Against all odds:The road to success in the development of human immune reconstitution mice

The mouse genome has a high degree of homology with the human genome,and its physiological,biochemical,and developmental regulation mechanisms are similar to those of humans;therefore,mice are widely used as experimental animals.However,it is undeniable that interspecies differences between humans and mice can lead to experimental errors.The differences in the immune system have become an impor-tant factor limiting current immunological research.The application of immunodefi-cient mice provides a possible solution to these problems.By transplanting human immune cells or tissues,such as peripheral blood mononuclear cells or hematopoietic stem cells,into immunodeficient mice,a human immune system can be reconstituted in the mouse body,and the engrafted immune cells can elicit human-specific immune responses.Researchers have been actively exploring the development and differen-tiation conditions of host recipient animals and grafts in order to achieve better im-mune reconstitution.Through genetic engineering methods,immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts.From initially only being able to reconstruct single T lymphocyte lineages,it is now possible to reconstruct lymphoid and myeloid cells,providing important research tools for immunology-related studies.In this review,we compare the differences in immune systems of humans and mice,describe the devel-opment history of human immune reconstitution from the perspectives of immuno-deficient mice and grafts,and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution,aiming to provide important references for im-munological related researches.

The in vitro reconstitution of nucleosome and its binding patterns with HMG1/2 and HMG14/17 proteins

Using atomic force microscopy (AFM), the dynamic process of the in vitro nucleosome reconstitution followed by slow dilution from high salt to low salt was visualized. Data showed that the histone octamers were dissociated from DNA at 1M NaCl. When the salt concentration was slowly reduced to 650 mMand 300 mM, the core histones bound to the naked DNA gradually. Once the salt concentration was reduced to 50 mM the classic 'beads-on-a-string' structure was clearly visualized. Furthermore, using the technique of the in vitro reconstitution ofnucleosome,the mono- and di- nucleosomes were assembled in vitro with both HS2core (-10681 to -10970 bp) and NCR2 (-372to -194 bp) DNA sequences in the 5'flanking sequence of human b-globin gene. Data revealed that HMG 1/2 and HMG 14/17 proteins binding to both DNA sequences are changeable following the assembly and disassembly of nucleosomes. We suggest that the changeable binding patterns of HMG 14/17 and HMG1/2 proteins with these regulatory elements may be critical in the process of nucleosome assembly, recruitment of chromatin-modifying activities, and the regulation of human b-globin gene expression.

Graves’ Disease as a Late Manifestation of Immune Reconstitution Syndrome after Highly Active Antiretroviral Therapy in an HIV-1 Infected Patient

Context: Highly active antiretroviral therapy (HAART) inhibits the HIV replication and consequently increases CD4 levels and decreases viral load. This immune system improvement can trigger various immunological phenomena, entity called Immune Reconstitution Syndrome (IRS). Graves’ disease is a late Immune Reconstitution consequence. Patient: We report the case of a 48 years old man with HIV infection who developed Graves’ disease three years after he was on effective HAART because of the Immune Reconstitution Syndrome. At presentation he had a very low CD4 T-cell count (17 cells/μL). When he started HAART he presented a lipodystrophy syndrome. HAART was changed because of the persistent low CD4-T cells count (less than 100 cell/μL). Afterwards serum lipid levels began to decrease and that was the first manifestation of Graves’ disease, which was diagnosed when CD4 T-cells increased up to 343 cell/μL. Our patient developed Graves’ disease 36 months after initiating effective HAART with protease inhibitors which was coincident with viral suppression and a rise of CD4 T cells. Conclusion: The most immunosuppressed patients with a CD4 T cell count less than 100 cells/μL are at greatest risk for the development of Immune Reconstitution Syndrome after HAART initiation. We conclude that clinicians will have to consider the importance of the early diagnosis of thyroid disease to bring an adequate treatment.

Current knowledge on the multiform reconstitution of intestinal stem cell niche

The development of“mini-guts”organoid originates from the identification of Lgr5+intestinal stem cells(ISCs)and circumambient signalings within their specific niche at the crypt bottom.These in vitro self-renewing“mini-guts”,also named enteroids or colonoids,undergo perpetual proliferation and regulated differentiation,which results in a high-performance,self-assembling and physiological organoid platform in diverse areas of intestinal research and therapy.The triumphant reconstitution of ISC niche in vitro also relies on Matrigel,a heterogeneous sarcoma extract.Despite the promising prospect of organoids research,their expanding applications are hampered by the canonical culture pattern,which reveals limitations such as inaccessible lumen,confine scale,batch to batch variation and low reproducibility.The tumor-origin of Matrigel also raises biosafety concerns in clinical treatment.However,the convergence of breakthroughs in cellular biology and bioengineering contribute to multiform reconstitution of the ISC niche.Herein,we review the recent advances in the microfabrication of intestinal organoids on hydrogel systems.

