AIDS research and human retroviruses最新文献

Human immunodeficiency virus (HIV) infection weakens immunity. Monitoring the immune status of the patient has become an important aspect of evaluating the progression of the disease and informing follow-up after treatment. Estimation of CD4 counts is quite costly and requires expertise in flow cytometry. In certain pathologies, free light chains (FLCs) are secreted in serum and urine and the magnitude can be used to monitor the severity, progression, and therapeutic monitoring of the disease. Urine as a specimen proves cost-effective and presents reduced risks during sample collection. The stability of light chains in urine at room temperature over extended periods simplifies the management of sample transportation as well. Hence, a pilot cross-sectional study was planned to evaluate the levels of urinary immunoglobulins in patients with HIV. The study was conducted at PGIMER, Dr. Ram Manohar Lohia Hospital (presently ABVIMS), New Delhi. Sixty-nine consecutive ART-naive HIV patients aged between 18 and 40 years and 69 age- and sex-matched healthy controls were included in the study. Urinary FLC kappa (κ) and lambda (λ) were measured using an immunoglobulin ELISA kit. Baseline urinary κ light chain levels were significantly higher in cases when compared with controls (p < .001) and were found to be increased with increasing WHO immunological classes (p < .001) and inversely related to CD4 cell count. However, no significant difference in mean urinary λ immunoglobulin light chain between cases and controls was found and no correlation with CD4 cell count or with stages of WHO immunological classification of HIV disease was observed. It is suggested that urinary free κ chain measurements combined with serum light chain measurements may be a useful marker in the follow-up and monitoring of response to therapies in patients with HIV where testing by flow cytometry is not available.

The recently Food and Drug Administration (FDA)-approved cabotegravir (CAB) has demonstrated efficacy as an antiretroviral agent for HIV treatment and prevention, becoming an important tool to stop the epidemic in the United States of America (USA). However, the effectiveness of CAB can be compromised by the presence of specific integrase natural polymorphisms, including T97A, L74M, M50I, S119P, and E157Q, particularly when coupled with the primary drug-resistance mutations G140S and Q148H. CAB's recent approval as a pre-exposure prophylaxis (PrEP) may increase the number of individuals taking CAB, which, at the same time, could increase the number of epidemiological implications. In this context, where resistance mutations, natural polymorphisms, and the lack of drug-susceptibility studies prevail, it becomes imperative to comprehensively investigate concerns related to the use of CAB. We used molecular and cell-based assays to assess the impact of T218I and T218S in the context of major resistance mutations G140S/Q148H on infectivity, integration, and resistance to CAB. Our findings revealed that T218I and T218S, either individually or in combination with G140S/Q148H, did not significantly affect infectivity, integration, or resistance to CAB. Notably, these polymorphisms also exhibited neutrality concerning other widely used integrase inhibitors, namely raltegravir, elvitegravir, and dolutegravir. Thus, our study suggests that the T218I and T218S natural polymorphisms are unlikely to undermine the effectiveness of CAB as a treatment and PrEP strategy.

Recent studies have reported increasing complexity in human immunodeficiency virus 1 (HIV-1) genotypes among men who have sex with men (MSM) in China. In an HIV-1 molecular epidemiological study conducted among MSM in Yunnan Province, China, we discovered that four samples could potentially represent a circulating recombinant form (CRF). In this study, we conducted further analysis on their nearly full-length genome (NFLG) sequences. The NFLG sequences formed a distinct monophyletic clade in the phylogenetic tree. Recombination analysis indicated that the four sequences were constructed upon the backbone of CRF149_01B, with the insertion of three CRF07_BC fragments. Consequently, they were designated as CRF150_cpx. Evolutionary analyses suggested that CRF150_cpx emerged between approximately 2014 and 2015. The identification of new CRFs not only deepens our understanding of HIV recombination but also aids in comprehending the prevalence and transmission history of HIV among specific populations.

Cytokines are key mediators of immune regulation, orchestrate communication between immune cells, and play a pivotal role in shaping the immune landscape during chronic infection and cancer. The therapeutic potential of IL-15/IL-15Rα and IL-12 has been explored individually in various immunotherapeutic strategies, though not as a combination. Therefore, we investigated whether the combination of IL-15/IL-15Rα and IL-12 treatment would enhance the potency and quality of either NK cells, SIV-specific CD8 T cells, or both, compared with single cytokine treatment. Our findings reveal that in vitro IL-15/IL-15Rα and IL-15/IL-15Rα plus IL-12 treatment results in an expansion of functional CD8 T cells and NK cells from uninfected and chronically infected macaques with simian/human immunodeficiency virus. Additionally, the cytokine combination significantly reduced CCR5 expression on total CD4 T cells, limiting the number of viral targets. This study supports the potential utilization of combined IL-15/IL-15Rα plus IL-12 treatment for chronic viral infections and cancer.

