated Lymphoid Tissue (GALT): Effects on Local Environment and Comorbidities.

HIV-1 replication in the gastrointestinal (GI) tract causes severe CD4+ T-cell depletion and disruption of the protective epithelial barrier in the intestinal mucosa, causing microbial translocation, the main driver of inflammation and immune activation, even in people living with HIV (PLWH) taking antiretroviral drug therapy. The higher levels of HIV DNA in the gut compared to the blood highlight the importance of the gut as a viral reservoir. CD4+ T-cell subsets in the gut differ in phenotypic characteristics and differentiation status from the ones in other tissues or in peripheral blood, and little is still known about the mechanisms by which the persistence of HIV is maintained at this anatomical site. This review aims to describe the interaction with key subsets of CD4+ T cells in the intestinal mucosa targeted by HIV-1 and the role of gut microbiome and its metabolites in HIV-associated systemic inflammation and immune activation that are crucial in the pathogenesis of HIV infection and related comorbidities.

Enzymes of purine metabolism — biomarkers for the diagnostics of tuberculous pleurisy in patients with HIV infection

The objective of the study was to evaluate the information content of determining the activity of adenosine deaminase and adenosine deaminase-2 in the diagnosis of tuberculous pleurisy in patients with HIV infection.Materials and methods. A total of 378 patients with pleural effusion were retrospectively examined. In 215 cases, tuberculous pleurisy was detected (TP); and 163 patients had non-tuberculous pleural effusion (non-TP). As much as 27 patients in the TP group were HIV co-infected (TP/HIV+), the remaining 188 patients were HIV — negative (TP/HIV–). In all the patients, the activity of total adenosine deaminase (ADA) and its isoenzymes (ADA-1 and ADA-2) in the pleural fluid was determined.Results and discussion. In the TP group, the activity of total ADA (95.5 [67.7; 115.4] versus 82.0 [59.6; 100.0] U/L, p=0.1), ADA-1 (14.2 [5.8; 20.5] versus 12.1 [6.1; 23.7] U/L, p=0.9) and ADA-2 (78,1 [38.1; 93.1] versus 62.4 [35.4; 82.2] U/L, p=0,1) did not depend on HIV status. The activity of these indicators was determined above the threshold level — total ADA in 96.3% and 95.2%, ADA-1 in 25.9% and 30.8% and ADA-2 in 92.6% and 83.3% of cases in the «TP/HIV+» and «TP/HIV–» groups, respectively. A negative correlation between ADA-1 activity and HIV viral load in the group of patients with tuberculous pleurisy and HIV infection (r=–0.45; p=0.008), as well as in the subgroup of TP/HIV+ patients who received (r=–0.9; p=0.008) and in those who didn’t receive ART (r=–0.47; p=0.04) was obtained. Our results show that a total ADA activity increase in the patients with tuberculous pleurisy, regardless of patients’ HIV status, occur due to ADA-2. Thus, the increase in activity of total ADA and ADA-2 in our study was caused by active tuberculosis, not by the presence or absence of HIV co-infection. Also, the ADA-2 activity in HIV-infected patients is likely consistent with ADA-2 important role in cellular immune responses.Conclusion. Our data indicate the participation of purine metabolism enzymes in the pathogenesis of HIV infection. At the same time, adenosine deaminase activity is not a specific biomarker of individual changes characteristic of HIV infection. The study results suggest that the total adenosine deaminase and adenosine deaminase-2 activity increase is a valuable and diagnostically significant marker of tuberculous pleurisy in HIV-infected patients. The value of adenosine deaminase and adenosine deaminase-2 activity remains high even in the patients having severe immunosuppression, which allows them to be actively used for rapid diagnostics and hence, early TB therapy initiation.

CLINICAL AND PATHOGENETIC FEATURES OF DAMAGE TO THE NERVOUS SYSTEM AT THE INITIAL CLINICAL STAGES OF HIV-INFECTION

The aim of the study – investigating the features of clinical symptoms in HIV-positive people in the early stages of the disease and their pathogenetic justification.
 The study used theoretical methods based on the analysis and synthesis of studying the information of the modern world from the PubMed and Scopus databases, clinical observations, as well as deductive-inductive methods.
 Conclusions. As a result of the war in Ukraine, the epidemiological control of infectious diseases on the territory of the country was violated. HIV-infection and the absence or atypicality of its clinical symptoms in infected patients deserve special attention, which is based on a detailed understanding of the pathological processes of neuroAIDS. Damage to astrocyte cells disrupts the connection of cells of the structural and functional complex of the brain with other cells and forms the fundamental basis for understanding clinical symptoms. Most often in the form of: neuropsychic, cognitive somatic and neurological disorders. The pathogenic effect of the virus contributes to spasm of cerebral microvessels, is the cause of local hypoxic lesions, microstrokes, and in late cases – lacunar cerebral infarcts. The active involvement of brain cells in the pathogenesis of HIV-infection has been confirmed by many studies. Along with standard diagnostic methods, it is advisable to use psychoneurological and cognitive tests and scales. 
 A number of shortcomings have been identified that can reduce the reliability of diagnostic studies when establishing a diagnosis. 
 Understanding the pathogenetic picture will allow choosing «indicators» for the general diagnostic scheme and increasing the probability of establishing the correct diagnosis, adjusting ART and predicting the further development of the disease.

