HIV-induced Disease Research Articles

Prevalence of metabolic dysfunction-associated steatotic liver disease in people living with HIV and on antiretroviral treatment: A systematic review and meta-analysis protocol.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common hepatic condition globally. The prevalence of MASLD continues to increase, paralleling the consistent rising rates of risk factors such as obesity and type 2 diabetes. Literature suggests that human immunodeficiency virus-infected (HIV-infected) individuals may have an increased risk of developing MASLD due to a complex interplay of factors including antiretroviral therapy. Since the development and widespread use of effective antiretroviral therapy (ART), HIV-induced liver disease has continued to be the predominant cause of liver-related morbidity and mortality. This protocol serves to narrate the methods that will be employed in conducting the published literature search for the systematic review and meta-analysis which will report on the global prevalence of MASLD on people living with HIV and on ARV treatment. The search of literature will be done using search engines or electronic databases including PubMed, Google Scholar, African Journal Online, and ResearchGate. Specific keywords will be used to search literature that has reported on the prevalence of MASLD among HIV patients receiving antiretroviral treatment, this will ensure the reproducibility of the study. Cross-sectional and longitudinal observational studies, retrospective cohort studies, clinical trial studies, meta-analyses, and systematic reviews that were published in the English language from 1990 to 2024 will be included. Animal studies will be excluded. Three independent reviewers will conduct the selection process and select studies that meet the eligibility criteria. A quality assessment tool, Downs and Blacks will be used to assess the risk of bias of the selected studies. A review manager will be used for meta-analysis of collected data and the Grading of Recommendations Assessment, Development, and Evaluation tool will assess the strength of evidence. The review will not require ethical clearance as it will only include data that is publicly available in published reports. The results of this review will be disseminated through publications. This study is registered with PROSPERO (CRD42024516814).

Cytomegalovirus colitis unmasking human immunodeficiency virus infection as a cause of IgA vasculitis

BackgroundHuman immunodeficiency virus (HIV) has a protean clinical picture, in rare instances manifesting as systemic autoimmune disorders such as vasculitides. HIV-induced autoimmune diseases often do not respond well to systemic immunosuppressive therapy. Opportunistic infections may occur in patients with either acquired immunodeficiency syndrome (AIDS) or heavy immunosuppressive treatment, and can further complicate the clinical presentation.Case presentationA patient presenting with immunoglobulin A (IgA) vasculitis (IgAV) with treatment-refractory purpuric skin rash and suspect intestinal vasculitis was discovered to have AIDS. HIV was the trigger of IgAV, and cytomegalovirus (CMV) colitis mimicked intestinal vasculitis. Antiretroviral treatment improved both CMV colitis and the control of the autoimmune disease.ConclusionsAn autoimmune disease relapsing despite adequate immunosuppressive treatment and/or the presence of recurrent severe opportunistic infections may be clues to an underlying HIV infection.

Role of SIRT1 in HIV-associated kidney disease.

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

HIV-induced diseases in adults

Now, when the coronavirus pandemic has swept the whole world, few people recall that AIDS was called the plague of XX century. Manifestations of acquired immunodeficiency syndrome are the terminal stage of infection of the body with the human immunodeficiency virus, which belongs to retroviruses and leads to the development of secondary immunodeficiency. The first case of HIV infection in an adult was described in 1981 in America. A young homosexual sought help for a fungal infection resistant to treatment in one of the hospitals of San Francisco. Some time after the treatment, pneumonia developed in the young man, from the complications of which he soon died. Human immunodeficiency virus got its name only in 1982, and the disease caused by it began to be called acquired immunodeficiency syndrome. Today there are more than 40 million infected people in the world, 2/3 of whom live in Africa. Nearly 100 million people have been infected with HIV since the beginning of the epidemic, and the number of victims is twice as much as the number of people killed in the World War I. Despite the fact that this infection is not transmitted by airborne droplets, in the household and via contact, the growth rate of this disease continues to shock. So, every day about 5 thousand people in the world become infected with HIV, about 1 million die every year from the complications of this disease. It should be noted that only 71% of infected people know about their status, while all the rest continue to be a potential source of the spread of this terrible infection.

Pathogenic Role of Type I Interferons in HIV-Induced Immune Impairments in Humanized Mice.

