Untreated HIV Patients Research Articles

Immune checkpoints and pancreatic beta cell dysfunction in HIV.

We explored the impact of immune dysregulation on pancreatic beta cell injury in HIV patients. Analyzing 105 participant samples, we observed lower IL-21 levels and elevated immune checkpoint levels (e.g. PD-1, CD27+, CD40+) in untreated HIV patients. Notably, soluble TIM-3 correlated positively with improved beta cell function and inversely with beta cell stress, suggesting its potential role in beta cell protection in untreated HIV.

Brain-derived neurotrophic factor is associated with cardiometabolic risk factors in HIV patients on combination antiretroviral therapy in Ghana

BackgroundBrain-derived neurotrophic factor (BDNF) has been implicated in the development of cardiometabolic risk factors in some populations. However, few studies have investigated the role of BDNF and cardiometabolic risk factors in HIV patients despite the plethora of evidence linking HIV infection with the dysregulation of circulating BDNF levels. We investigated the association between serum BDNF and cardiometabolic risk factors in HIV patients in a primary hospital in Ghana. We recruited 450 participants, comprising 150 combination antiretroviral (cART)-treated HIV patients, 150 cART-naïve HIV patients, and 150 non-HIV controls. Data on sociodemographic parameters and medical history were collected using a structured questionnaire. Fasting venous blood samples were collected to measure plasma glucose levels, lipid profiles, and BDNF. Metabolic syndrome (MetS) was defined using the joint interim statement criteria.ResultsCompared to untreated HIV patients and uninfected controls, the proportion of participants having MetS was high in cART-exposed HIV patients (26.8% vs 21.1% vs 52.1%, respectively, p < 0.001). Generally, BDNF levels were higher in uninfected controls compared with untreated and cART-exposed HIV patients [7.1 (3.4–13.3) vs 4.9 (2.7–9.6) vs 5.6 (2.9–8.9) ng/ml, p = 0.025]. In participants without MetS, square root-transformed serum BDNF was lowest in cART-exposed HIV patients, followed by untreated HIV patients, with uninfected controls having the highest (1.8 ± 0.8 vs 2.4 ± 1.2 vs 2.9 ± 1.2 ng/ml, p < 0.001). MetS was associated with serum BDNF levels in only the cART-exposed HIV patients [OR (95% CI) = 2.98 (1.64–5.41), p < 0.001]. In cART-exposed HIV patients, an increase in BDNF was associated with increased likelihood of having impaired fasting glucose [2.49 (1.51–4.11), p < 0.001], high systolic blood pressure [1.64 (1.1–2.46), p = 0.016], and hypertriglyceridemia [2.73 (1.65–4.52), p < 0.001], as well as decreased likelihood of having low HDL cholesterol levels [0.32 (0.19–0.56), p < 0.001].ConclusionIn our study population, MetS was higher in cART-exposed HIV patients. HIV patients have low levels of serum BDNF, especially those without MetS. BDNF was associated with MetS and its components in HIV patients on cART management.

Risk assessment of first-line treatment failure in untreated HIV patients in Northwestern Federal District of the Russian Federation

The HIV infection epidemic in Russia continues to evolve, and HIV infection cases have been registered in all territorial entities of the Russian Federation. 2021 Treatment coverage was 82.2% and 56.4% individuals under dispensary observation and living with diagnosed HIV infection. 79.9% receiving ART subjects were shown to achieve undetectable viral load. Highly active antiretroviral therapy (HAART) currently represents a combination of three (less frequently four) antiretroviral drugs targeting pathways involved in various stages of HIV replication in vivo. Treatment failure is a problem facing doctors and patients using HAART. The most common cause of therapeutic failure is the development of HIV drug resistance. The emergence of resistance is associated with processes involving mutation occurring in the viral genome influenced by evolutionary factors. Therefore, it is important clinically and programmatically to learn more about the rate of first-line treatment failure, the rate of switching to a second-line ART regimen, and to identify patients at risk to develop strategies for preventing development of further failure cases. The study was aimed at analyzing ineffectiveness of first-line ART therapy in patients in Northwestern Federal District of the Russian Federation. Materials and methods. Sequencing reactions were performed using the AmpliSens HIV Resist-Seq. Assembly of consensus sequences from fragments obtained during sequencing was carried out using Unipro UGENE software. Isolate genotyping was performed using the MEGA-X software with the Neighbor-joining algorithm. Results. The HIV pol genes in 239 patients with first-line ART failure and 100 nave patients were sequenced; all sequences genotyped as HIV-1 subsubtype A6. According to analysis, 82% of patients had at least one significant mutation associated with drug resistance for the corresponding viral subtype. In total, we encountered 87 different drug resistance mutations. Conclusion. We have shown increased proportion of patients with first-line ART failure among all patients with treatment failure. The main cause for such changes is probably related to the prevalence of primary drug resistance, estimated here at 8%. Specific differences were found between drug resistance mutation profiles in patients without suppressed viral load and patients with virological breakthrough. The overall results of the study indicate a need to diagnose and characterize HIV drug resistance prior to initiation of therapy in order to avoid ineffective first-line antiretroviral treatment.