Alpha-GalCer Administration after Allogeneic Bone Marrow Transplantation Improves Immune Reconstitution in Mice

Objective To explore the effect of α-galactosyleramide （α-GalCer） on immune reconstitution under acute graft-versus-host disease （aGVHD）. Methods BALB/c mice were transplanted with allogeneic C57BL/6 bone marrow cells and splenocytes （both 1 × 10^7） after receiving lethal total-body irradiation, α-GalCer （100 ug/kg） or vehicle （dimethyl- sulfoxide） was administered intraperitoneally immediately after transplantation. The effects of α-GalCer on immune reconstitufion, proliferation of T cells and B cells, hematopoiesis, and thymic microenvironment were assessed. Results The α-GalCer group exhibited higher percentages of CD3^＋, CD4^＋, CD8^＋, B220^＋, CD40＋, and CD86＋cells compared with the vehicle group. The number of colony forming unit per 1000 CD34^＋ cells in the et-GalCer group was higher than in the vehicle group （P=0.0012）. In vitro proliferation assays showed that the α-GalCer group had higher percentages of CD3^＋, CD4^＋, CD8^＋, and B220^＋ cells compared with the vehicle group. As for the results of in vivo proliferation assays, the numbers of CD3^＋, CD4^＋, CD8^＋, and B220^＋ cells were higher in the α-GalCer group than in the normal group, especially the number of B220^＋ cells （P=0.007）. Significant difference was not found in thymocyte count between the α-GalCer group and the vehicle group, nor in the percentages of CD3^＋, CD4^＋, and CD8^＋ cells. Conclusion Administration of tl-GalCer after allogeneic bone marrow transplantation may promote immune reconstitution in the presence of aGVHD.

Acute Respiratory Distress Syndrome (ARDS) Case Report after a Caesarean Section Related to the Immune Reconstitution Inflammatory Syndrome

During pregnancy, a cellular immunosuppressant status is produced. It is characterized by anti-inflammatory cellular responses that allow embryonic implantation. The reversal of these changes during the postpartum period may result in overt clinical manifestations of otherwise quiescent or latent infections. We present an Acute Respiratory Distress Syndrome (ARDS) case after a caesarean section related to the Immune Reconstitution Inflammatory Syndrome (IRIS) in a Guinean black woman. The patient was treated with large doses of corticosteroids showing a great clinical and radiological improvement.

Paleogeographic Reconstitution and Tangential Tectonic in the Backland of Tunisian Dorsal (Fahs Area: J. Rouas and Ruissate)

The Tunisian Dorsal backland is the Eastern Atlas side of maghrebides. Field data of Fahs area allowed us to develop new interpretations and to characterize the main structural features of the studied devices (Jebel Rouas and Ruissate). Heritage of Zaghouan accident, Triassic salt movements and strike-direction of major synsedimentary faults are the principal causes and results of the skinned and superimposed geometric architecture, generated by the reversed extensional (Jurassic-Cretaceous) tectonics. The actual geometry of Jebel Rouas and Ruissate represents a fault propagation fold, affecting Jurassic and Cretaceous sets. The backland of this thrust fault defines an imbrications structures of Barremian series. Tectonic records activities show the existence of angular unconformities (Oligocene and Eocene series on the Cretaceous sets considered as bedrock), slumps, tectonic breccias and synsedimentary faults are all of them controlled by a deep major accident;N-S to NE-SW and NW-SE. Features of the study area are probably related first;to the blockage of Zaghouan thrust oriented NE-SW in the foreland;then, to the intense halokinetic activity, which facilitates the layers displacement acting as decollment level. The detailed structural and stratigraphic study of Fahs area and its neighbors shows the presence of an intense tangential tectonic during upper Miocene, affecting Meso-Cenozoic sets, because all the structures involved are sealed by Oligocene and Miocene thinned series. This is accentuated by the existence of different sets of decollment at different depths, which are represented by a displacement to the SE through the backland of the Tunisian Dorsal. We define these features as an imbrication and thrusting Out of sequence system.

