Slit2-Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia.

The secretory protein Slit2 and its receptors Robo1 and Robo4 are considered to regulate mobility and permeability of endothelial cells and other cell types. However, the roles of Slit2 and its two receptors in endothelial inflammatory responses remain to be clarified. In this study, we show that, in primary HUVECs, Slit2 represses LPS-induced secretion of certain inflammatory cytokines/chemokines, cell adhesion molecule ICAM-1 upregulation, and monocyte adhesion. Slit2's anti-inflammatory effect is mediated by its dominant endothelial-specific receptor Robo4. However, the minor receptor Robo1 has proinflammatory properties and is downregulated by Slit2 via targeting of miR-218. Elucidation of molecular mechanism reveals that Slit2 represses inflammatory responses by inhibiting the Pyk2-NF-κB pathway downstream of LPS-TLR4. Further studies reveal that LPS enhances endothelial inflammation by downregulating the anti-inflammatory Slit2 and Robo4 in HUVECs in vitro, as well as in arterial endothelial cells and liver in vivo during endotoxemia. These results suggest that Slit2-Robo4 signaling is important in regulating LPS-induced endothelial inflammation, and LPS, in turn, enhances inflammation by interfering with the expression of the anti-inflammatory Slit2-Robo4 during the disease state. This implies that Slit2-Robo4 is a key regulator of endothelial inflammation, and its dysregulation during endotoxemia is a novel mechanism for LPS-induced vascular pathogenesis.

The adaptor protein SLP-76 regulates HIV-1 release and cell-to-cell transmission in T cells.

HIV-1 infection in T cells is regulated by TCR activation. However, the cellular proteins of the TCR pathway that regulate HIV-1 infection are poorly characterized. In this study, in HIV-1 infection, we observed a significant reduction of HIV-1 virus production in Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76)-deficient Jurkat T cells compared with wild-type and SLP-76-reconstituted Jurkat T cells. We further confirmed the role of SLP-76 in HIV-1 infection by small interfering RNA-mediated knockdown in MT4 cells and PBMCs. Structural-functional analysis revealed that the N-terminal domain of SLP-76 was important for regulating HIV-1 infection. Further mechanistic studies revealed that lack of SLP-76 impaired virus release, but did not affect viral entry, integration, and transcription. We also showed that SLP-76 plays a critical role in cell-to-cell transmission of HIV-1. Signaling studies revealed that SLP-76 associated with viral negative regulatory factor protein and multiple signaling molecules during HIV-1 infection. Furthermore, SLP-76 facilitated the association of negative regulatory factor and F-actin, suggesting that SLP-76 mediates the formation of a signaling complex that may regulate viral release via cytoskeletal changes. Taken together, our studies demonstrate a novel role for the adaptor molecule SLP-76 in regulating HIV-1 infection in T cells with the potential to develop innovative strategies against HIV-1.

Ocular Syphilis - Clinical Features and Outcome in HIV Positive and HIV Negative Patients from a Tertiary Eye Center from India - A Comparative Study.

PURPOSE: To study and compare the clinical characteristics and outcome of ocular syphilis between HIV positive and HIV negative patients. METHODS: Retrospective hospital-based case series from a tertiary eye care hospital in India. Patients with uveitis and positive syphilis serology were included. Demographics, clinical features, investigations, imaging and treatment modalities were noted. RESULTS: Hundred and five (105) eyes of 66 patients were analyzed. Males were predominantly affected (n = 57/66, 86.4%). Secondary syphilis was the most common stage of presentation (n = 48/66, 72.7%). Two groups were identified: HIV positive (HIVP) patients (n = 39/66, 59%) and HIV negative (HIVN) patients (n = 27/66, 41%). 12/39 (30.8%) patients were newly diagnosed with HIV at the time of ocular presentation. Panuveitis was the most common presenting feature in both groups (n = 66/105 eyes, 62.8%). Diffuse necrotizing retinitis was more common in HIV patients (HIVP - 15 Vs HIVN - 5 eyes). Ocular co-infections were more common in HIV patients, ocular tuberculosis, the commonest in both groups. Intravenous penicillin and titrated dose of systemic steroids were the mainstay of treatment. Improvement in mean logMAR was noted from 1.415 to 0.828 with p-value < 0.001. At final follow-up, 71.8% patients showed visual improvement. Complete resolution of ocular inflammation was noted in 95.5% patients. CONCLUSION: Ocular syphilis poses a diagnostic challenge considering the varied presentations and clinical course both in immunocompromised and immunocompetent groups. Clinical presentations are not always classical. High index of suspicion with supportive laboratory investigations and with characteristic OCT features helps diagnosis. All uveitis patients, especially with those suspected with infectious etiology, need to be tested for syphilis serology to prevent vision loss in this resurgent disease.

