The Potential of Clostridium butyricum to Preserve Gut Health, and to Mitigate Non-AIDS Comorbidities in People Living with HIV.

A dramatic reduction in mortality among people living with HIV (PLWH) has been achieved during the modern antiretroviral therapy (ART) era. However, ART does not restore gut barrier function even after long-term viral suppression, allowing microbial products to enter the systemic blood circulation and induce chronic immune activation. In PLWH, a chronic state of systemic inflammation exists and persists, which increases the risk of development of inflammation-associated non-AIDS comorbidities such as metabolic disorders, cardiovascular diseases, and cancer. Clostridium butyricum is a human butyrate-producing symbiont present in the gut microbiome. Convergent evidence has demonstrated favorable effects of C. butyricum for gastrointestinal health, including maintenance of the structural and functional integrity of the gut barrier, inhibition of pathogenic bacteria within the intestine, and reduction of microbial translocation. Moreover, C. butyricum supplementation has been observed to have a positive effect on various inflammation-related diseases such as diabetes, ulcerative colitis, and cancer, which are also recognized as non-AIDS comorbidities associated with epithelial gut damage. There is currently scant published research in the literature, focusing on the influence of C. butyricum in the gut of PLWH. In this hypothesis review, we speculate the use of C. butyricum as a probiotic oral supplementation may well emerge as a potential future synergistic adjunctive strategy in PLWH, in tandem with ART, to restore and consolidate intestinal barrier integrity, repair the leaky gut, prevent microbial translocation from the gut, and reduce both gut and systemic inflammation, with the ultimate objective of decreasing the risk for development of non-AIDS comorbidities in PLWH.

PSGL-1, a Strategic Biomarker for Pathological Conditions in HIV Infection: A Hypothesis Review.

P-selectin glycoprotein ligand-1 (PSGL-1) has been established to be a cell adhesion molecule that is involved in the cellular rolling mechanism and the extravasation cascade, enabling the recruitment of immune cells to sites of inflammation. In recent years, researchers have established that PSGL-1 also functions as an HIV restriction factor. PSGL-1 has been shown to inhibit the HIV reverse transcription process and inhibit the infectivity of HIV virions produced by cells expressing PSGL-1. Cumulative evidence gleaned from contemporary literature suggests that PSGL-1 expression negatively affects the functions of immune cells, particularly T-cells, which are critical participants in the defense against HIV infection. Indeed, some researchers have observed that PSGL-1 expression and signaling provokes T-cell exhaustion. Additionally, it has been established that PSGL-1 may also mediate virus capture and subsequent transfer to permissive cells. We therefore believe that, in addition to its beneficial roles, such as its function as a proinflammatory molecule and an HIV restriction factor, PSGL-1 expression during HIV infection may be disadvantageous and may potentially predict HIV disease progression. In this hypothesis review, we provide substantial discussions with respect to the possibility of using PSGL-1 to predict the potential development of particular pathological conditions commonly seen during HIV infection. Specifically, we speculate that PSGL-1 may possibly be a reliable biomarker for immunological status, inflammation/translocation, cell exhaustion, and the development of HIV-related cancers. Future investigations directed towards our hypotheses may help to evolve innovative strategies for the monitoring and/or treatment of HIV-infected individuals.

Influence of HIV infection on cognition and overall intelligence in HIV-infected individuals: advances and perspectives.