Recent findings on the critical pathogenic role of type 1 interferons (IFN-I) in HIV-1 persistence in humanized mice suggest that inhibiting IFN-I signaling transiently will reverse HIV-induced inflammatory diseases and rescue anti-HIV immunity to control HIV-1 reservoirs. In both humanized mice and in monkeys, IFN-I signaling is functionally defined to play an important role in suppressing early HIV-1 and SIV infection. During persistent infection in humanized mice, however, IFN-I signaling is revealed to induce T cell depletion and impairment. Interestingly, in HIV-infected mice with effective combination antiretroviral therapy (cART), blocking IFN-I signaling reverses HIV-induced inflammation, rescues anti-HIV T cells, and reduces HIV-1 reservoirs. These findings functionally define the role of IFN-I in HIV-1 reservoir persistence and suggest that blocking IFN-I signaling will provide a novel therapeutic strategy to (i) reverse inflammation-associated diseases in HIV patients under cART, (ii) rescue host anti-HIV immunity, and (iii) reduce or control HIV-1 reservoirs.

Abstract 17112: Transgenic Endothelial-Specific HIV-Nef Expression Induces Pulmonary Hypertension and Systemic Vascular Dysfunction, Which Can Be Reverted by Treatment With Statin

Introduction: HIV patients on ART perplexingly remain at higher risk for developing cardiovascular diseases including acute peripheral arterial disease and pulmonary hypertension. A likely culprit for observed vascular changes is HIV protein Nef, detected both intracellularly and extracellularly in the absence of HIV RNA or DNA. Nef is known to induce endothelial dysfunction through the activation of NADPH; statins are known to inhibit NADPH activation. Hypothesis: Nef expression in endothelial cells will trigger cardiopulmonary and vascular pathology; Nef effects will be reversed by statin. Methods: Endothelial-specific expression of HIV-Nef was achieved by mating the VE-Cadherin-Tet off mice with TRE-Nef mice. The resulting Nef+ double transgenics and their Nef- negative littermates were maintained without doxycycline to induce Nef expression. Changes in pulmonary acceleration and ejection times were analyzed by ultrasound (INVEVO2100). Additionally, we assessed the ability of bradykinin-preconstricted aortic rings to dilate in response to acetylcholine in NO-dependent manner. Results: Between week 10 and week 13 of age, Nef expressing mice displayed gradual reduction of PAT/PET ratio (down to the 75% of the original PAT/PET ratio at week 10), indicative of developing pulmonary hypertension (N=6). PAT/PET ratio in Nef-negative mice did not change significantly between week 10 and 13 of age. Importantly, statin treatment initiated at week 10 completely suppressed PAT/PET changes developing in Nef-expressing mice. Arterial rings from Nef expressing mice (n=4) showed significantly impaired dilatation in response to acetylcholine (10% relaxation in Nef+ mice vs 40% relaxation in Nef-negative littermates, p=0.03), indicative of changes in systemic circulation. This difference was significantly attenuated in Nef+ mice receiving statin treatment. Conclusions: Our data suggests that mice with endothelial expression of HIV-Nef display pathological changes in pulmonary and systemic circulation. Statin treatment significantly attenuates changes in parameters indicative of pulmonary and systemic hypertension, suggesting that statin will be beneficial for patients with HIV-induced cardiopulmonary and vascular diseases.

"APP"reciating the complexity of HIV-induced neurodegenerative diseases.

"APP"reciating the complexity of HIV-induced neurodegenerative diseases.

Applications of the FIV Model to Study HIV Pathogenesis.

Feline immunodeficiency virus (FIV) is a naturally-occurring retrovirus that infects domestic and non-domestic feline species, producing progressive immune depletion that results in an acquired immunodeficiency syndrome (AIDS). Much has been learned about FIV since it was first described in 1987, particularly in regard to its application as a model to study the closely related lentivirus, human immunodeficiency virus (HIV). In particular, FIV and HIV share remarkable structure and sequence organization, utilize parallel modes of receptor-mediated entry, and result in a similar spectrum of immunodeficiency-related diseases due to analogous modes of immune dysfunction. This review summarizes current knowledge of FIV infection kinetics and the mechanisms of immune dysfunction in relation to opportunistic disease, specifically in regard to studying HIV pathogenesis. Furthermore, we present data that highlight changes in the oral microbiota and oral immune system during FIV infection, and outline the potential for the feline model of oral AIDS manifestations to elucidate pathogenic mechanisms of HIV-induced oral disease. Finally, we discuss advances in molecular biology, vaccine development, neurologic dysfunction, and the ability to apply pharmacologic interventions and sophisticated imaging technologies to study experimental and naturally occurring FIV, which provide an excellent, but often overlooked, resource for advancing therapies and the management of HIV/AIDS.