Depth, size of infiltrate, and the microbe - The trio that prognosticates the outcome of infective keratitis.

PURPOSE: To analyze the influence of infiltrate size, depth, and organism on the outcome of microbial keratitis. DESIGN: Retrospective comparative study. METHODS: Medical records of patients with infective keratitis, who reported from January 2015 to December 2019 to a tertiary eye care center, were analyzed. Size and depth of ulcer at presentation were the factors used to group patients, and the influence on the outcome of the organism causing it was analyzed. Grouping was as follows: group A: ulcer size <6 mm/anterior to midstromal infiltrate, group B: ulcer < 6 mm/full-thickness infiltrate, group C: ulcer >6 mm/anterior to midstromal infiltrate, group D: ulcer > 6 mm/full-thickness infiltrate. Patients with viral keratitis or unidentified organism were excluded. Response to treatment and best-corrected visual acuity (BCVA) at the final follow-up were the outcome measures. RESULTS: In the study, 1117/6276 patients were included, with 60.8% patients in group A. A significant improvement in visual acuity was noted in groups A/B compared to groups C/D. Group A had the best response to medical management, irrespective of the organism. Higher risk for surgery was noted in group C compared to group B, with group A as the reference. Overall resolution with medical treatment was noted in 70% miscellaneous keratitis, 64.8% bacterial keratitis, 64.3% mixed keratitis, 62.5% acanthamoeba keratitis, 52.6% fungal keratitis, and 12.1% Pythium keratitis. Bacteria and acanthamoeba responded better to medical management than fungal keratitis, whereas Pythium had the highest risk for surgery. CONCLUSION: An interplay between virulence of the organism along with depth and size of the infiltrate determines the outcome of microbial keratitis.

N-terminal Slit2 inhibits HIV-1 replication by regulating the actin cytoskeleton.

BACKGROUND: Slit2 is a ~ 200 kDa secreted glycoprotein that has been recently shown to regulate immune functions. However, not much is known about its role in HIV (human immunodeficiency virus)-1 pathogenesis. RESULTS: In the present study, we have shown that the N-terminal fragment of Slit2 (Slit2N) (~120 kDa) inhibits replication of both CXCR4 and CCR5-tropic HIV-1 viruses in T-cell lines and peripheral blood T-cells. Furthermore, we demonstrated inhibition of HIV-1 infection in resting CD4+ T-cells. In addition, we showed that Slit2N blocks cell-to-cell transmission of HIV-1. We have shown that Slit2N inhibits HIV-1 infection by blocking viral entry into T-cells. We also ruled out Slit2N-mediated inhibition of various other steps in the life cycle including binding, integration and viral transcription. Elucidation of the molecular mechanism revealed that Slit2N mediates its functional effects by binding to Robo1 receptor. Furthermore, we found that Slit2N inhibited Gp120-induced Robo1-actin association suggesting that Slit2N may inhibit cytoskeletal rearrangements facilitating HIV-1 entry. Studies into the mechanism of inhibition of HIV-1 revealed that Slit2N abrogated HIV-1 envelope-induced actin cytoskeletal dynamics in both T-cell lines and primary T-cells. We further showed that Slit2N specifically attenuated the HIV-1 envelope-induced signaling pathway consisting of Rac1, LIMK and cofilin that regulates actin polymerization. CONCLUSIONS: Taken together, our results show that Slit2N inhibits HIV-1 replication through novel mechanisms involving modulation of cytoskeletal dynamics. Our study, thus, provides insights into the role of Slit2N in HIV-1 infection and underscores its potential in limiting viral replication in T-cells.