It is now well understood that HIV-positive individuals, even those under effective ART, tend to develop a spectrum of cognitive, motor, and/or mood conditions which are contemporarily referred to as HIV-associated neurocognitive disorder (HAND), and which is directly related to HIV-1 infection and HIV-1 replication in the central nervous system (CNS). As HAND is known to induce difficulties associated with attention, concentration, and memory, it is thus legitimate and pertinent to speculate upon the possibility that HIV infection may well influence human cognition and intelligence. We therefore propose herein to review the concept of intelligence, the concept of cells of intelligence, the influence of HIV on these particular cells, and the evidence pointing to differences in observed intelligence quotient (IQ) scores between HIV-positive and HIV-negative individuals. Additionally, cumulative research evidence continues to draw attention to the influence of the gut on human intelligence. Up to now, although it is known that HIV infection profoundly alters both the composition and diversity of the gut microbiota and the structural integrity of the gut, the influence of the gut on intelligence in the context of HIV infection remains poorly described. As such, we also provide herein a review of the different ways in which HIV may influence human intelligence via the gut-brain axis. Finally, we provide a discourse on perspectives related to HIV and human intelligence which may assist in generating more robust evidence with respect to this issue in future studies. Our aim is to provide insightful knowledge for the identification of novel areas of investigation, in order to reveal and explain some of the enigmas related to HIV infection.

An Overview of Diagnostic and Management Strategies for Talaromycosis, an Underrated Disease.

Underrated and neglected, talaromycosis is a life-threatening fungal disease endemic to the tropical and subtropical regions of Asia. In China, it has been reported that talaromycosis mortality doubles from 24 to 50% when the diagnosis is delayed, and reaches 100% when the diagnosis is missed. Thus, the accurate diagnosis of talaromycosis is of utmost importance. Herein, in the first part of this article, we provide an extensive review of the diagnostic tools used thus far by physicians in the management of cases of talaromycosis. The challenges encountered and the perspectives which may aid in the discovery of more accurate and reliable diagnostic approaches are also discussed. In the second part of this review, we discuss the drugs used to prevent and treat T. marneffei infection. Alternative therapeutic options and potential drug resistance reported in the contemporary literature are also discussed. We aim to guide researchers towards the discovery of novel approaches to prevent, diagnose, and treat talaromycosis, and therefore improve the prognosis for those afflicted by this important disease.

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

ABSTRACT: 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.

Candida albicans can foster gut dysbiosis and systemic inflammation during HIV infection.

Candida albicans (C. albicans) is a ubiquitous fungal commensal component of the human microbiota, and under certain circumstances, such as during an immunocompromised state, it may initiate different types of infection. Moreover, C. albicans continuously and reciprocally interacts with the host immune system as well as with other elements of the gut microbiota, thus contributing significantly to both gut homeostasis and host immunity. People living with HIV (PLWH), including those receiving antiretroviral therapy, are characterized by a depletion of CD4 + T-cells and dysbiosis in their gut. C. albicans colonization is frequent in PLWH, causing both a high prevalence and high morbidity. Gut barrier damage and elevated levels of microbial translocation are also fairly common in this population. Herein, we take a closer look at the reciprocity among C. albicans, gut microbiota, HIV, and the host immune system, thus throwing some light on this complex interplay.

SARS-CoV-2 pre-exposure prophylaxis: A potential COVID-19 preventive strategy for high-risk populations, including healthcare workers, immunodeficient individuals, and poor vaccine responders.

The unprecedented worldwide spread of SARS-CoV-2 has imposed severe challenges on global health care systems. The roll-out and widespread administration of COVID-19 vaccines has been deemed a major milestone in the race to restrict the severity of the infection. Vaccines have as yet not entirely suppressed the relentless progression of the pandemic, due mainly to the emergence of new virus variants, and also secondary to the waning of protective antibody titers over time. Encouragingly, an increasing number of antiviral drugs, such as remdesivir and the newly developed drug combination, Paxlovid® (nirmatrelvir/ritonavir), as well as molnupiravir, have shown significant benefits for COVID-19 patient outcomes. Pre-exposure prophylaxis (PrEP) has been proven to be an effective preventive strategy in high-risk uninfected people exposed to HIV. Building on knowledge from what is already known about the use of PrEP for HIV disease, and from recently gleaned knowledge of antivirals used against COVID-19, we propose that SARS-CoV-2 PrEP, using specific antiviral and adjuvant drugs against SARS-CoV-2, may represent a novel preventive strategy for high-risk populations, including healthcare workers, immunodeficient individuals, and poor vaccine responders. Herein, we critically review the risk factors for severe COVID-19 and discuss PrEP strategies against SARS-CoV-2. In addition, we outline details of candidate anti-SARS-CoV-2 PrEP drugs, thus creating a framework with respect to the development of alternative and/or complementary strategies to prevent COVID-19, and contributing to the global armamentarium that has been developed to limit SARS-CoV-2 infection, severity, and transmission.