The Impact of Antiretroviral Therapy on Lung Immunology.

Despite the introduction of antiretroviral therapy (ART), human immunodeficiency virus-1 (HIV) continues to cause a major impact worldwide. HIV-induced lung disease continues to represent a significant source of morbidity and mortality, although the spectrum of pulmonary diseases has changed. HIV significantly affects the lung, causing acute and chronic cellular changes in the alveolar space. The impact of ART on lung immunology still needs to be fully elucidated. Similar to the periphery, ART affects HIV viral load and reconstitutes CD4(+) T cells in the lung. ART has been associated with significant decreases in bronchoalveolar lavage lymphocytes and increases in B-cell numbers and functionality, resulting in improved immune responses to vaccinations. There are substantial clinical implications of these ART-induced alterations, including the emergence of immune reconstitution inflammatory syndrome and the increased incidences of noninfectious lung diseases, such as lung cancer and chronic obstructive lung disease. There continues to be many unanswered questions regarding the effects of ART on lung health and, in particular, the immune system. Growing knowledge in this area will hopefully diminish the incidence of these noninfectious lung diseases and further improve the health of individuals living with HIV.

HBV and HIV co-infection: Impact on liver pathobiology and therapeutic approaches.

The consequences of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infection on progression of severe liver diseases is a serious public health issue, worldwide. In the co-infection cases, about 90% of HIV-infected population is seropositive for HBV where approximately 5%-40% individuals are chronically infected. In HIV co-infected individuals, liver-related mortality is estimated over 17 times higher than those with HBV mono-infection. The spectrum of HIV-induced liver diseases includes hepatitis, steatohepatitis, endothelialitis, necrosis, granulomatosis, cirrhosis and carcinoma. Moreover, HIV co-infection significantly alters the natural history of hepatitis B, and therefore complicates the disease management. Though several studies have demonstrated impact of HIV proteins on hepatocyte biology, only a few data is available on interactions between HBV and HIV proteins. Thus, the clinical spectrum as well as the complexity of the co-infection offers challenging fronts to study the underlying molecular mechanisms, and to design effective therapeutic strategies.

Abstract 15570: A Novel Ex Vivo Test System to Assess Cardiovascular Toxicity of HIV-Nef in PBMC From HIV Positive Donors

Background: To address how cardiovascular disease is increased in HIV patients with and without therapy, we have tested the effects of HIV-infected T cell when in contact to human coronary endothelial cells (HCAEC). We found that these T cells could induce endothelial dysfunction and cell death at a much larger extent than free virus itself. We could identify HIV-Nef protein, a major pathogenic factor in HIV disease progression and HIV-induced end organ disease, as the mechanism for this finding. Because of our finding that HIV-Nef is transferred from T cells to HCAEC to induce cell death, we asked whether PBMC form HIV-infected patients can recapitulate these findings. Methods: PBMC were isolated from either healthy donors or from untreated HIV patients or from those on ART using standard Ficoll purification, and intracellular Nef was determined by flow cytometry and ELISA. PBMC were co-cultivated with HCAEC for 24 hours, washed off and HCAEC were analyzed for Nef by immunofluorescence microscopy representation and ELISA. Further, HCAEC were analyzed for apoptosis by TUNEL. Results: HIV-Nef protein was found in PBMC of untreated HIV-positive and surprisingly also in patients receiving virally suppressive anti-retroviral therapy (ART). Importantly, we could demonstrate in untreated HIV patients Nef protein transfer to HCAEC and increased induction of endothelial apoptosis (see figure, ** p<0.01). Currently, equivalent studies with PBMC from patients on ART are in progress. Conclusion: This study demonstrates that Nef-positive PBMC at least in untreated HIV patients can be transferred to HCAEC to cause endothelial cell apoptosis. This will be the basis for future studies analyzing the role of NADPH oxidases and reactive oxygen species in this toxic activity of Nef. Based on this assay system we can address the hypothesis that HIV-Nef plays a pivotal role in the development of cardiovascular diseases in HIV patients with or without ART.