Relationships between the factors of innate immune system and results of neurocognitive function parameters in the persons living with HIV infection: interim results of the study

HIV infection is closely associated with damage to the nervous system, even despite usage of antiretroviral therapy. Thus, the patients are at a high risk for neurological complications. Due to limited permeability of the blood-brain barrier, the opportunity of its damage, both directly by the proteins of HIV-infected cells and indirectly, by immune system, e.g., inducing the production of inflammatory mediators, the involvement of the central nervous system in pathogenesis of HIV infection seems to be only a matter of time. HIV-associated neurocognitive disorders (HAND) comprise a poly-etiological pathological condition associated with direct and indirect damage to neurons in HIV infection. The role of interaction between the innate immune system and nervous system mediators in viral infections suggests that the specific changes in content and ratios of pro- and anti-inflammatory cytokines that are among the most polypotent mediators of immune regulation can be detectable in the persons prone to the development of HAND in HIV infection. The purpose of the present study was to characterize the features of serum content and the relationship between the indexes of innate immunity factors with the results of neurocognitive testing in the persons living with HIV.
 123 persons were included in the study, of which 93 subjects live with HIV infection. They were divided into 3 groups according to the stages of HIV infection, according to the Russian Classification of HIV infection. 30 persons represented a group of healthy volunteers, comparable in age and gender with the members of main groups, and served as a control group. Determination of IL-1 and IL-10 contents in blood serum was carried out by solid-phase enzyme immunoassay. The level of CD4+T lymphocytes was determined by flow cytometry. Neurocognitive testing using Schulte tables, the Munsterberg test was conducted by a medical psychologist, according to generally accepted methods.
 A significant increase in the serum IL-10 content in subjects from the main groups was revealed as compared with the control group, as well as in group III compared with the values groups I and II. The levels of IL- 1, CD4+T lymphocytes were significantly lower in group III, compared with all other groups. The personal performance index determined by testing with Schulte tables was reduced in all groups, relative to the controls, with a significant predominance of the results in groups I and II over the results of the participants from group III. The scores in Munsterberg test were equally diminished in all the main groups compared to the control values. When assessing the Spearman coefficient, the presence of various correlation profiles was established, depending on the stage of the disease.

Evaluation of colonoscopy results in HIV infected cases

Objective: GI system plays an important role in the clinical symptoms and pathogenesis of HIV infection. Significant progress has been made towards understanding the role of the GI system in both the early and late stages of HIV infection. In this study, our aim is to evaluate the results of colonoscopy in HIV-infected patients followed up in our clinic. Material and Methods: HIV (+) cases followed in our clinic were included in our study. The computer records of the cases were retrospectively examined and the findings of the patients who underwent colonoscopy were recorded. Age, gender, CD4 values and colonoscopy results of these patients were recorded simultaneously. Results: A total of 27 HIV-infected patients who underwent colonoscopy were included in our study. The mean age of the cases was 41.2, and the rate of males was 92.6% (25/27). It was observed that the mean age of patients with colonoscopy findings was 41.8, and the mean age of those without colonoscopy findings was 41.1. It was determined that 44.4% (12/27) of our cases in total had colonoscopic findings. While normal colonoscopic findings were reported in 15 (55.6%) of patients, benign anorectal diseases (fissure, hemorrhoids) were found in 7 (25.9%) and polyps were found in 3 of them (11.1%). CMV colitis was diagnosed in 2 (7.4%) patients with pathological diagnosis. Conclusion: As a result, although the number of our cases is small, it is observed that approximately 55% of patients have normal colonoscopy findings, but those with perianal disease and polyps have a higher CD4 count than those with normal colonoscopy. It has been revealed that patients with CMV infection also have a CD4 count of <200. Studies with more patients in HIV-infected patients will contribute to the diagnosis, follow-up, and treatment preferences of the patients.