Influence of Wheat Protein Contents and Fractions on Dough RheologicalProperties as Determined by Using a Reconstitution Method

A strong gluten wheat cultivar Shannong 12 and a medium-strength wheat cultivar Shannong 11 were used to investigate the effects of wheat protein contents and protein fractions on dough rheological properties using a reconstitution method. The results indicated that the peak height, peak width, peak integral, resistance to extension and area under the curve were increased when protein content increased to 120, 140, and 160% （w/w） of the protein content in the base flours for doughs made from each wheat cultivar. All protein fractions were added to each of the base flours at three levels （0.25, 0.50 and 1.00%, w/w） based upon the protein content. The mixograph dough development time, peak width, and resistance to extension increased when the glutenin, insoluble glutenin, soluble glutenin, and glutenin macropolymer were added and increased systematically with increasing levels of these fractions. Peak integral increased by adding and increasing protein content, however, albumin-globulin had no obvious effects. Extensibility at rupture decreased when the glutenin, insoluble glutenin, soluble glutenin, and glutenin macropolymer were added, and decreased systematically with increasing levels of these fractions. However, extensibility at rupture increased when the monomeric protein, albumin-globulin, and gliadin were added, and increased systematically with increasing levels of these fractions.

Enhancing Effects of Ligustrazine on Expression of CD31 and Hematopoietic Reconstitution in Syngenic Bone Marrow Transplantation of Mice

Summary： The effect of ligustrazine on the expression of CD31 in syngenic bone marrow transplantation （BMT） mice was studied. Fifty-six Balb/c mice were divided into 3 groups： normal control group. BMT control group, and ligustrazine treated group. Syngenic BMT mouse models were established according to the literatures. In BMT control group and the ligustrazine treated group, the mice were given respecxively orally 0.2 mL saline and 2 mg ligustrazine twice a day. On the 7th, 14th, and 21st day after BMT, the mice were killed. The expression of CD31 on the surface of bone marrow nuclear cells （BMNC） was detected by flow cytometry. Peripheral blood leukocytes, platelets and BMNC were counted. Histological observation of bone marrow was made. The results showed thai in ligustrazine treated group the peripheral blood leukocylcs, platelets and BMNC counts, and the expression of CD31 on the day 7, 14, 21 after BMT were higher than in BMTcontrol group （P〈0.01 or P〈0.05）. In conclusion, ligustrazine could obviously enhance the CD31 expression on the surface of BMNC after syngcnic BMT in mice, which may be one of the mecha- nisms underlying the ligustrazine accelerating hematopoietic reconstitution in syngenic BMT.

Hematopoiesis reconstitution and anti-tumor effectiveness of Pai-Neng-Da capsule in acute leukemia patients with haploidentical hematopoietic stem cell transplantation

BACKGROUND With the rapid development of haploidentical hematopoietic stem cell transplantation(haplo-HSCT),primary poor graft function(PGF)has become a lifethreatening complication.Effective therapies for PGF are inconclusive.New Chinese patent medicine Pai-Neng-Da(PND)Capsule exerts dual effect in promoting hematopoiesis recovery and regulating immunity.Still,the application of PND capsule in hematopoietic stem cell transplantation,especially in the haplo-HSCT setting,has not yet been reported.AIM To evaluate the role of PND capsule in acute leukemia patients with haplo-HSCT.METHODS We retrospectively collected data of acute leukemia patients who underwent haplo-HSCT at the Affiliated People’s Hospital of Ningbo University between April 1,2015 and June 30,2020.Twenty-nine consecutive patients received oral PND capsule from the sixth day to the first month after haplo-HSCT were included in the PND group.In addition,31 patients who did not receive PND capsule during haplo-HSCT were included in the non-PND group.Subsequently,we compared the therapeutic efficacy according to the western medical evaluation indexes and Chinese medical symptom scores,and the survival between the PND group and the non-PND group,using the chi-square test,Fisher’s exact test,and the Kaplan-Meier method.RESULTS The duration of platelet engraftment was shorter in the PND group than in the non-PND group(P=0.039).The PND group received a lower frequency of red blood cells and platelet transfusions than the non-PND group(P=0.033 and P=0.035,respectively).In addition,PND capsule marginally reduced the rate of PGF(P=0.027)and relapse(P=0.043).After 33(range,4-106)months of follow-up,the 3-year relapse-free survival(P=0.046)and progression-free survival(P=0.049)were improved in the PND group than in the non-PND group.Also,the therapeutic efficacy of the PND group according to Chinese medical symptom scores was significantly better than that of the non-PND group(P=0.022).Moreover,the adverse events caused by PND capsule were mild.Nevertheless,there were no significant differences in the duration of neutrophil engraftment,the risk of infection within 100 days after haplo-HSCT,the acute graft-versus-host disease,or the 3-year overall survival between the two groups.CONCLUSION PND capsule could promote hematopoiesis reconstitution,improve the therapeutic efficacy of Chinese medical symptom scores,present anti-tumor effectiveness,and prolong the survival of acute leukemia patients with haplo-HSCT.