Methamphetamine Increases Brain Viral Load and Activates Natural Killer Cells in Simian Immunodeficiency Virus-Infected Monkeys

Methamphetamine (Meth) abuse increases risky behaviors that contribute to the spread of HIV infection. In addition, because HIV and Meth independently affect physiological systems including the central nervous system, HIV-induced disease may be more severe in drug users. We investigated changes in blood and brain viral load as well as differences in immune cells in chronically simian immunodeficiency virus-infected rhesus macaques that were either administered Meth or used as controls. Although Meth administration did not alter levels of virus in the plasma, viral load in the brain was significantly increased in Meth-treated animals compared with control animals. Meth treatment also resulted in an activation of natural killer cells. Given the prevalence of Meth use in HIV-infected and HIV at-risk populations, these findings reveal the likely untoward effects of Meth abuse in such individuals.

A Decrease in the Cellular Phosphodiester to Phosphomonoester Lipid Ratio is Characteristic of HIV-1 Infection

The ability to detect HIV-1 in tissues that are not readily amenable to biopsy greatly limits the diagnosis and control of HIV infection, and ultimately, our ability to understand HIV-induced disease pathology. In view of this, we explored the utility of diagnostically measuring HIV-1 infection using (31)P nuclear magnetic resonance ((31)P-NMR). (31)P-NMR enables the correlation of infection to changes in the concentration of specific intracellular metabolites, macromolecules and of bioenergetic parameters that are key to mammalian cell physiology. Examples include primary components of biological membranes such as phosphomonoester (PME) and phosphodiester (PDE) lipids. Using (31)P-NMR we found that changes in the ratio of PDE/PME in human cell lines and primary isolates were significantly altered following HIV-1 infection. Our findings showed that the ratio of cellular PDE/PME uniformly decreased 2.00-2.26 fold in HIV-1 infected cells. Using the altered PDE/PME ratio as a selection criterion, we next assessed HIV-1 infection in lymphocytes isolated from both HIV-1 seropositive and non-infected human subjects. A decreased PDE/PME ratio was characteristic of HIV-1 infection in each instance. These results demonstrate that changes in cellular phospholipids induced during HIV-1 infection may be used to uncover basic mechanisms of HIV-1 pathology, and potentially, may be extrapolated to explore the application of NMR analysis as a technique for imaging infected organs and tissues in situ.

Small Ruminant Lentiviruses and Human Immunodeficiency Virus: Cousins that Take a Long View

Small ruminant lentiviruses (SRLV) and human immunodeficiency viruses (HIV) are related retroviruses that cause multisystem disease usually over a long period of time. The viruses show similarities and differences in biological and pathogenic features. The basic retroviral genomic organization is complicated by the presence of a variable number of accessory genes in both viruses, though the structure is more complex in HIV. Both are mucosal pathogens, and infect cells of the monocyte-macrophage lineage. The main difference in cell tropism is that, unlike HIV, SRLV do not infect lymphocytes. A major feature of both pathogens is restricted replication and virus latency, which are partly responsible for the establishment of chronic infection usually lasting for life. The pathologies observed are similar in the early stages of both infections, and possibly following highly active anti-retroviral therapy (HAART). While the pathogenesis of HIV-induced disease during symptomatic stages is mainly due to secondary infections and neoplastic conditions, the early and post-HAART stages are associated with chronic inflammatory changes that resemble those found in SRLV diseases which are thought to be mediated by anti-virus immune responses.

Natural Host Genetic Resistance to Lentiviral CNS Disease: A Neuroprotective MHC Class I Allele in SIV-Infected Macaques

Human immunodeficiency virus (HIV) infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS) have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS) disease using a well-characterized simian immunodeficiency (SIV)/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis) was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5). Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001). Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease.

Enhancement of HIV-specific cytotoxic T lymphocyte responses by zidovudine (AZT) treatment

Zidovudine or 3'-azido-2'-3'-dideoxy-thymidine (AZT) is an antiviral drug widely used to treat HIV-infected patients. Because cytotoxic T lymphocytes (CTL) are thought to contribute actively to resistance against HIV-induced disease, we studied sequentially 10 HIV-infected individuals under zidovudine treatment for a period of 6-12 months. For a given patient all lymphocyte suspensions corresponding to the complete zidovudine therapy period were tested on the same day and on the same target cells. Patients were selected for expression of HLA-A2 and/or HLA-A3 class I transplantation antigen. HLA-restricted cytotoxicity specific for env, gag and nef HIV proteins was quantified for each patient at 6 week intervals. The data clearly indicated that zidovudine has a beneficial effect on the CTL response during the first 6-12 weeks of treatment, inducing cytotoxicity levels up to 100-fold stronger than base line. This effect was usually short lived. However, patients who maintained strong levels of cytotoxicity had better clinical and survival outlook than patients who had lost all detectable cytotoxic lymphocytes. It is proposed that AZT, among other effects, delays the onset of disease in HIV-infected patients by contributing to the stimulation of the HIV-specific CTL response.