A clinical, aetiological, and public health perspective on central nervous system infections in Bolivia, 2017\u20132018

Central nervous system (CNS) infections are important causes of morbidity and mortality worldwide. In Bolivia, aetiologies, case fatality, and determinants of outcome are poorly characterised. We attempted to investigate such parameters to guide diagnosis, treatment, prevention, and health policy. From Nov-2017 to Oct-2018, we prospectively enrolled 257 inpatients (20.2% HIV-positive patients) of all ages from healthcare centers of Cochabamba and Santa Cruz, Bolivia with a suspected CNS infection and a lumbar puncture performed. Biological diagnosis included classical microbiology, molecular, serological and immunohistochemical tests. An infectious aetiology was confirmed in 128/257 (49.8%) inpatients, including, notably among confirmed single and co-infections, Cryptococcus spp. (41.7%) and Mycobacterium tuberculosis (27.8%) in HIV-positive patients, and Mycobacterium tuberculosis (26.1%) and Streptococcus pneumoniae (18.5%) in HIV-negative patients. The total mortality rate was high (94/223, 42.1%), including six rabies cases. In multivariate logistic regression analysis, mortality was associated with thrombocytopenia (Odds ratio (OR) 5.40, 95%-CI 2.40–11.83) and hydrocephalus (OR 4.07, 95%-CI 1.35–12.23). The proportion of untreated HIV patients, late presentations of neurotuberculosis, the rate of pneumococcal cases, and rabies patients who did not benefit from a post-exposure prophylaxis, suggest that decreasing the burden of CNS infections requires reinforcing health policy regarding tuberculosis, rabies, S. pneumoniae vaccination, and HIV-infections.

Low Frequency of Integrase Inhibitor Resistance Mutations Among Therapy-Naïve HIV Patients in Southeast China.

BackgroundWith the widespread use of integrase strand transfer inhibitors (INSTIs) in the clinical setting, transmission of INSTIs-resistance mutations may increase. Data regarding transmitted drug resistance mutations (TDRM) to INSTIs in Chinese HIV patients are limited. The aim of this study was to summarize the INSTIs TDRM, including the frequency of protease inhibitors (PIs) and reverse transcriptase (RT) inhibitors (RTIs) mutations in treatment-naïve patients in Southeast China.MethodsHIV-1 positive patients were retrospectively selected between April 2018 and October 2020 from the Mengchao Hepatobiliary Hospital of Fujian Medical University, the largest designated HIV/AIDS care hospital in Southeast China. Individuals who were antiretroviral therapy-naïve and received antiretroviral drug resistance testing at baseline were included. Clinical data including demographic data, CD4 counts, HIV-RNA loads, and drug resistance mutations were collected.ResultsA total of 147 patients were enrolled. INSTIs TDRM was rare, with only one primary integrase mutation E138K observed in one sample and one secondary mutation E157Q detected in another sample. The overall prevalence of INSTIs TDRM was 1.36%. A substantial proportion of patients harbored common INSTIs-associated polymorphic variants. Two samples harbored the T215S, M184V and K70E mutations related to nucleoside RTIs (NRTIs). Twelve patients carried nonnucleoside RTIs (NNRTIs)-resistance mutations. Two individuals harbored PIs-resistance mutations: Q58E in one patient and M46I, I54V, V82A, L10F, and Q58E mutations in another patient. The total TDRM rate for RTIs and PIs was 10.20% (15/147), but only 0.68% (1/147) was according to the WHO recommendations on TDRM.ConclusionThe rate of INSTIs TDRM was low among therapy-naïve HIV patients in Southeast China. INSTIs as a first-line regimen are suitable for untreated HIV-1 patients in Southeast China. But special attention must be still paid to INSTIs TDRM in clinical practice.