Possible Synergistic Role of Cryo-Alcohol Therapy in Infectious Scleritis-Scope and Rationale for Expanding Indications and Review of the Literature.

PURPOSE: The purpose of this study was to highlight the use of topical ethanol as an adjunct to cryotherapy, termed cryo-alcohol therapy, in the management of fungal/acanthamoeba scleritis along with a review of the literature. METHOD: Retrospective interventional case reports of fungal and acanthamoeba scleritis along with a review of the literature. RESULTS: The patient with circumferential necrotic fungal scleritis resolved in 6 weeks achieving a best-corrected visual acuity (BCVA) of 20/20, and the patient with acanthamoeba scleritis is awaiting optical keratoplasty after complete resolution in 8 weeks. The literature review from January 1990 to December 2020 revealed BCVA >20/200 in 50% of the eyes with a mean time to resolution being 4.16 ± 2.13 months in fungal scleritis, with 27.02% and 75% of the eyes requiring evisceration in fungal and acanthamoeba scleritis, respectively. CONCLUSIONS: Cryotherapy is a useful adjunct in managing refractory infectious scleritis, and its efficacy can be enhanced by combining the use of topical ethanol to aid in faster recovery and reduce visual morbidity.

Bilateral Scleritis with Heterogeneous Etiologies: A Diagnostic Dilemma.

PURPOSE: To report a patient with bilateral scleritis who was initially treated for infectious scleritis, and subsequently diagnosed as granulomatosis with polyangiitis (GPA). METHOD: Retrospective chart review. RESULT: A 48-year-old female with a known history of diabetes presented with pain, redness, and blurring of vision in the right eye. She was diagnosed as scleritis with retinal detachment and underwent vitrectomy, with silicone oil tamponade and intravitreal injections of antibiotics, and antifungal agents. She presented with active scleritis with additional multiple pus points. Several scleral biopsies failed to yield any microorganism and finally, the painful blind eye was enucleated. The enucleated specimen grew gram-positive bacteria which were identified as Staphylococcus arlettae by polymerase chain reaction (PCR)-based sequencing of the 16S rRNA gene. Nine months after the onset of symptoms in the right eye, the patient developed necrotizing scleritis in the left eye. Laboratory investigation revealed a positive cytoplasmic- anti-neutrophil cytoplasmic autoantibody, which was previously negative during the right eye involvement. She was diagnosed with GPA by a rheumatologist and treated accordingly. CONCLUSION: Retinal detachment may be associated with scleritis, and ANCA testing may not detect GPA in its early stages. Once infection has been excluded, clinicians should not be afraid to use high-dose immunosuppression instead of surgery to treat retinal detachment associated with scleritis.

Draft Genome Sequence of Mycobacterium tuberculosis Strain SNMICRO 2047-20, Isolated from Intraocular Infection.

Here, we communicate the draft genome sequence of an ocular Mycobacterium tuberculosis strain (SNMICRO 2047-20) that was isolated from the vitreous fluid of a patient diagnosed with endophthalmitis. The genome sequence was 4,391,538 bp long with 3,898 protein-encoding genes and clustered to the East African-Indian lineage.

Correction: Activation of the Connective Tissue Growth Factor (CTGF)-Transforming Growth Factor ß 1 (TGF-ß 1) Axis in Hepatitis C Virus-Expressing Hepatocytes.

[This corrects the article DOI: 10.1371/journal.pone.0046526.].