Elevated serum levels of IL-8 in patients with HIV infection.

Serum levels of IL-8 were determined in HIV-infected individuals and the results were compared with those for HIV- controls. The IL-8 levels were measured by an ELISA with a MoAb and a polyclonal antibody to recombinant IL-8. The means and 95% confidence intervals of IL-8 in sera of 36 HIV-infected individuals and 32 matched controls were 275 and 216-349 pg/ml, and 8 and 4-14 pg/ml, respectively, showing a 34-fold increase in IL-8 in the circulation of HIV-infected individuals. This increase does not appear to be related to the disease state, infection or systemic medical agents. This finding suggests the possible involvement of IL-8 in the pathogenesis of HIV-induced disease.

Increased Expression of Monocyte CD44v6 Correlates with the Development of Encephalitis in Rhesus Macaques Infected with Simian Immunodeficiency Virus

In people infected with human immunodeficiency virus type 1 (HIV-1), the accumulation of macrophages in the brain correlates with encephalitis and dementia. We hypothesized that a pattern of surface marker expression in blood monocytes may serve as a marker for central nervous system (CNS) disease. Using the simian immunodeficiency virus (SIV)-rhesus monkey model, we analyzed functionally relevant surface markers on monocytes and macrophages from the blood and brain in animals that did or did not develop SIV encephalitis. At necropsy, multiple markers (CD44v6, CCR2, and CCR5 on blood monocytes and brain microglia and/or macrophages, and CX3CR1 on blood monocytes) allowed us to distinguish animals with encephalitis from those without. Furthermore, the level of expression of CD44v6 on the 2 main populations of blood monocytes--those that express either low or high levels of CD16--was significantly increased in animals with encephalitis. A longitudinal analysis of blood monocyte markers revealed that as early as 28 days after inoculation, CD44v6 staining could distinguish the 2 groups. This provides a potential peripheral biomarker to identify individuals who may develop the HIV-induced CNS disease. Furthermore, given its role in cellular adhesion and as an osteopontin receptor, CD44v6 upregulation on monocytes offers functional clues to the pathogenesis of such complications, and provides a target for preventative and therapeutic measures.

Developing Neuroprotective Strategies for Treatment of HIV-Associated Neurocognitive Dysfunction

Important advances have been made in recent years in identifying the molecular mechanisms of HIV neuropathogenesis. Defining the pathways leading to HIV dementia has created an opportunity to therapeutically target many steps in the pathogenic process. HIV itself rarely infects neurons, but significant neuronal damage is caused both by viral proteins and by inflammatory mediators produced by the host in response to infection. Highly active antiretroviral therapy (HAART) does not target these mediators of neuronal damage, and the prevalence of HIV-associated neurocognitive dysfunction has actually been rising in the post-HAART era. This review will briefly summarize our current understanding of the mechanisms of HIV-induced neurological disease, and emphasize translation of this basic research into potential clinical applications.

Dementia and Neurocognitive Disorders Due to HIV-1 Infection

Human immunodeficiency virus-type 1 (HIV-l) infection is the most common preventable and treatable cause of neurocognitive impairment in individuals under age 50 years. Although the incidence of HIV-associated dementia has decreased over the past few years due to combination antiretroviral therapy (cART), the prevalence of less severe HIV-associated neurocognitive impairment continues to increase. HIV-associated neurocognitive impairment is a significant burden to persons living with HIV infection, caregivers, and the health care system. Neurocognitive changes associated with HIV are typically subcortical, consisting of the triad of cognitive, behavior, and motor dysfunction. HIV-associated dementia and HIV-associated neurocognitive impairment are clinical diagnostic syndromes with neuropsychological performance testing, neuroimaging, and cerebral spinal fluid studies providing additional information. With the advent of more effective cART, the incidence of fatal opportunistic complications has dramatically diminished. Accordingly, the present review focuses on primary HIV-induced disease of the central nervous system, rather than its opportunistic complications.