APOL1 risk variants and the development of HIV-associated nephropathy.

HIV-associated nephropathy (HIVAN) remains a concern among untreated HIV patients, notably of African descent, as patients can reach end-stage renal disease within 3years. Two variants (G1 and G2) of the APOL1 gene, common in African populations to protect against African sleeping sickness, have been associated with an increased risk of several glomerular disorders including HIVAN, hypertension-attributed chronic kidney disease, and idiopathic focal segmental glomerulosclerosis and are accordingly named renal risk variants (RRVs). This review examines the mechanisms by which APOL1 RRVs drive glomerular injury in the setting of HIV infection and their potential application to patient management. Innate antiviral mechanisms activated by chronic HIV infection, especially those involving type 1 interferons, are of particular interest as they have been shown to upregulate APOL1 expression. Additionally, the downregulation of miRNA 193a (a repressor of APOL1) is also associated with the upregulation of APOL1. Interestingly, glomerular damage affected by APOL1 RRVs is caused by both loss- and gain-of-function changes in the protein, explicitly characterizing these effects. Their intracellular localization offers a further understanding of the nuances of APOL1 variant effects in promoting renal disease. Finally, although APOL1 variants have been recognized as a critical genetic player in mediating kidney disease, there are significant gaps in their application to patient management for screening, diagnosis, and treatment.

Microbiome, Autoimmune Diseases and HIV Infection: Friends or Foes?

Several studies highlighted the importance of the interaction between microbiota and the immune system in the development and maintenance of the homeostasis of the human organism. Dysbiosis is associated with proinflammatory and pathological state-like metabolic diseases, autoimmune diseases and HIV infection. In this review, we discuss the current understanding of the possible role of dysbiosis in triggering and/or exacerbating symptoms of autoimmune diseases and HIV infection. There are no data about the influence of the microbiome on the development of autoimmune diseases during HIV infection. We can hypothesize that untreated patients may be more susceptible to the development of autoimmune diseases, due to the presence of dysbiosis. Eubiosis, re-established by probiotic administration, can be used to reduce triggers for autoimmune diseases in untreated HIV patients, although clinical studies are needed to evaluate the role of the microbiome in autoimmune diseases in HIV patients.

Feasibility of visual inspection with acetic acid (VIA) screening for cervical cancer in Tanzania with emphasis on special populations.

5527 Background: Following the report that VIA screening reduced cervical cancer mortality by 31% in India (ASCO LBA2 2013; Shastri SS, et al JNCI 2014), the W.H.O. endorsed VIA guidelines for Africa, where the global disease burden is highest. In Tanzania, cervical cancer is a major source of morbidity and mortality, with nearly 10,000 new cases and 7,000 deaths annually. Due to lack of resources, therapies are limited and patient outcomes are further confounded by the relatively high prevalence of concurrent HIV infection. We report on the feasibility of VIA screening in Tanzania with emphasis on unique populations. Methods: Our two 5-day VIA screen-and-treat workshops in Buzuruga and Sangabuye Health Centres in Mwanza, Tanzania were approved by the University of California, Irvine IRB and local health authorities. Participants were recruited from surrounding communities and offered free cervical VIA screening, cryotherapy when indicated, and HIV rapid testing. Acetowhite lesions and/or abnormal vascular markings were VIA+. Chi-square and Fisher exact tests were performed with statistical significance assigned at 0.05. Results: During July 2018, 825 of 917 registered participants underwent VIA screening and 25.1% (n=207) were VIA+. 147 VIA+ non-pregnant women received same day cryotherapy and 15 (1.8%) with lesions suspicious for cancer were referred to Bugando Medical Center. In the subanalysis of 64 HIV+ patients (23 diagnosed at the workshops, 41 with prior diagnosis on ART), HIV infection was not associated with VIA positivity (p=0.497). Additionally, a non-significant trend of higher VIA+ screens among newly diagnosed untreated HIV patients (27.7%) vs patients with known HIV on ART (17.5%) was observed (p=0.556). Conclusions: VIA screening for cervical cancer, while feasible in Tanzania, will require follow-up and repetitive screening. Although cervical cancer is an AIDS-defining illness, lack of correlation between HIV infection and VIA-positivity may reflect the availability of W.H.O.-subsidized ART in sub-Saharan Africa to attenuate HPV-mediated neoplastic transformation, as previously reported by others. Further study of this phenomenon is warranted.