Evaluation of cytokine levels in response to mitogen among HIV-1-infected blood cells and their relationships to the number of T cells

BackgroundHuman immunodeficiency virus-1 (HIV-1) infection causes loss and anergy of CD4+ and CD8+ T cells, leading to opportunistic infections, including tuberculosis (TB). QuantiFERON®-TB (QFT) is used as a diagnostic tool to detect TB, but it exhibits limited accuracy among subjects with low CD4+ T cell numbers, including HIV-1-infected individuals. The present study aimed to determine the effect of HIV-1 infection and patients’ blood T cell numbers on cytokine production in response to mitogen (Mit) stimulation. MethodsThe number of CD4+ and CD8+ T cells in HIV-1-infected individuals was quantified. Levels of various cytokines in Mit-stimulated and un-stimulated (Nil) supernatants of QFT gold “in tube” were assessed using a MAGPIX System. The correlation between cytokine levels and CD4+/CD8+ T cell counts in response to Mit was analyzed. The cytokine levels were compared between HIV-1-infected and healthy subjects. ResultsHIV-1-infected individuals (110) and control subjects (27) were enrolled. Interferon (IFN)-γ, interleukin-1 receptor antagonist (IL-1RA), IL-6, IL-8, and regulated on activation, normal T cell expressed and secreted (RANTES) values in Mit-Nil tubes showed a significant correlation with CD4+ T cell counts, while IFN-γ, IL-6, and IFN-γ-induced protein 10 (IP-10) values in Mit-Nil tubes had significant correlation with CD8+ T cell counts. IL-1RA, IL-8, IP-10, platelet-derived growth factor (PDGF)-BB, and RANTES levels in Nil tubes were significantly higher in the HIV-1-infected group. IFN-γ, IL-2, IL-5, IL-6, IP-10, and macrophage inflammatory protein-1β values in Mit-Nil tubes were significantly higher, and PDGF-BB and RANTES levels were significantly lower in the HIV-1-infected group. ConclusionThe functions of HIV-1-infected T cells and uninfected T cells, such as spontaneous and responsive cytokine production in response to Mit, were different. Our findings may be useful for developing new clinical tools for patients with low T cell counts. Additionally, the study provides new insights into the pathogenesis of HIV-1 infection.

Dynamics of Plasmatic Levels of Pro- and Anti-Inflammatory Cytokines in HIV-Infected Individuals with M. tuberculosis Co-Infection.

Tuberculosis (TB) and HIV have profound effects on the immune system, which can lead to the activation of viral replication and negatively regulate the activation of T cells. Dysregulation in the production of cytokines necessary to fight HIV and M. tuberculosis may ultimately affect the results of the treatment and be important in the pathogenesis of HIV infection and TB. This work presents the results of a study of the expression of pro- and anti-inflammatory cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-1RA) in drug-naïve patients with dual infection of HIV/TB at the late stages of HIV-infection, with newly diagnosed HIV and TB, and previously untreated HIV in the process of receiving antiretroviral (ART) and TB treatment vs. a cohort of patients with HIV monoinfection and TB monoinfection. The study revealed that during a double HIV/TB infection, both Th1 and Th2 immune responses are suppressed, and a prolonged dysregulation of the immune response and an increased severity of the disease in pulmonary/extrapulmonary tuberculosis is observed in HIV/TB co-infection. Moreover, it was revealed that a double HIV/TB infection is characterized by delayed and incomplete recovery of immune activity. High levels of IL-6 were detected in patients with HIV/TB co-infection before initiation of dual therapy (2.1-fold increase vs. HIV), which persisted even after 6 months of treatment (8.96-fold increase vs. HIV), unlike other cytokines. The persistent enhanced expression of IL-6 in patients with dual HIV/TB co-infection allows the consideration of it as a potential marker of early detection of M. tuberculosis infection in HIV-infected individuals. The results of multivariate regression analysis showed a statistical trend towards an increase in the incidence of IRIS in patients with high IL-1Ra levels (in the range of 1550–2500 pg/mL): OR = 4.3 (95%CI 3.7–14.12, p = 0.53), which also allows IL-1Ra to be considered as a potential predictive biomarker of the development of TB-IRIS and treatment outcomes.

Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study.

Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.

Exploring the conformational dynamics and flexibility of intrinsically disordered HIV-1 Nef protein using molecular dynamic network approaches.

The online version contains supplementary material available at 10.1007/s13205-021-02698-8.

Новые аспекты этиологии и патогенеза ВИЧ-инфекции (обзор литературы)

The paper presents the review on current ideas about the etiology and pathogenesis of HIV infection. It highlights the issues of the immune response in this disease, as well as the problems of HIV resistance to modern drugs.

The Effect of Antiretroviral Therapy on IL-6, IL-1β, TNF-α, IFN-γ Levels and their Relationship with HIV-RNA and CD4+ T Cells in HIV Patients.