Effect of Cooking and Reconstitution Methods on the Loss of Bioactive Compounds in Pigmented and Unpigmented Potatoes

Total phenolics, anthocyanins and antioxidant capacity of five coloured/pigmented (AR2009-10, Adirondack Red, Adirondack Blue, Congo, and POROIPG22-1) and two unpigmented potato genotypes (“Anuschka” and “Russet Burbank”) were assessed in fresh (with and without skin) and commercially processed/cooked/reconstituted products. Ascorbate profiles of the seven genotypes also were investigated using fresh tuber/tissue only. The results showed that genotypes greatly varied in their contents of bioactive compounds. Ascorbate profiles of the genotypes were not associated to any particular flesh colour/pigment. However, the pigmented potatoes had 1.5 to 2.5 times more the phenolics, 2 to 3 times more antioxidant capacity and higher levels of anthocyanins (13.98 to 38.57 mg C3GE-100g FW) compared to unpigmented genotypes. No anthocyanins were detected in the unpigmented potatoes. Significant losses of total phenolics, anthocyanins and total antioxidant capacity were found during peeling (18% - 23%), blanching process (40% - 60%) and further cooking/ reconstitution (7% - 12%) with no prominent genotype differences. Together, 65 to 90% of these bioactive compounds were lost during processing. The results suggested that pigmented potatoes contained higher amounts of total phenolics and anthocyanins and blanching step took away the most of the original bioactive compounds.

Study on the Effect of Ligustrazine on Hematopoietic Reconstitution in Bone Marrow Transplantation Mice

To explore tile effects of ligustrazine on hematopoietic reconstitution and its mechanism after bone marrow transplantation (BMT), the allogenic BMT mice were given intra-abdominal injection of 2,mg ligustrazine twice a day. On the 1st, 7th, 14th, and 28th day after BMT, peripheral blood cells and bone marrow nuclear cells (BMNC) were counted, and the histological features were evaluated. On the 7th, 14th, 21st day after BMT, CXCR4 expression on the BMNC was assayed. The results showed that peripheral blood cell counts and BMNC counts in ligustrazine-treated group on the 7th, 14th, 28th day were higher than those in BMT group (P<0. 01 or P<O. 05). The percentage of hematopoietic tissue volume, fat tissue hyperplasia and congestion and dilation degree of microvessel in ligustrazine-treated group on the 7th, 14th, 21st, 28th day was higher than those in BMT group. The CXCR4 expression levels in ligustrazine-treated group were higher than in BMT group (P<0.01 or P<0. 05) on the 7th and 14th day, and were lower than in BMT group on the 21st day (P<0. 01 ). It is concluded that the ligustrazine can accelerate hematopoietic reconstruction, enhance growth of hematopoietic tissues and promote the repair of microvessels. The CXCR4 expres- sion levels on BMNC may be responsible for the effect of ligustrazine.

Role of traditional Chinese medicine in incomplete immune reconstitution of HIV/AIDS:a review

Despite continuous progress,the prevention and treatment of human immunodeficiency virus(HIV)/acquired immune deficiency syndrome(AIDS)remain the world’s most serious public health challenges.A key problem is the degree of immune function reconstruction after antiretroviral therapy.Antiretroviral therapy has enriched the treatment of HIV/AIDS and improved the present conditions and the life quality of HIV/AIDS patients.However,some patients still fail to achieve normalization of CD4+T lymphocyte counts although persistent virological suppression.These patients are referred to as immunological non-responders,and usually present with severe immunological dysfunction.To date,since the underlying mechanism of incomplete immune reconstitution in HIV/AIDS has not been fully elucidated,remaining to be the focus and difficulties of current research.It is still a challenge to explore a safe,effective,and reliable therapeutic method for immunological non-responders.Due to fewer side effects and lower drug resistance,traditional Chinese medicine is often sought to provide alternative pharmacotherapy for regulating the immunity of immunological non-responders in China.In this review,we aimed at summarizing the latest and most comprehensive information on traditional Chinese medicine therapeutic methods for promoting immune reconstruction.In addition,outlooks and perspectives for possible future research that related are also discussed.