Human T cell lymphotropic virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma (ATLL), a fetal malignant infection. Recently, HTLV-1 new asymptomatic carriers (ACs) have frequently been reported among blood donors. Reaching the profound concept of HTLV-1-associated molecular pathogenesis could result in finding novel therapeutic strategies. The current study aimed to determine leukemia-related signaling regulation in ATLL. Thirty participants were evaluated in 3 groups, including 10 ATLL patients, 10 ACs, and 10 normal controls. Blood samples were isolated without any chemotherapy history from ATLL patients. Also, blood samples were recovered from ACs and normal individuals. White blood cells isolation was done on the collected blood samples. After this, RNA was extracted from the prepared samples and used for the cDNA synthesis. TAX and HTLV-1 basic leucine zipper factor as viral genes and cellular genes, including MKP-1, EVI-1, JNK-1, FOXO-1, AKT-1, DEPTOR, MTOR, and JUN, were investigated using real-time PCR. The mean age of ATLL patients was 53.2 ± 7.32 years, and 9 (90%) were male. The EVI-1 and FOXO-1 expression levels were significantly associated with ATLL patients compared with the internal control. However, the significant differences in expression of other genes in the remaining groups were not seen. Discovering viral and cellular signaling pathways that regulate HTLV-1 transformation is essential. A novel therapeutic strategy for ATLL-regulating cellular signaling pathways in vivo could be considered. Therefore, clinical trials using activators and inhibitors of related cellular signaling pathways for cell therapy of ATLL are recommended. It is recommended that more investigation be conducted on FOXO-1 and EVI-1 to target these genes and reveal the molecular pathogenesis of ATLL.

A newer integrase strand transfer inhibitor (INSTI) cabotegravir was recently approved for both therapy and prophylaxis and can play an essential role in the fight against AIDS. It shares similar resistance profile to dolutegravir, the cornerstone of Brazilian antiretroviral (ARV) treatment, with about 600 thousand people living with HIV in Brazil currently on regimens that contain this INSTI. Health services in the São Paulo metropolitan area are responsible for a large proportion of ARV dispensation in the country. Estimating transmitted drug resistance mutation (TDRM) in the area before cabotegravir introduction may provide a useful baseline information. Partial HIV-1 pol gene was sequenced (Sanger) from 192 newly diagnosed individuals from São Paulo and nearby cities (2020 to March 2023) at integrase, with 85 also at protease/reverse transcriptase regions. Retrotranscribed plasma RNA, amplified with nested PCR, was edited (Recall or Sequencher) and analyzed at Rega and Stanford db. Surveillance drug resistance mutations (SDRM) to INSTI class was detected in three cases (1.6%; 95% CI: 0.5%-5%), two E138K and one R263K, with 7.8% (95% CI: 5%-13%) with resistance mutations (major or accessory). SDRM for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and PI classes were identified in 7 (8.2% CI: 95% 4%-16%) cases. Subtype B predominated (69%), followed by subtype C (16%), now the second most prevalent infection in this area. Among 131 patients treated for over 6 months, 92% were virally suppressed below 200 copies/mL, with low TCD4 counts independently associated to failure. SDRM to INSTI class is rare in the area. Intermediate rates of transmitted resistance to other ARV classes are comparable to previous estimates. Viral suppression rates may depend on TCD4 counts, another negative impact of late diagnosis in care that deserves more attention.

Advancements in long-acting (LA) HIV treatment and cure research with analytical treatment interruptions (ATIs) have generated important scientific and implementation questions. There is an urgent need to examine challenges navigating the evolving HIV treatment and cure research landscape. From August to October 2022, we conducted 26 semistructured interviews with biomedical researchers and community members representing a predominantly woman demographic to explore the complexity of navigating the rapidly evolving HIV therapeutic and HIV cure research landscape. We purposively sampled individuals recruited from the AIDS Clinical Trials Group and the Martin Delaney Collaboratories for HIV Cure Research. Audio files were transcribed verbatim and analyzed through a thematic approach, using an inductive and iterative process. Among 26 participants, 10 were biomedical researchers and 16 community members, including 11 were people with HIV. Three main themes emerged: (1) We are at a pivotal moment in the evolving landscape of HIV therapeutics and LA HIV treatment and HIV cure research should not be siloed but considered together; (2) There are challenges with engagement in HIV cure research and in switching between oral daily antiretroviral treatment and LA formulations and, mainly, the prolonged pharmacokinetic tail of these compounds matched with limited patient education about their impacts; and (3) There are unique opportunities as a result of this evolving therapeutic landscape, including the key role of decision support for people with HIV, centering around patient autonomy, and the need to learn from the lived experiences of people with HIV who choose LA treatment and/or participation in HIV cure research. Despite a bias toward the woman gender, our study identifies key considerations for navigating concurrent LA HIV treatment and HIV cure research with ATIs from both community members and biomedical researchers' perspectives. Achieving optimal HIV control remains a formidable challenge, necessitating robust interdisciplinary collaborations and engagement with key stakeholders.