Serum cytokine levels over the course of HIV infection usually increase with immunosuppression and decrease after antiretroviral treatment (ART). The aim of the study is to compare cytokine levels between HIV-infected patients (HIP) and controls and investigate the relationship between CD4+T cell count, HIV-RNA levels, and cytokine levels. The study subjects comprised ART-naive HIP (n=30) with no comorbidities and age-and sex-matched healthy controls. We measured levels of IL-6, IL-1β, TNF-α, and IFN-γ in serum samples of HIP at the beginning and at month 6 of ART and in controls. The mean age of the study subjects was 38.7 ±10.3 years, with men making up 86.7% of the study subjects (n=26). IL-6, IL-1β, and TNF-α levels were significantly higher in both ART-naive (p<0.001, p=0.002, p=0.001) and ART-experienced HIP (p<0.001) than controls. The IFN-γ level was lower in both ART-naive and ART-experienced HIP compared to controls (p=0.082 and p=0.002). There was a positive correlation between the CD4+T cell count and serum concentration of IFN- γ(r=0.320, p<0.05). While the serum IFN-γ concentration showed a negative correlation with the HIVRNA level(r=-0.412, p<0.001), the serum IL-1β, IL-6, and TNF-α concentrations showed a positive correlation with the HIV-RNA level (r=0.349, p<0.001; r:0.54, p<0.001; r:0.438, p<0.00). Although serum concentrations of IL-6, IL-1β and TNF-α showed a significant decrease after ART, they were still significantly higher than the controls. IFN-γ responded differently to ART compared to the other cytokines, indicating that it may play a distinct and important role in the pathogenesis of HIV infection.

The Role of Immunomodulatory Receptors in the Pathogenesis of HIV Infection: A Therapeutic Opportunity for HIV Cure?

Immune activation is the hallmark of HIV infection and plays a role in the pathogenesis of the disease. In the context of suppressed HIV RNA replication by combination antiretroviral therapy (cART), there remains immune activation which is associated to the HIV reservoirs. Persistent virus contributes to a sustained inflammatory environment promoting accumulation of “activated/exhausted” T cells with diminished effector function. These T cells show increased expression of immunomodulatory receptors including Programmed cell death protein (PD1), Cytotoxic T Lymphocyte Associated Protein 4 (CTLA4), Lymphocyte activation gene 3 (LAG3), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin domain containing 3 (TIM3) among others. More importantly, recent reports had demonstrated that, HIV infected T cells express checkpoint receptors, contributing to their survival and promoting maintenance of the viral reservoir. Therapeutic strategies are focused on viral reservoir elimination and/or those to achieve sustained cART-free virologic remission. In this review, we will discuss the immunological basis and the latest advances of the use of checkpoint inhibitors to treat HIV infection.

Co-Pathogenesis of Human Herpesvirus with HIV In Africa

Human Herpesviruses (HHV’s) are ubiquitous in human populations globally, and they cause significant morbidity and mortality. HHV’s establish a latent infection that is accompanied by periodic virus reactivation as a result of HIV infections. Further, HIV/AIDS infection in sub-Saharan Africa is perceived to be a significant health concern as it accounts for up to 70% of infectious diseases in the region. Until now, the role played by HHVs is increasingly being recognized. The co-infection of HIV with HHV’s changes severity or the natural course of HIV infection which defines the AIDS conditions in HIV infected individuals. Presently, treatment of HIV/AIDS by antiviral drugs targets the clinical manifestations of both HIV and HHVs at their productive stage and boost the immunity of HIV infected individuals, but they are ineffective at eliminating these viruses (HHVs and HIV) from the infected persons. This review focuses on outlining the epidemiology, distribution and role played by HHV’s in the pathogenesis of HIV infection in African countries. Additionally, this information is significant in crystallizing and providing an update on recent advancements on HHV’s and HIV infections in Africa and possible future directions in this field of research.

РОЛЬ ОТДЕЛЬНЫХ СУБПОПУЛЯЦИЙ CD4+ Т-ЛИМФОЦИТОВ В ПАТОГЕНЕЗЕ ВИЧ-ИНФЕКЦИИ

CD4+ T-cell pool is composed of cells residing in different maturation stages. Naive CD4+ T-lymphocytes, CD4+ stem memory T-cells, CD4+ central and effector memory T-lymphocytes perform var-ious functions in maintaining the immune system homeostasis. Despite phenotypic differences, each of those cells can be infected with HIV. Specific features of distinct CD4+ T-lymphocyte subsets determine their role in HIV-infection pathogenesis. By analyzing changes of CD4+ T-lymphocyte subset composi-tion, one can estimate the degree of the immune system damage and make predictions of immune recov-ery under highly active antiretroviral therapy. The article summarizes the main events occurring with CD4+ T-cell subsets during HIV-infection.