HIV Infection Predisposes to Increased Chances of HBV Infection: Current Understanding of the Mechanisms Favoring HBV Infection at Each Clinical Stage of HIV Infection.

Human immunodeficiency virus (HIV) selectively targets and destroys the infection-fighting CD4+ T-lymphocytes of the human immune system, and has a life cycle that encompasses binding to certain cells, fusion to that cell, reverse transcription of its genome, integration of its genome into the host cell DNA, replication of the HIV genome, assembly of the HIV virion, and budding and subsequent release of free HIV virions. Once a host is infected with HIV, the host's ability to competently orchestrate effective and efficient immune responses against various microorganisms, such as viral infections, is significantly disrupted. Without modern antiretroviral therapy (ART), HIV is likely to gradually destroy the cellular immune system, and thus the initial HIV infection will inexorably evolve into acquired immunodeficiency syndrome (AIDS). Generally, HIV infection in a patient has an acute phase, a chronic phase, and an AIDS phase. During these three clinical stages, patients are found with relatively specific levels of viral RNA, develop rather distinctive immune conditions, and display unique clinical manifestations. Convergent research evidence has shown that hepatitis B virus (HBV) co-infection, a common cause of chronic liver disease, is fairly common in HIV-infected individuals. HBV invasion of the liver can be facilitated by HIV infection at each clinical stage of the infection due to a number of contributing factors, including having identical transmission routes, immunological suppression, gut microbiota dysbiosis, poor vaccination immune response to hepatitis B immunization, and drug hepatotoxicity. However, there remains a paucity of research investigation which critically describes the influence of the different HIV clinical stages and their consequences which tend to favor HBV entrenchment in the liver. Herein, we review advances in the understanding of the mechanisms favoring HBV infection at each clinical stage of HIV infection, thus paving the way toward development of potential strategies to reduce the prevalence of HBV co-infection in the HIV-infected population.

Pre-treatment and acquired antiretroviral drug resistance among people living with HIV in Tianjin, China.

OBJECTIVES: This study investigated the prevalence and patterns of pre-treatment and acquired HIV drug resistance mutations among people living with HIV (PLWH) on antiretroviral therapy (ART) for 12 (±3) months in Tianjin, China. METHODS: From Jan 2018 to Dec 2020, PLWH with HIV-1 RNA greater than 1000 copies/mL visiting the ART clinic in the Tianjin Second People's Hospital were enrolled. Viral RNA isolated from blood samples were taken for genotypic resistance testing using an in-house method. Major drug resistance mutations were analyzed for reverse transcriptase and protease Sanger sequences using the Stanford University HIV Drug Resistance Database. Multivariable Poisson regressions were used to evaluate the factors associated with drug resistance mutations. RESULTS: HIV drug resistance testing was successfully performed on 584 ART-naive and 71 ART-experienced participants. Pre-treatment drug resistance mutation prevalence was 13.5% (79/584) to any antiretroviral drug, 12.5% (73/584) to non-nucleoside reverse transcriptase inhibitors (NNRTIs), 1.5% (9/584) to nucleoside reverse-transcriptase inhibitors (NRTIs), and 0.3% (2/584) to protease inhibitors (PIs). Acquired drug resistance to any antiretroviral drug among PLWH on ART with viral load >1000 copies/mL was 88.7% (63/71). The prevalence of mutation for NNRTIs, NRTIs, and PIs were 93.7% (59/63), 82.5% (52/63), and 3.2% (2/63), respectively. CONCLUSIONS: Pre-treatment and acquired drug resistance mutations were highly prevalent among PLWH in Tianjin; therefore, routine baseline genotypic resistance testing and adequate intervals of viral load surveillance are urgently needed for the long-term treatment success. Our findings provide important evidence for first- and second-line regimen drugs for PLWH, especially in China.