Acceleration of Immune Reconstitution after Bone Marrow Transplantation in Mice by Bone Marrow Stromal Cell Line Transfected with IL-6 Gene

To observe potential effect of the engineered bone marrow stromal cell line QXMSC1 secreting IL-6 (QXMSCIL-6) on accelerating immune reconstitution in syngeneic bone marrow transplantation in mice, QXMSC1 was transfected with the eukaryocytic expression vector pcDNAIL-6, which contained hIL-6 cDNA by liposome-mediated gene transfecting technique. G418-resistance clone was selected by limiting dilution. The highest secreting clone was selected by ELISA assay and used in animal experiments. The recipient mice (BALB/c) were lethally irradiated and cotransplanted syngeneic bone marrow (10 7/mice) and the QXMSC1IL-6 (5×10 5/mice). Lymphocyte proliferation induced by ConA and LPS, helper T lymphocyte precursor (HTLp), cytotoxic T lymphocyte precursor (CTLp), plaque-forming cell (PFC), delayed type hypersensitivity (DTH) were examined 30, 60 days in post transplantation respectively. The results showed that lymphocytes proliferation to ConA and LPS, HTLp, CTLp increased, DTH and PFC were improved by cografted stromal cells QXMSC1IL-6 on 30, 60 days after BMT. These results demonstrated that the bone marrow stromal cell line QXMSC1IL-6 transfected with IL-6 (QXMSC1IL-6) accelerated immune reconstitution in syngeneic bone marrow transplantation.

Preparation of wood-based hydrogel membranes for efficient purification of complex wastewater using a reconstitution strategy

To avoid resource wastage and secondary environmental pollution,recycling and reusing waste wood powder is still a great challenge.Moreover,the poor viscosity and irregular pore size of wood powder limit its practical application.This study,employed a green and convenient wood powder reconstitution strategy to achieve highly adhesive bonding and pore size control between wood powder particles,thus preparing a high-strength and super hydrophilic wood powder membrane.The wood powder fibers were partially dissolved and regenerated to create a reconstituted wood powder hydrogel membrane,using waste wood powder as the raw material.The wood powder reconstitution strategy offers advantages such as environmental friendliness,simplicity,cost-effectiveness,and strong universality.Furthermore,the materials exhibit excellent self-cleaning properties and superhydrophilicity.Driven by gravity,the membrane can purify oily wastewater and dyes.Additionally,the reconstitution strategy offers a new pathway for recycling wood powder.

Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease

Background:With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation(UCBT),the correlation between immune reconstitution(IR)after UCBT and graft-versus-host disease(GVHD)has been reported successively,but reports on double-negative T(DNT)cell reconstitution and its association with acute GVHD(aGVHD)after UCBT are lacking.Methods:A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology,the First Affiliated Hospital of USTC,between August 2018 and June 2021.IR differences were compared between the patients with and without aGVHD.Results:The absolute number of DNT cells in the healthy Chinese population was 109(70-157)/μL,accounting for 5.82(3.98-8.19)%of lymphocytes.DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation.Importantly,the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year(F=4.684,P=0.039 and F=5.583,P=0.026,respectively).In addition,the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased,and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD(HR=0.46,95%confidence interval[CI]:0.23-0.93;P=0.031).Conclusions:Compared to the number of DNT cells in Chinese healthy people,the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow.In addition,the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.

Identification of missing CYP450 enzymes involved in paclitaxel biosynthesis and heterologous reconstitution of baccatin III

Paclitaxel,a tetracyclic diterpenoid,has garnered attention for its potent anti-cancer properties and intricate molecular structure,making it a significant target for chemical synthesis and biosynthesis[1].However,its natural sources are extremely limited,as it is derived exclusively from the bark of endangered genus Taxus plants,which contain paclitaxel in very low concentrations(0.01%−0.05%)[2-3].Recent advances in synthetic biology present promising opportunities to enhance paclitaxel levels in Taxus cell cultures or to enable the reconstitution of its production in heterologous hosts,such as yeast or tobacco(Nicotiana benthamiana).