Utility of Treponemal Testing from Aqueous Fluid in the Diagnosis of Ocular Syphilis in Patients with HIV/AIDS.

PURPOSE: Ocular syphilis is re-emerging globally especially in patients with human immunodeficiency virus (HIV). Atypical manifestations of ocular syphilis and/or other associated opportunistic infections often lead to a diagnostic dilemma. We evaluated the utility of aqueous humor (AH) Treponema pallidum hemagglutination assay (TPHA) titers in the diagnosis of ocular syphilis. METHODS: Retrospective case series of five HIV positive patients with positive syphilis serology in whom AH sampling was performed. All patients had ocular manifestations suspicious of infectious etiology. RESULTS: Panuveitis with/without retinitis was the commonest presentation. Along with blood investigations, polymerase chain reaction (PCR) testing from AH was done for Mycobacterium tuberculosis (MTB), Herpes Simplex Virus (HSV), Varicella Zoster Virus (VZV), Cytomegalovirus (CMV), and Toxoplasma gondii. In addition, serum antibody titers for Toxoplasma, rapid plasma reagin (RPR) and TPHA tests for syphilis were done. In patients with raised serum RPR/TPHA, aqueous TPHA titers were also assessed. Mean serum RPR titer was ≥ 1:32 and TPHA titer was ≥1:1280. Aqueous humor titers of TPHA was high in all patients (range ≥ 1:320 to ≥1:5120). Aqueous PCR was negative for all other infectious etiologies in four patients. In one patient, PCR-CMV was also positive, suggestive of a dual infection. Post-treatment with highly active antiretroviral therapy (HAART) and appropriate anti-syphilitic regime, complete resolution of lesions with corresponding fall in the serum RPR/TPHA titers were noted in all patients. CONCLUSIONS: Ocular syphilis with atypical presentations is usually diagnosed based on a positive syphilis serology and by excluding other infectious causes. In the present study, we have shown an excellent correlation between raised AH TPHA titers with serological values and the clinical presentation. Considering the ease of collection of AH in contrast to vitreous fluids, the AH-TPHA assay could potentially be a valuable tool in the diagnosis of ocular syphilis.

Coexistence of Fungal Keratitis in Bilateral Sequential Microsporidial Keratitis - A Rare Case Presentation.

AIM: To report a case of bilateral microsporidiosis with coexisting fungal infection in one eye. METHOD: Retrospective interventional case report. RESULTS: A 61-year-old man with uncontrolled diabetes presented with clinical and microbiological features of non-resolving fungal keratitis in the right eye since 3 months and underwent therapeutic penetrating keratoplasty (TPK) for the same. Fungal filaments along with oval bodies suspicious of microconidia were noted on calcofluor stain. A week following TPK, the patient presented with features of viral keratouveitis in the left eye which on microbiology was confirmed as microsporidiosis. Retrospectively, the right eye microbiology slides were reassessed, which confirmed the coexistence of fungus with microsporidiosis by acid-fast stain and polymerase chain reaction. CONCLUSION: Structural resemblance of microconidia with microsporidial spores can be misleading, thus creating a need for awareness regarding the possible coexistence along with a need to suspect microsporidiosis in nonresponding clinically resembling viral keratitis.

Microbiological profile of canaliculitis and their antibiotic susceptibility patterns: A 11-year review at a referral eye care centre.