Association of HIV-infection, antiretroviral treatment and metabolic syndrome with large artery stiffness: a cross-sectional study

BackgroundEffective combined antiretroviral therapy (cART) has improved life expectancy among people living with HIV-1 infection. Treated HIV-1infection increases the prevalence of metabolic syndrome (MS). Despite sub-Saharan Africa having among the highest rates of HIV-1 infection, the effects of MS in HIV-1-infected individuals on cardiovascular risk is poorly explored. The aim of the study was to assess whether MS and/or HIV-1 treatment correlates with large elastic artery stiffness in HIV-1-infected patients treated with first-line cART.MethodsThe study sample comprised of 102 subjects free of cardiovascular disease and major risk factors divided into two groups based on HIV-1 infection, treatment, and MS status: HIV-1+/cART+/MS+ (n = 12); HIV-1+/cART−/MS+ (n = 16); HIV-1−/ MS+ (n = 10); HIV-1+/cART+/MS− (n = 42); HIV-1+/cART−/MS− (n = 32); HIV-1−/ MS− (n = 39). MS was established according the International Diabetes Federation definition. Large artery stiffness was measured using applanation tonometry to assess aortic pulse wave velocity (aPWV) and aortic augmentation index at heart rate of 75 bpm (AIx@HR75). cART included lamivudine/zidovudine and nevirapine or efavirenz.ResultsThe prevalence of MS in the HIV-1-infected patients was 28%. There were no significant differences in aPWV in the non-MS groups. However, in subjects with MS, aPWV was significantly higher in the HIV-1 cART patients (9.0 ± 1.9 m/s) compared with both controls (7.5 ± 1.8 m/s; P = 0.018) and untreated HIV-1 patients (7.7 ± 1.3 m/s; P = 0.023), and these differences remained after adjustment for blood pressure and sex. Aortic PWV was significantly elevated (P = 0.009) in HIV-1 cART patients with MS compared to their counterparts without MS. Untreated HIV-1 patients with MS also demonstrated increased aPWV compared to their counterparts without MS (P = 0.05). Aortic AIx@HR75 was, on average, ~ 5% higher in HIV-1 cART patients with MS (28.3 ± 62% compared with untreated HIV-1 patients with MS (23.5 ± 9%; P = 0.075). Sub-group multivariate analysis identified MS as an independent predictor of increased aPWV in HIV-1 cART patients.ConclusionsOur study established that presence of MS in HIV-1 patients on treatment was associated with increased aPWV and hence increased arterial stiffness in sub-Saharan African HIV-1 patients on first-line cART.

A Surveillance on Protease Inhibitor Resistance-Associated Mutations Among Iranian HIV-1 Patients

Background: Drug resistance is emerging as one of the greatest challenges in the development of effective treatment for HIV infection. The importance of clinical studies in this field stems from the world wide growing of treatment drug-resistant mutations. Objectives: This study was performed to determine the HIV subtype and the resistance mutations to the protease inhibitors in both untreated HIV patients and patients under treatment with protease inhibitors (PIs) in Iran. Methods: The study was conducted on two groups of participants. The first group consisted of 25 HIV patients who did not receive any antiretroviral treatment. The second group included 25 HIV patients who have being treated with a combination of protease inhibitors. After genome extraction, a nested polymerase chain reaction was performed to amplify the protease gene. Upon confirmation using electrophoresis, the amplicons or PCR products were sequenced and analyzed to determine the drug resistance mutations as well as the viral subtypes. Results: No mutations were found in the first group; however, 32% of the samples in the second group had PI related drug-resistance mutations. The major mutations were V82A and M46I, which were seen in 12% of the samples, while the minor mutation F53L was seen in 16% of the samples. The subtype analysis showed that 94% of the samples were subtype CRF35_AD, and 6% were of defined as subtype A. Conclusions: The present study reports updates on the mutations related to protease resistance in Iranian HIV patients receiving treatment. Our data, as well as existing reports, support the need for the optimization of treatment to prevent emergence of resistant viruses and a search for new antiretroviral drug candidates for HIV patients.