Single-Cell Sequencing Facilitates Elucidation of HIV Immunopathogenesis: A Review of Current Literature.

Knowledge gaps remain in the understanding of HIV disease establishment and progression. Scientists continue to strive in their endeavor to elucidate the precise underlying immunopathogenic mechanisms of HIV-related disease, in order to identify possible preventive and therapeutic targets. A useful tool in the quest to reveal some of the enigmas related to HIV infection and disease is the single-cell sequencing (scRNA-seq) technique. With its proven capacity to elucidate critical processes in cell formation and differentiation, to decipher critical hematopoietic pathways, and to understand the regulatory gene networks that predict immune function, scRNA-seq is further considered to be a potentially useful tool to explore HIV immunopathogenesis. In this article, we provide an overview of single-cell sequencing platforms, before delving into research findings gleaned from the use of single cell sequencing in HIV research, as published in recent literature. Finally, we describe two important avenues of research that we believe should be further investigated using the single-cell sequencing technique.

The diverse roles of miRNAs in HIV pathogenesis: Current understanding and future perspectives.

Despite noteworthy progress made in the management and treatment of HIV/AIDS-related disease, including the introduction of the now almost ubiquitous HAART, there remains much to understand with respect to HIV infection. Although some roles that miRNAs play in some diseases have become more obvious of late, the roles of miRNAs in the context of HIV pathogenesis have not, as yet, been elucidated, and require further investigations. miRNAs can either be beneficial or harmful to the host, depending upon the genes they target. Some miRNAs target the 3' UTR of viral mRNAs to accomplish restriction of viral infection. However, upon HIV-1 infection, there are several dysregulated host miRNAs which target their respective host factors to either facilitate or abrogate viral infection. In this review, we discuss the miRNAs which play roles in various aspects of viral pathogenesis. We describe in detail the various mechanisms thereby miRNAs either directly or indirectly regulate HIV-1 infection. Moreover, the predictive roles of miRNAs in various aspects of the HIV viral life cycle are also discussed. Contemporary antiretroviral therapeutic drugs have received much attention recently, due to their success in the treatment of HIV/AIDS; therefore, miRNA involvement in various aspects of antiretroviral therapeutics are also elaborated upon herein. The therapeutic potential of miRNAs are discussed, and we also propose herein that the therapeutic potential of one specific miRNA, miR-34a, warrants further exploration, as this miRNA is known to target three host proteins to promote HIV-1 pathogenesis. Finally, future perspectives and some controversy around the expression of miRNAs by HIV-1 are also discussed.

Are HIV-1-Specific Antibody Levels Potentially Useful Laboratory Markers to Estimate HIV Reservoir Size? A Review.

Despite the benefits achieved by the widespread availability of modern antiretroviral therapy (ART), HIV RNA integration into the host cell genome is responsible for the creation of latent HIV reservoirs, and represents a significant impediment to completely eliminating HIV infection in a patient via modern ART alone. Several methods to measure HIV reservoir size exist; however, simpler, cheaper, and faster tools are required in the quest for total HIV cure. Over the past few years, measurement of HIV-specific antibodies has evolved into a promising option for measuring HIV reservoir size, as they can be measured via simple, well-known techniques such as the western blot and enzyme-linked immunosorbent assay (ELISA). In this article, we re-visit the dynamic evolution of HIV-1-specific antibodies and the factors that may influence their levels in the circulation of HIV-positive individuals. Then, we describe the currently-known relationship between HIV-1-specific antibodies and HIV reservoir size based on study of data from contemporary literature published during the past 5 years. We conclude by highlighting current trends, and discussing the individual HIV-specific antibody that is likely to be the most reliable antibody for potential future utilization for quantification of HIV reservoir size.