PURPOSE: To analyze the microbiological profile and in vitro antibiotic susceptibility patterns of bacterial isolates in canaliculitis, an infection of the lacrimal drainage system of the eye. METHODS: The laboratory records of patients presenting with canaliculitis from whom specimens were obtained for microbiological investigations at our tertiary eye care centre in South India from January 2010 to December 2020, were reviewed. RESULTS: A total of 130 canalicular pus samples were collected from 112 patients and submitted for microbiological studies during the study period. A total of 183 micro-organisms were isolated from 115 culture-positive specimens. The micro-organisms isolated were predominantly aerobic Gram-positive bacteria (83.44%), with Coagulase-negative Staphylococci (CoNS/Other Staphylococcus spp) (31.69%), Corynebacterium spp (15.3%), Staphylococcus aureus (9.84%) and Viridans Streptococci (9.84%) accounting for a majority of the isolates. Actinomycesspp (6.56%) was the most common anaerobic bacterium isolated. Our study revealed several bacteria not previously associated with canaliculitis namely Ottowia spp, Elizabethkingiameningoseptica, Aeromonassalmonicida, Capnocytophagaochracea and Campylobacter gracilis. Polymicrobial aetiology was observed in 39.13% of culture-positive samples. Analysis of antibiotic susceptibility patterns of the isolates revealed a high proportion of Gram-positive bacteria susceptible to chloramphenicol (90.16%) compared to fluoroquinolones including ciprofloxacin (74.42%), norfloxacin (64.15%) and gatifloxacin (60.49%). CONCLUSION: This study represents the largest series of canaliculitis reporting the microbiological profile and antibiotic susceptibilities of the isolated micro-organisms, till date. Gram-positive bacteria accounted for a majority of isolates, predominated by Staphylococcus spp. The increasing resistance of Gram-positive bacteria to fluoroquinolones warrants antibiotic treatment in canaliculitis is based on in vitro antimicrobial susceptibility patterns.

Fungal Endophthalmitis: Analysis of 730 Consecutive Eyes from 7 Tertiary Eye Care Centers in India.

PURPOSE: To evaluate the clinical and microbiological features of a large cohort with culture-confirmed fungal endophthalmitis across India. DESIGN: Cross-sectional, hospital-based, retrospective medical record review. PARTICIPANTS: Seven large tertiary eye care centers from different regions of India. METHODS: Patient data were pooled from electronic or physical medical records of each participating center. Fellowship-trained vitreoretinal specialists clinically managed all patients, and in-house microbiology laboratories performed all microbiological workups. The clinical and microbiological procedures were broadly uniform across all participating centers. The essential treatment consisted of vitreous surgery as well as intravitreal and systemic therapies with antifungal agents. MAIN OUTCOME MEASURES: Clinical outcome of the causative event and causative fungus. RESULTS: In the period from 2005 to 2020, 7 centers treated 3830 cases of culture-proven endophthalmitis, and of these, 19.1% (n = 730) were cases of culture-confirmed fungal endophthalmitis. It included 46.9% cases of postoperative (87.4% postcataract surgery), 35.6% of traumatic, and 17.5% of endogenous endophthalmitis. The fungi included 39.0% of Aspergillus (high prevalence in central, east, and south zones), 15.1% of Candida (high prevalence in west zone), and 15.9% of Fusarium (high prevalence in north and west zones). The time to symptom development was between 1 week and 4 weeks in more than one third of the patients, except in patients with traumatic endophthalmitis. Less than half of the patients had hypopyon on presentation. The presenting visual acuity (PVA) in most patients was <20/400. Nearly all patients needed vitrectomy and an average of 2 intravitreal injections of antifungal agents. At least 10% of eyes needed therapeutic keratoplasty, and up to 7% of eyes were eviscerated. After treatment, the final (best corrected) visual acuity (FVA) was >20/400 in 30.5% (n = 222) of eyes and >20/40 in 7.9% (n = 58) of eyes, and 12% (n = 88) of eyes lost light perception. A post hoc analysis showed the male sex to be significantly more associated with traumatic endophthalmitis than with postoperative (P < 0.0001) and endogenous (P = 0.001) endophthalmitis, more isolation of Candida species in patients with endogenous endophthalmitis than in those with postoperative (P = 0.004) and traumatic (P < 0.0001) endophthalmitis, better PVA in eyes with Candida species infection (P < 0.0001), and poorer FVA in eyes with Aspergillus species infection. CONCLUSIONS: Fungal endophthalmitis is not uncommon in India. The inclusion of antifungal agents with antibiotics as the first empirical intravitreal therapy before microbiological confirmation should be considered when a fungal infection is suspected.