Richer gut microbiota with distinct metabolic profile in HIV infected Elite Controllers

Gut microbiota dysbiosis features progressive HIV infection and is a potential target for intervention. Herein, we explored the microbiome of 16 elite controllers (EC), 32 antiretroviral therapy naive progressors and 16 HIV negative controls. We found that the number of observed genera and richness indices in fecal microbiota were significantly higher in EC versus naive. Genera Succinivibrio, Sutterella, Rhizobium, Delftia, Anaerofilum and Oscillospira were more abundant in EC, whereas Blautia and Anaerostipes were depleted. Additionally, carbohydrate metabolism and secondary bile acid synthesis pathway related genes were less represented in EC. Conversely, fatty acid metabolism, PPAR-signalling and lipid biosynthesis proteins pathways were enriched in EC vs naive. The kynurenine pathway of tryptophan metabolism was altered during progressive HIV infection, and inversely associated with microbiota richness. In conclusion, EC have richer gut microbiota than untreated HIV patients, with unique bacterial signatures and a distinct metabolic profile which may contribute to control of HIV.

Immunological and epidemiological factors affecting candidiasis in HIV patients beginning antiretroviral therapy in an Asian clinic

ObjectivesOropharyngeal candidiasis (OPC) is common in HIV patients beginning antiretroviral therapy (ART). Here we address the response to ART, and the roles of poor oral hygiene and defects in local innate immunity with a focus on salivary β-defensins, as they are implicated in control of candidiasis but have not been investigated in this context. DesignART naïve HIV-infected adults (n=82) with <200 CD4+ T-cells/mm3 attending clinics at Cipto Mangunkusumo Hospital, Jakarta, were examined at the commencement of ART, and 73 were re-examined after 3 months. OPC was detected by clinical examination, and Candida albicans and fungal burdens were determined following culture on CHROMagar and saboroud-dextrose agar (resp). Salivary β-defensins (−2 and −3) were quantified by ELISA. Healthy control subjects (n=40) matched the patients by age and gender. ResultsOPC was evident in 47 patients before ART, and associated with greater fingal burdens. No OPC was detected in healthy controls and culture positivity was rare. ART decreased the prevalence of OPC to 8/73 HIV patients re-examined after 3 months, with reduced total fungal and C. albicans burdens. The incidence of OPC was independent of oral hygiene. Hyposalivation was more common in untreated HIV patients (16%) than after 3 months on ART and was rare in healthy controls. HIV patients were also more likely to have acidic saliva. Salivary β-defensin-2 was elevated in the presence of C. albicans pseudohyphae and OPC after 3 months on ART, but β-defensin-3 was not affected by OPC or ART. ConclusionsART reduces the prevalence of OPC, and the total fungal and C. albicans burden. Levels of salivary β-defensin-2 may associate with OPC in HIV patients responding to ART.

Brief Report: Increased Frequency of CD39+ CD56bright Natural Killer Cells in HIV-1 Infection Correlates With Immune Activation and Disease Progression.

The expression pattern of the ectonucleotidases CD39 and CD73 on natural killer (NK) cells was examined in peripheral blood mononuclear cell of 61 HIV-1-infected patients. Increased frequencies of CD39CD56 NK cells were detectable in untreated HIV patients, which was associated with high viral load, low CD4 T-cell count, and CD8 T-cell activation. Additionally, levels of CD39 on NK cells were inducible by in vitro stimulation of NK cells, correlating with aryl hydrocarbon receptor and interleukin 10 expression. Here, we provide the first evidence of increased CD39CD56 NK cell frequencies during HIV infection, which might have consequences for NK cell function and HIV pathogenesis.

Antiretroviral treatment and time since HIV-1 diagnosis are associated with large artery stiffness in sub-Saharan African HIV-1 patients