Selective elimination of host cells harboring replication-competent human immunodeficiency virus reservoirs: a promising therapeutic strategy for HIV cure.

ABSTRACT: Many seminal advances have been made in human immunodeficiency virus (HIV)/AIDS research over the past four decades. Treatment strategies, such as gene therapy and immunotherapy, are yielding promising results to effectively control HIV infection. Despite this, a cure for HIV/AIDS is not envisioned in the near future. A recently published academic study has raised awareness regarding a promising alternative therapeutic option for HIV/AIDS, referred to as "selective elimination of host cells capable of producing HIV" (SECH). Similar to the "shock and kill strategy," the SECH approach requires the simultaneous administration of drugs targeting key mechanisms in specific cells to efficiently eliminate HIV replication-competent cellular reservoirs. Herein, we comprehensively review the specific mechanisms targeted by the SECH strategy. Briefly, the suggested cocktail of drugs should contain (i) latency reversal agents to promote the latency reversal process in replication-competent reservoir cells, (ii) pro-apoptotic and anti-autophagy drugs to induce death of infected cells through various pathways, and finally (iii) drugs that eliminate new cycles of infection by prevention of HIV attachment to host cells, and by HIV integrase inhibitor drugs. Finally, we discuss three major challenges that are likely to restrict the application of the SECH strategy in HIV/AIDS patients.

HIV-1 CRF07_BC transmission dynamics in China: two decades of national molecular surveillance.

ABSTRACTBy analyzing an unprecedentedly large, longitudinal HIV-1 CRF07_BC sequence dataset collected from China in the past two decades, we sought to build CRF07_BC lengthwise transmission networks, and understand its transmission dynamics. We divided CRF07_BC into two clusters based on phylogenetic analysis and an estimation of the pairwise genetic distance at 0.7%. Of 6213 sequences, 3607 (58.1%) linked to ≥1 other sequence. CRF07_BC was divided into two clusters: 07BC_O and 07BC_N. The 07BC_O is the original CRF07_BC, circulating in people who inject drugs (PWID) and heterosexuals, predominantly in southwestern and northwestern provinces of China. The 07BC_N is a new cluster, identified mostly in men having sex with men (MSM) in the northern provinces of China. Bayesian analysis indicates that CRF07_BC has experienced two phases of exponential growth, which was first driven by 07BC_O then 07BC_N. Compared to 07BC_O, the proportion of the parameter of population transmission risk (TR) of 07BC_N has risen constantly. The power-law function analyses reveal that 07BC_N has increased over years with higher degree. In 07BC_N, only 13.16% of MSM were linked to other risk groups, but these links represent 41.45%, 54.25%, and 55.07% of links among heterosexual females, heterosexual males, and male PWID respectively. This study indicates that CRF07_BC has evolved into two clusters in China, and their distributions are distinct across risk groups and geographical regions. 07BC_N shows a greater risk of transmission, and has gradually replaced 07BC_O. Furthermore, the results show that strengthening the MSM interventions could lower the rapidity of 07BC_N transmission in all risk groups.

P-Selectin Glycoprotein Ligand 1: A Potential HIV-1 Therapeutic Target.

Antiretroviral therapy (ART), which is a life-long therapeutic option, remains the only currently effective clinical method to treat HIV-1 infection. However, ART may be toxic to vital organs including the liver, brain, heart, and kidneys, and may result in systemic complications. In this context, to consider HIV-1 restriction factors from the innate immune system to explore novel HIV therapeutics is likely to be a promising investigative strategy. In light of this, P-selectin glycoprotein ligand 1 (PSGL-1) has recently become the object of close scrutiny as a recognized cell adhesion molecule, and has become a major focus of academic study, as researchers believe that PSGL-1 may represent a novel area of interest in the research inquiry into the field of immune checkpoint inhibition. In this article, we review PSGL-1's structure and functions during infection and/or inflammation. We also outline a comprehensive review of its role and potential therapeutic utility during HIV-1 infection as published in contemporary academic literature.