HIV-1 gp120-induced migration of dendritic cells is regulated by a novel kinase cascade involving Pyk2, p38 MAP kinase, and LSP1.

Targeting dendritic cell (DC) functions such as migration is a pivotal mechanism used by HIV-1 to disseminate within the host. The HIV-1 envelope protein is the most important of the virally encoded proteins that exploits the migratory capacity of DCs. In the present study, we elucidated the signaling machinery involved in migration of immature DCs (iDCs) in response to HIV-1 envelope protein. We observed that M-tropic HIV-1 glycoprotein 120 (gp120) induces phosphorylation of the nonreceptor tyrosine kinase, Pyk2. Inhibition of Pyk2 activity using a pharmacologic inhibitor, kinase-inactive Pyk2 mutant, and Pyk2-specific small interfering RNA blocked gp120-induced chemotaxis, confirming the role of Pyk2 in iDC migration. In addition, we also illustrated the importance of Pyk2 in iDC migration induced by virion-associated envelope protein, using aldithriol-2-inactivated M-tropic HIV-1 virus. Further analysis of the downstream signaling mechanisms involved in gp120-induced migration revealed that Pyk2 activates p38 mitogen-activated protein kinase, which in turn activates the F-actin-binding protein, leukocyte-specific protein 1, and enhances its association with actin. Taken together, our studies provide an insight into a novel gp120-mediated pathway that regulates DC chemotaxis and contributes to the dissemination of HIV-1 within an infected person.

Distribution and risk factors of postoperative endophthalmitis in people with diabetes.

PURPOSE: To evaluate (i) the distribution of postoperative endophthalmitis (POE) in patients who underwent cataract surgery, (ii) risk factors in diabetic versus nondiabetic patients, and (iii) distribution of POE in those who had undergone rapid reduction of preoperative blood sugar levels versus those with normal blood sugar levels. METHODS: Medical records were reviewed from January 1995 to July 2021. In total, 391 eyes of 391 patients who developed POE after cataract surgery were studied. Patients with POE were divided into Group A, patients with diabetes (n = 128), and Group B, patients without diabetes (n = 263), and the associations of various clinical factors in the two groups were studied. Patients with diabetes with raised random blood sugars (RBS) preoperatively were subjected to a rapid reduction of blood sugar (RBS <200 mg%) to be considered eligible for surgery. Microbiological profile of patients was examined. RESULTS: The cumulative incidence of POE over 26 years was 0.09%. Those who underwent a rapid reduction in preoperative blood sugar levels had higher rates of POE (53.1%) compared with (46.9%) those with blood sugar levels under control (P = 0.486). Men with diabetes had 1.634 times higher odds of POE (P = 0.048), and those with diabetes and hypertension had 3.961 times greater odds of having POE (P < 0.001) when adjusted for age, alcohol, smoking, and socioeconomic strata and presence of posterior capsule rupture. Positive culture results were observed in 45/128 (35%) patients with diabetes and 71/263 (27%) patients without diabetes. Staphylococcus epidermidis was the most commonly identified organism and was detected in 10/45 (22%) in those with diabetes and 21/71 (29%) in those without diabetes of all the culture-positive cases. CONCLUSION: In patients with POE, the odds are greater for men with diabetes, those with a history of hypertension, as well as those who undergo a rapid reduction of preoperative blood sugar.

LPS-induced MCP-1 expression in human microvascular endothelial cells is mediated by the tyrosine kinase, Pyk2 via the p38 MAPK/NF-kappaB-dependent pathway.