BackgroundHIV-1 infection in northern populations is associated with increased large artery stiffness, both in the absence and presence of combination antiretroviral treatment (cART). It is unclear if similar changes occur in sub-Sahara African HIV-infected persons. The study aimed to determine whether HIV-1 infection with and without cART is associated with large artery stiffness in a cohort of HIV-1-infected patients in Tanzania. MethodsIn this cross-sectional study, 146 subjects were recruited: 40 uninfected controls, 51 HIV-1-infected untreated persons, and 55 on cART for at least 12 months. Patients were screened for history of hepatic, renal, haematological or cardiovascular disease, diabetes, dyslipoproteinaemia, and hypertension. Following screening, 4 untreated and 21 cART HIV-1 patients were excluded; leaving 47 HIV-1-infected untreated and 34 cART patients to be studied. cART included first line treatment: lamivudine/zidovudine with nevirapine or efavirenz. Large artery stiffness was assessed using applanation tonometry via pulse wave analysis to determine aortic pulse wave velocity (aPWV) and augmentation index corrected to a heart rate of 75 bpm (AIx@HR75). ResultsAortic PWV was higher (p = 0.017) in the HIV-1-infected patients on cART (aPWV: 8.2 ± 1.8 m/s) vs. untreated patients (7.3 ± 1.5 m/s) and independent of blood pressure differences. AIx@HR75 was significantly increased in cART HIV-1 (29 ± 8%) vs. untreated HIV-1 patients (23 ± 10%; p = 0.038) and controls (23 ± 10%; p = 0.032). Duration of HIV-1 and cART were independent predictors of arterial stiffening in HIV-1 patients. ConclusionsThe surrogate markers for arterial stiffness suggest an increased cardiovascular risk in sub-Saharan African HIV-1 patients on first line therapy.

Partial recovery of senescence and differentiation disturbances in CD8+ T cell effector-memory cells in HIV-1 infection after initiation of anti-retroviral treatment.

Immune senescence as well as disturbed CD8+ T cell differentiation are a hallmark of chronic HIV infection. Here, we investigated to what extent immune senescence is reversible after initiation of anti-retroviral treatment (ART). Peripheral blood mononuclear cells (PBMCs) from a cohort of HIV patients with different disease courses, including untreated viral controllers (n = 10), viral non-controllers (n = 16) and patients on ART (n = 20), were analysed and compared to uninfected controls (n = 25) by flow cytometry on bulk and HIV-specific major histocompatibility complex (MHC) class I tetramer+ CD8+ T cells for expression of the memory markers CCR7 and CD45RO, as well as the senescence marker CD57 and the differentiation and survival marker CD127. Furthermore, a subset of patients was analysed longitudinally before and after initiation of ART. Frequencies of CD57+ CD8+ T cells decreased after initiation of ART in central memory (Tcm) but not in effector memory T cell populations (TemRO and TemRA). The frequency of CD127+ CD8+ cells increased in Tcm and TemRO. We observed a reduction of CD127- T cells in Tcm, TemRO and partially in TemRA subsets after initiation of ART. Importantly, HIV-specific CD8+ TemRO cells predominantly displayed a CD127- CD57+ phenotype in untreated HIV-patients, whereas the CD127+ CD57- phenotype was under-represented in these patients. The frequency of the CD127+ CD57- CD8+ T cell subpopulation correlated strongly with absolute CD4+ counts in HIV-infected patients before and after initiation of ART. These findings can be interpreted as a phenotypical correlate of CD8+ memory T cell differentiation and the premature 'ageing' of the immune system, which was even observed in successfully virally suppressed HIV patients.

Accelerated CD4+ cell count decline in untreated HIV-1 patients points toward increasing virulence over the course of the epidemic.

Based on the assumption that the rate of CD4 cell count loss in treatment-naïve patients is correlated with the virulence of HIV-1, we evaluated 4616 patients. Patients who entered a German national database between 1985 and 1995 had a median annual CD4 cell count loss of 48 cells/μl, whereas those registered between 1999 and 2009 had a median annual CD4 cell count loss of 68 cells/μl (P < 0.001). This suggests that HIV-1 virulence has increased over the course of the epidemic.

A curative regimen would decrease HIV prevalence but not HIV incidence unless targeted to an ART-naïve population.

HIV curative strategies currently under development aim to eradicate latent provirus, or prevent viral replication, progression to AIDS, and transmission. The impact of implementing curative programs on HIV epidemics has not been considered. We developed a mathematical model of heterosexual HIV transmission to evaluate the independent and synergistic impact of ART, HIV prevention interventions and cure on HIV prevalence and incidence. The basic reproduction number was calculated to study the potential for the epidemic to be eliminated. We explored scenarios with and without the assumption that patients enrolled into HIV cure programs need to be on antiretroviral treatment (ART). In our simulations, curative regimes had limited impact on HIV incidence if only ART patients were eligible for cure. Cure implementation had a significant impact on HIV incidence if ART-untreated patients were enrolled directly into cure programs. Concurrent HIV prevention programs moderately decreased the percent of ART treated or cured patients needed to achieve elimination. We project that widespread implementation of HIV cure would decrease HIV prevalence under all scenarios but would only lower rate of new infections if ART-untreated patients were targeted. Current efforts to identify untreated HIV patients will gain even further relevance upon availability of an HIV cure.