Longitudinal analysis of immune reconstitution and metabolic changes in women living with HIV:A real-world observational study

Background:Women comprise more than half of people living with human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS)worldwide and incomplete immune recovery and metabolic abnormalities affect them deeply.Studies of HIV antiretroviral therapy(ART)have a low female representation in China.We aimed to investigate immune reconstitution and metabolic changes of female HIV-positive cohort in China longitudinally.Methods:HIV-positive women who initiated ART from January 2005 to June 2021 and were followed up regularly at least once a year were included in this study.Immunological indicators(cluster of differentiation 4[CD4]counts and CD8 counts),viral load(VL),and metabolic indicators were collected at follow-up.All data were collected from the China Disease Prevention and Control Information System(CDPCIS).VL was tested half a year,1 year after receiving ART,and every other year subsequently according to local policy.CD4/CD8 ratio normalization was considered as the primary outcome and defined as a value≥1.Incidence rate and probability of CD4/CD8 ratio normalization were estimated through per 100 person-years follow-up(PYFU)and Kaplan-Meier curve,respectively.Multivariate Cox regression was used to identify independent risk factors associated with CD4/CD8 ratio normalization.We further studied the rate of dyslipidemia,hyperuricemia,diabetes,liver injury,and renal injury after ART initiation with the chi-squared tests or Fisher’s exact probability tests,and a generalized estimating equation model was used to analyze factors of dyslipidemia and hyperuricemia.Results:A total of 494 female patients with HIV/AIDS started ART within 16 years from January 2005 to June 2021,out of which 301 women were enrolled with a median duration of ART for 4.1 years(interquartile range,2.3-7.0 years).The overall incidence rate of CD4/CD8 ratio normalization was 8.9(95%confidence interval[CI],7.4-10.6)per 100 PYFU,and probabilities of CD4/CD8 normalization after initiating ART at 1 year,2 years,5 years,and 10 years follow-up were 11.7%,23.2%,44.0%,and 59.0%,respectively.Independent risk factors associated with CD4/CD8 normalization were baseline CD4 cell counts<200 cells/μL,CD8 counts>1000 cells/μL,and more than 6 months from the start of combined ART(cART)to first virological suppression.Longitudinally,the rate of hypercholesterolemia(total cholesterol[TC])and high triglyceride(TG)showed an increasing trend,while the rate of low high-density lipoprotein cholesterol(HDL)showed a decreasing trend.The rate of hyperuricemia presented a downtrend at follow-up.Although liver and renal injury and diabetes persisted during ART,the rate was not statistically significant.Older age and protease inhibitors were independent risk factors for increase of TC and TG,and ART duration was an independent factor for elevation of TC and recovery of HDL-C.Conclusions:This study showed that women were more likely to normalize CD4/CD8 ratio in comparison with findings reported in the literature even though immune reconstruction was incomplete.

Metformin may be a viable adjunctive therapeutic option to potentially enhance immune reconstitution in HIV-positive immunological non-responders

Incomplete immune reconstitution remains a global challenge for human immunodeficiency virus(HIV)treatment in the present era of potent antiretroviral therapy(ART),especially for those individuals referred to as immunological non-responders(INRs),who exhibit dramatically low CD4^(+)T-cell counts despite the use of effective antiretroviral therapy,with long-term inhibition of viral replication.In this review,we provide a critical overview of the concept of ART-treated HIV-positive immunological non-response,and also explain the known mechanisms which could potentially account for the emergence of immunological non-response in some HIV-infected individuals treated with appropriate and effective ART.We found that immune cell exhaustion,combined with chronic inflammation and the HIV-associated dysbiosis syndrome,may represent strategic aspects of the immune response that may be fundamental to incomplete immune recovery.Interestingly,we noted from the literature that metformin exhibits properties and characteristics that may potentially be useful to specifically target immune cell exhaustion,chronic inflammation,and HIV-associated gut dysbiosis syndrome,mechanisms which are now recognized for their critically important complicity in HIV disease-related incomplete immune recovery.In light of evidence discussed in this review,it can be seen that metformin may be of particularly favorable use if utilized as adjunctive treatment in INRs to potentially enhance immune reconstitution.The approach described herein may represent a promising area of therapeutic intervention,aiding in significantly reducing the risk of HIV disease progression and mortality in a particularly vulnerable subgroup of HIV-positive individuals.