Bacterial endotoxin (lipopolysaccharide or LPS) has potent pro-inflammatory properties and acts on many cell types including endothelial cells. Secretion of the CC chemokine, MCP-1 (CCL2) by LPS-activated endothelial cells contributes substantially to the pathogenesis of sepsis. However, the mechanism involved in LPS-induced MCP-1 production in endothelial cells is not well understood. Using human microvascular endothelial cells (HMVEC), we analyzed the involvement of the non-receptor tyrosine kinase, Pyk2, in LPS-mediated MCP-1 production. There was a marked activation of the non-receptor tyrosine kinase, Pyk2, in response to LPS. Inhibition of Pyk2 activity using a pharmacological inhibitor, Tyrphostin A9 significantly attenuated LPS-induced Pyk2 tyrosine phosphorylation, p38 MAP kinase (MAPK) activation, NF-kappaB activation, and MCP-1 expression. Furthermore, specific inactivation of Pyk2 activity by transducing microvascular endothelial cells with catalytically inactive Pyk2 mutant (AAV-Pyk2MT) or Pyk2-specific siRNA significantly blocked LPS-induced MCP-1 production. The supernatants of these LPS-stimulated cells with attenuated Pyk2 activity demonstrated decreased trans-endothelial monocyte migration in comparison to LPS-treated controls, thus confirming the inhibition of functional MCP-1 production. In summary, our data suggest a critical role for the Pyk2 mediated pathway involving p38 MAP kinase and NF-kappaB in LPS-induced MCP-1 production in human microvascular endothelial cells.

Intravitreal piperacillin-tazobactam in endophthalmitis caused by Mycobacterium abscessus in silico ne-filled eye: A case report.

A 28-year-old female came to us one month after retinal detachment surgery with a sudden painless drop in vision. The condition gradually worsened with ongoing treatment so she was taken up for lensectomy with silicone oil removal and intravitreal antibiotics and steroids. The microbiological analysis of silicone oil revealed Mycobacterium complex and gene sequencing isolated Mycobacterium abscessus, which showed antibiotic sensitivity to only piperacillin-tazobactam. Repeated intravitreal injections of the same led to the resolution of infection. This case report highlights the impact of sparsely used piperacillin-tazobactam in cases of Mycobacterium positive endophthalmitis, and the role of gene sequencing.

HIV Proteins and Endothelial Dysfunction: Implications in Cardiovascular Disease.

With the success of antiretroviral therapy (ART), a dramatic decrease in viral burden and opportunistic infections and an increase in life expectancy has been observed in human immunodeficiency virus (HIV) infected individuals. However, it is now clear that HIV- infected individuals have enhanced susceptibility to non-AIDS (Acquired immunodeficiency syndrome)-related complications such as cardiovascular disease (CVD). CVDs such as atherosclerosis have become a significant cause of morbidity and mortality in individuals with HIV infection. Though studies indicate that ART itself may increase the risk to develop CVD, recent studies suggest a more important role for HIV infection in contributing to CVD independently of the traditional risk factors. Endothelial dysfunction triggered by HIV infection has been identified as a critical link between infection, inflammation/immune activation, and atherosclerosis. Considering the inability of HIV to actively replicate in endothelial cells, endothelial dysfunction depends on both HIV-encoded proteins as well as inflammatory mediators released in the microenvironment by HIV-infected cells. Indeed, the HIV proteins, gp120 (envelope glycoprotein) and Tat (transactivator of transcription), are actively secreted into the endothelial cell micro-environment during HIV infection, while Nef can be actively transferred onto endothelial cells during HIV infection. These proteins can have significant direct effects on the endothelium. These include a range of responses that contribute to endothelial dysfunction, including enhanced adhesiveness, permeability, cell proliferation, apoptosis, oxidative stress as well as activation of cytokine secretion. This review summarizes the current understanding of the interactions of HIV, specifically its proteins with endothelial cells and its implications in cardiovascular disease. We analyze recent in vitro and in vivo studies examining endothelial dysfunction in response to HIV proteins. Furthermore, we discuss the multiple mechanisms by which these viral proteins damage the vascular endothelium in HIV patients. A better understanding of the molecular mechanisms of HIV protein associated endothelial dysfunction leading to cardiovascular disease is likely to be pivotal in devising new strategies to treat and prevent cardiovascular disease in HIV-infected patients.