Dysregulated Immune Activation in Second-Line HAART HIV+ Patients Is Similar to That of Untreated Patients.

BackgroundSuccessful highly active antiretroviral therapy (HAART) has changed the outcome of AIDS patients worldwide because the complete suppression of viremia improves health and prolongs life expectancy of HIV-1+ patients. However, little attention has been given to the immunological profile of patients under distinct HAART regimens. This work aimed to investigate the differences in the immunological pattern of HIV-1+ patients under the first- or second-line HAART in Brazil.MethodsCD4+ T cell counts, Viral load, and plasma concentration of sCD14, sCD163, MCP-1, RANTES, IP-10, IL-1β, IL-6, TNF-α, IL-12, IFN-α, IFN-γ, IL-4, IL-5, and IL-10 were assessed for immunological characterization of the following clinical groups: Non-infected individuals (NI; n = 66), HIV-1+ untreated (HIV; n = 46), HIV-1+ treated with first-line HAART (HAART 1; n = 15); and HIV-1+ treated with second-line HAART (HAART 2; n = 15).ResultsWe found that the immunological biosignature pattern of HAART 1 is similar to that of NI individuals, especially in patients presenting slow progression of the disease, while patients under HAART 2 remain in a moderate inflammatory state, which is similar to that of untreated HIV patients pattern. Network correlations revealed that differences in IP-10, TNF-α, IL-6, IFN-α, and IL-10 interactions were primordial in HIV disease and treatment. Heat map and decision tree analysis identified that IP-10>TNF-α>IFN-α were the best respective HAART segregation biomarkers.ConclusionHIV patients in different HAART regimens develop distinct immunological biosignature, introducing a novel perspective into disease outcome and potential new therapies that consider HAART patients as a heterogeneous group.

ISG15 expression correlates with HIV-1 viral load and with factors regulating T cell response

Given the multifactorial nature of action of type I interferon (IFN) in HIV-1 infection and the need to firmly establish the action of key components of IFN pathways, we compared the IFN stimulated gene (ISG)15 expression with that of other well-characterized ISGs, evaluating its relationship with immunosuppressive factors regulating T-cell response in HIV-1 patients. PBMC from 225 subjects were included: healthy donors (n=30), naïve (n=93) and HAART treated HIV-1 subjects (n=102). Levels of ISG15-mRNA, ISG56-mRNA, APOBEC3G/3F-mRNA, TRAIL-mRNA, IDO-mRNA, proviral load andISG15 (rs15842 and rs1921) SNPs were evaluated by using TaqMan assays. We found that ISG15, ISG56, APOBEC3G/3F levels were increased in untreated HIV-1 patients compared to healthy donors, being ISG15 the highest ISG expressed. The amount of ISG15 correlated with viral load and with CD4+ T cell counts whereas no relationship was found between all ISGs analyzed and proviral load or HIV-1 tropism. ISG15 expression was reduced following long-term antiretroviral therapy. In addition, ISG15 levels were correlated with those of TRAIL and IDO in HIV-1 viremic patients. Lastly, ISG15 SNPs had no influence on ISG15 levels. We demonstrates that ISG15 is elevated in viremic HIV-1 patients and is associated with high TRAIL and IDO levels.

Emergence of drug-resistance in HIV dynamics under distinct HAART regimes

In this paper we propose a model for the dynamics of HIV epidemics under distinct HAART regimes, and study the emergence of drug-resistance. The model predicts HIV dynamics of untreated HIV patients for all stages of the infection. We compute the local and the global stability of the disease-free equilibrium of the model. We simulate the model for two distinct HIV patients, the rapid progressors and the long-term non-progressors. We study the effects of equal RTI and PI efficacies, as well as distinct drug efficacies, namely RTI-based and PI-based therapeutics. Treatment is initiated when the CD4+ T cells count is less than 350 cells mm−3. The PI-based drugs seem to produce better outcomes, with respect to disease progression, than RTI-based regimes.