Broadly neutralizing antibodies (bnAbs) offer a promising alternative for HIV prevention and treatment, with the potential to cross the blood–brain barrier. However, the extent to which viral genetic variation between the peripheral blood and central nervous system impacts bnAb sensitivity remains insufficiently characterized. This study investigates sequence differences and neutralization profiles of matched plasma- and cerebrospinal fluid (CSF)-derived HIV-1 subtype C (HIV-1C) variants in patients coinfected with cryptococcal meningitis. Matched plasma and CSF samples were obtained from seven participants with HIV-cryptococcal meningitis coinfection in Durban, KwaZulu-Natal, South Africa. HIV-1C env was amplified, cloned into a vector, and sequenced by Sanger sequencing. Amino acid sequences within bnAb epitopes were compared between plasma- and CSF-derived clones. Additionally, we generated Env-pseudotyped viruses and assessed their neutralisation sensitivity using eight bnAbs targeting five known bnAb epitopes on HIV-1 Env. Discordant bnAb escape mutations and variations in neutralization sensitivity between plasma and CSF were observed in the CD4 binding site, V2 Apex and the V3 glycan supersite. Despite these variations, VRC07-523LS demonstrated broad neutralisation activity, with no significant differences in sensitivity across plasma and CSF variants. However, only minor neutralization sensitivity variations were observed in the MPER and gp120-gp41 interface between plasma and CSF compartments. These findings highlight potential differences in amino acid signatures and neutralisation sensitivity between matched plasma- and CSF-derived HIV-1C variants. Our findings show that bnAb targeting the CD4-binding site (VRC07-523LS) maintain cross-compartment efficacy and have a potential in the clearance of viral reservoirs.
Persistence of viral reservoirs prevents a cure or functional cure for HIV. Efforts to eradicate viral reservoirs have been constrained by the difficulties of identifying and eliminating rare, heterogeneous viral reservoir cells in vivo. Single-modality interventions such as “shock and kill” have faced persistent challenges despite decades of effort, highlighting the need for complementary strategies that more precisely target infected cells. In this review, I summarize our 20 years of effort in developing an HIV Rev-dependent lentiviral vector for selective targeting of viral reservoirs. This lentiviral vector expresses therapeutic genes under the control of HIV Tat and Rev, conferring high specificity. In vitro, superinfection of HIV-infected cells with the Rev-dependent particle can lead to the identification and selective killing of infected cells. In vivo, injection of Rev-dependent lentiviral particles into SIV-infected rhesus macaques stimulates antiviral immunity, leading to reduction of viral reservoirs and inhibition of viral rebound. We designate this Rev vector-based therapeutic approach as Rev-dependent HIV Immunotherapy (RHIT). The RHIT approach integrates three complementary reservoir-targeting strategies: (1) RHIT-mediated killing of reservoir cells via Rev-dependent therapeutic gene expression; (2) RHIT-mediated inhibition of active HIV replication via defective interfering particles; and (3) RHIT-induced anti-HIV immunity via induction of neutralizing antibodies and cell-mediated immune responses. In this review, I also discuss limitations and challenges for the future development of RHIT.
Abstract Background The interaction between HIV-1 and the host immune system plays a crucial role in the natural control and progression of the infection. Previous studies have identified APOBEC3G, Tetherin, SAMHD1, and SERINC5 as HIV-1 host restriction factors, which are counteracted by the viral proteins Vif, Vpu, and Nef, respectively. The blood expression levels of some of these host proteins are correlated with HIV load, suggesting that interindividual differences in the spontaneous control of HIV infection might lead to the identification of novel HIV restriction factors. Our study enrolled 150 participants from the Swiss HIV Cohort Study with human genome-wide genotyping data, pre-antiretroviral treatment peripheral blood mononuclear cells (PBMC) aliquots and HIV load measurements. Results Using BrB-seq, we quantified mRNA expression of all protein-coding genes and found significant associations between 792 genes and HIV load. Pathway analysis revealed that higher viral load associated with the upregulation of innate immune response, proteasome complex, mitochondrial and cell-cycle related activity, and with the downregulation of ribosomal transcripts and genes involved in cytokine-cytokine receptor interaction, including IL4R , IL7R , and TCF7 . Mendelian Randomization confirmed the viral restriction activity of TRABD2A and identified new candidates as potential restriction factors. Conclusions These findings provide novel insights into the host–virus interplay and suggest additional genes such as TNFSF10, TTC3 and GRAP that may contribute to the natural control of HIV-1 infection.