In China, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are integral to the antiretroviral therapy (ART) regimen for persons living with HIV (PWH), comprising over 80% of such treatments. To broaden treatment options and improve therapeutic effectiveness, Ainuovirine (ANV), a new NNRTI, was authorized for ART in 2021. Nevertheless, the clinical efficacy of ANV and its impact on blood biochemical markers remain somewhat underexplored. This study seeks to evaluate ANV's clinical performance in ART and its influence on relevant treatment parameters. A retrospective analysis was performed on 208 patients treated with an ANV-based regimen from July 2021 to July 2023, monitoring indicator changes from baseline to week 24. The primary endpoint was the proportion of participants achieving HIV-1 RNA levels of less than 50 copies/mL by week 24. Secondary endpoints involved assessing variations in CD4⁺ T cell counts and blood biochemical markers from baseline. These outcomes were also compared with data from 241 patients treated with an Efavirenz (EFV)-based regimen in the same time frame. The findings suggest that the ANV-based regimen is as effective as the EFV-based regimen in viral suppression (p > .05) and offers superior improvements in lipid profiles, liver function, and immune system indicators, alongside fewer adverse reactions. These results affirm ANV's efficacy and safety as an antiretroviral therapy option, offering Acquired Immune Deficiency Syndrome patients a wider array of treatment possibilities and the potential for better treatment outcomes.

More than 62,000 individuals are currently on antiretroviral treatment within the public health system in Argentina. In 2019, more than 50% of people on ART received non-nucleoside reverse transcriptase inhibitors (NNRTIs). In this context, the second nationwide HIV-1 pretreatment drug resistance surveillance study was carried out between April and December 2019 to assess the prevalence of HIV-1 drug resistance in Argentina using the World Health Organization guidelines. This was a nationwide cross-sectional study enrolling consecutive 18-year-old and older individuals starting ARVs at 19 ART-dispensing centers. This allowed us to estimate a point prevalence rate of resistance-associated mutations (RAMs) with a confidence interval (CI) of 5% (for the total population and for those without antiretroviral exposure). Four-hundred forty-seven individuals were included in the study. The prevalence of mutations associated with resistance was detected in 27.7% (95% CI 25.6-34.9%) of the population. For NNRTI, it was 19.6% (95% CI 16.3-24.5%), for integrase strand transfer inhibitor (INSTI) 6.1% (95% CI 6.1-11.9%), for nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) 3% (95% CI 1.9-5.9%), and for protease inhibitors 1.5% (95% CI 0.7-3.6%). Naive individuals had variants of resistance to NRTIs in 16.8% (95% CI 12.8-21.4) and 5.7% (95% CI 2.9-15.9) to INSTI. For experienced individuals, the prevalence of variants associated with resistance was 30.38% (95% CI 20.8-42.2) for NRTIs and 7.7% (95% CI 2.9-15.9) for INSTI. This study shows an increase in the frequency of nonpolymorphic RAMs associated with resistance to NNRTI. This study generates the framework of evidence that supports the use of schemes based on high genetic barrier integrase inhibitors as the first line of treatment and the need for the use of resistance test before prescribing schemes based on NNRTI. We report for the first time the presence of a natural polymorphism associated with the most prevalent recombinant viral form in Argentina and the presence of a mutation linked to first-line integrase inhibitors such as raltegravir.

Glycoprotein 41 (gp41) of the human immunodeficiency virus type 1 (HIV-1) protein plays a critical role in membrane fusion. Gp41 binds to proteins in the plasma membrane of CD4⁺ T cells, particularly the T-cell antigen receptor (TCR). These findings indicate that gp41 is involved in the assembly of HIV-1 at the plasma membrane of T cells and affects the stimulation of the TCR. To control HIV-1, new inhibitors were introduced to target the gp41 protein. However, mutations in this region might reduce their efficacy. The Gp41 region was amplified from the sera of 30 patients using nested polymerase chain reaction. The sequences were analyzed by bioinformatics tools to identify mutations and gp41 structural features. Subtyping and the interaction between fusion inhibitors and gp41 proteins were also examined. As the first report from Iran, docking analysis between fusion inhibitors and Iranian gp41 proteins showed that mutations in gp41 could not reduce the efficacy of the fusion inhibitors. Most of the patients were infected with CRF35-AD. Several post-modification positions, including glycosylation and phosphorylation sites, were identified in the gp41 protein. Our findings revealed no known multinational drug resistance to gp41 inhibitors; thus, fusion inhibitors can effectively inhibit HIV in Iranian patients. In addition, the present study introduced a new gp41 region (36-44 aa), which considerably influences the interactions between gp41 inhibitors and the gp41 protein. This region may play a pivotal role in suppressing gp41 inhibitors in CFR35-AD. Furthermore, gp41 can be considered a good target for subtyping analysis via the phylogenetic method.