Direct-acting antiviral treatments display excellent outcomes even in older HCV-infected patients at increased risk of fibrosis.

BACKGROUND: This study compared the efficacy and tolerability of available direct-acting antiviral (DAA) regimens between individuals aged 60 years and older and younger patients in a real-life setting. Specifically, we aimed to provide evidence of the efficacy and safety of DAAs in the treatment of older adults in Tianjin, China. METHODS: In this retrospective observational cohort study, patients with chronic hepatitis C virus (HCV) were enrolled between April 2018 and December 2019 at 2 tertiary hospitals in Tianjin, China. We assessed the sustained virologic response (SVR) 12 weeks (SVR12) after DAA treatment, and adverse events in two groups using age stratification by comparing older adults (≥60 years) and younger adults (<60 years). Logistic regression analyses were performed to explore the risk factors associated with the SVR12. RESULTS: Of 1,106 patients, 440 (39.8%) were ≥60 years of age. The overall SVR12 rate was 97.8% in the entire cohort. In the older adult group, the SVR12 rate was 98.0% (431/440) compared to 97.7% (651/666) in the younger adult group. A multivariate analysis showed that (I) age was not predictive of SVR; and (II) the variables of treatment-experience [adjusted odds ratio (aOR) =27.53; 95% confidence interval (CI) =3.35-226.08; P=0.002] and aspartate aminotransferase (AST) (aOR =1.02; 95% CI =1.01-1.04; P=0.027) were independently associated with the SVR12 in the older adult group. All of the available DAA regimens were well-tolerated in older adult group. CONCLUSIONS: Chinese older adults with chronic HCV infection showed a significantly higher percentage of fibrosis; however, the available different DAA regimens were safe, well-tolerated, and achieved high rates of SVR in all age subgroups. Our observations suggest that DAA treatment should not be withheld even from older patients suffering from chronic HCV.

Microbiota-Meditated Immunity Abnormalities Facilitate Hepatitis B Virus Co-Infection in People Living With HIV: A Review.

Hepatitis B virus (HBV) co-infection is fairly common in people living with HIV (PLWH) and affects millions of people worldwide. Identical transmission routes and HIV-induced immune suppression have been assumed to be the main factors contributing to this phenomenon. Moreover, convergent evidence has shown that people co-infected with HIV and HBV are more likely to have long-term serious medical problems, suffer more from liver-related diseases, and have higher mortality rates, compared to individuals infected exclusively by either HIV or HBV. However, the precise mechanisms underlying the comorbid infection of HIV and HBV have not been fully elucidated. In recent times, the human gastrointestinal microbiome is progressively being recognized as playing a pivotal role in modulating immune function, and is likely to also contribute significantly to critical processes involving systemic inflammation. Both antiretroviral therapy (ART)-naïve HIV-infected subjects and ART-treated individuals are now known to be characterized by having gut microbiomic dysbiosis, which is associated with a damaged intestinal barrier, impaired mucosal immunological functioning, increased microbial translocation, and long-term immune activation. Altered microbiota-related products in PLWH, such as lipopolysaccharide (LPS) and short-chain fatty acids (SCFA), have been associated with the development of leaky gut syndrome, favoring microbial translocation, which in turn has been associated with a chronically activated underlying host immune response and hence the facilitated pathogenesis of HBV infection. Herein, we critically review the interplay among gut microbiota, immunity, and HIV and HBV infection, thus laying down the groundwork with respect to the future development of effective strategies to efficiently restore normally diversified gut microbiota in PLWH with a dysregulated gut microbiome, and thus potentially reduce the prevalence of HBV infection in this population.

CRF01_AE and CRF01_AE Cluster 4 Are Associated With Poor Immune Recovery in Chinese Patients Under Combination Antiretroviral Therapy.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) clades and clusters have different epidemic patterns and phenotypic profiles. It is unclear if they also affect patients' immune recovery (IR) in combination antiretroviral therapy (cART). METHODS: We conducted a cohort study on 853 patients under cART for evaluating the impacts of viral factor on host IR. We used generalized estimating equations for factors affecting CD4 recovery, Kaplan-Meier curves for probability of achieving IR, and Cox hazards model for factors influencing IR capability. RESULTS: Besides low baseline CD4 and old age, CRF01_AE and its cluster 4 were independently associated with lower CD4 cell level (P ≤ .003), slower IR (P ≤ .022), fewer patients (P < .001), and longer time achieving IR (P < .001), compared with CRF07_BC and CRF01_AE cluster 5. Higher percentage of CXCR4 (X4) viruses in the CRF01_AE and cluster 4-infected patients, compared with their respective counterparts (P < .001), accounted for the poor IR in infected patients (P < .001). Finally, we revealed that greater X4 receptor binding propensity of amino acids was exhibited in CRF01_AE clade (P < .001) and its cluster 4 (P ≤ .004). CONCLUSIONS: Our study demonstrates that the CRF01_AE clade and cluster are associated with poor IR in patients under cART, which is ascribed to a high proportion of viruses with X4 tropism. HIV-1 genotyping and phenotyping should be used as a surveillance tool for patients initiating cART. CCR5 inhibitors should be used with caution in regions with high prevalence of X4 viruses.

Safety and efficacy of allogeneic natural killer cell immunotherapy on human immunodeficiency virus type 1 immunological non-responders: a brief report.

BACKGROUND: Allogeneic natural killer (NK) cell immunotherapy is recognized as a promising anti-tumor strategy, but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1 (HIV-1) infected patients is unknown. This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders (INRs) receiving antiretroviral therapy (ART). METHODS: From February to April 2018, a prospective, randomized, controlled, open-label clinical trial, which enrolled 20 HIV-1 INRs following specific inclusion criteria, was conducted at Nankai University Second People's Hospital. Participants were randomly allocated (simple randomization 1:1) to either the combined treatment (NK + ART) group (n = 10) or the control (ART) group (n = 10). The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA)-Cw mismatched healthy donor were prepared (10 cells in each injection) and intravenously infused to each recruited patient of NK+ART group in three courses. Key immune parameters (CD4 count, CD8 count, CD4/CD8 ratio), laboratory tests (count of blood cells, biochemistry panel) and symptoms at baseline and at month 1, 3, 6, 9, 12, and 24 were measured/collected to analyze the safety and efficacy of the therapy. Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance (ANOVA) test. Generalized estimating equations (GEE) model was performed to evaluate the overall effect of the NK+ART group vs. the ART group. RESULTS: From baseline to 24 months, we noted a mean CD4 count augmentation (139 to 243 cells/µL) in the NK + ART group and (144 to 176 cells/µL) in the ART group (difference, 67; 95% CI, 10 to 124; P = 0.024). Our estimations revealed that NK+ART group could improve CD4 level (ß = 54.59, P = 0.006) and CD8 level (ß = 322.47, P = 0.010) on average among the six measurements compared with the ART group. Only two (2/10, 20%) participants in the NK+ART group developed a transient mild fever after the first course. CONCLUSIONS: This preliminary study informs that HIV-1 INRs, allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio. The practical effects, however, need long-term follow-up observations. Further study on the potential underlying mechanism is warranted. REGISTRATION INFO:: www.chictr.org.cn/showproj.aspx?proj=34912 (No. ChiCTR1900020634).