Abstract Background HIV-1 latency and persistence of viral reservoirs within memory CD4 + T cells remain a fundamental obstacle to achieving a cure despite suppressive antiviral treatments. HIV-1 persistence is sustained by the dynamic interactions between viral regulatory mechanisms and the host cellular environment. At the intersection between immunometabolism and virology, the quiescent metabolic profile of resting CD4 + T cells, defined as the balance between oxidative phosphorylation (OXPHOS) and aerobic glycolysis, supports the long-term maintenance of latent viral reservoirs. Existing “Shock and Kill” strategies have shown limited clinical impact, partly due to the metabolic constraints that limit robust viral reactivation. Targeting metabolic junctions to overcome this barrier may provide a complementary therapeutic avenue. Results We evaluated Zaprinast, a mitochondrial pyruvate carrier inhibitor (MPCi), for its capacity to reprogramme CD4 + T cell metabolism and promote latency reversal. Across multiple primary T-cell based models of HIV-1 latency, Zaprinast induced a moderate yet reproducible increase in HIV-1 gene expression and viral particle production, including in circulating reservoirs from antiretroviral-treated individuals cultured ex vivo . Metabolic profiling revealed a biphasic response: an initial, transient inhibition of mitochondrial respiration followed by a shift from an OXPHOS-dominant to a more glycolytic metabolic state, while maintaining mitochondrial function. This metabolic reprogramming of resting CD4 + T cells by Zaprinast was reversible and did not impair cell viability, trigger non-specific T cell activation or proliferation, nor elevate reactive oxygen species levels. Conclusions These results highlight that selective targeting of the quiescent metabolic state in resting CD4 + T cells can facilitate HIV-1 reactivation without compromising cellular integrity. This study identifies host metabolic reprogramming as a promising strategy to enhance latency reversal and complement existing cure strategies. Our work provides new insights into the importance of host metabolic states in governing viral persistence and underscores the translational potential of metabolic interventions in HIV-1 eradication research.
Antiretroviral inhibitors that target specific aspects of human immunodeficiency virus 1 (HIV-1) replication have made a huge impact on the management of the global AIDS pandemic and the health and well-being of people that live with HIV. Current maintenance therapies commonly consist of one or two nucleoside reverse transcriptase inhibitors co-formulated with a second-generation integrase strand transfer inhibitor (INSTI), and regimens containing the second-generation INSTI dolutegravir are in wide-use across the globe. INSTIs are active site inhibitors that block HIV-1 DNA integration– more precisely, the ability of the integrase enzyme to join the 3′ ends of the viral reverse transcript with host chromosomal DNA. High-level resistance to first-generation INSTIs readily occurs via amino acid substitutions proximal to the integrase active site. Second-generation INSTIs, by contrast, impart comparatively high genetic barriers to the generation of drug resistance. When observed, such changes within integrase tend to confer comparatively low level resistance to both first- and second-generation INSTIs. Moreover, there are several reports of clinical failure to dolutegravir in the absence of known integrase drug resistance mutations. Laboratory-based research has at the same time identified three non-integrase pathways that can lead to dolutegravir resistance, including changes within the viral surface and transmembrane envelope glycoproteins, the nucleocapsid protein, and the genomic RNA 3′ polypurine tract that serves to prime plus-strand DNA synthesis during reverse transcription. Each type of change has been shown to confer resistance to dolutegravir through a unique molecular mechanism. Herein, I review the non-integrase changes that are known to occur and the proposed mechanisms that lead to the generation of dolutegravir resistance. The potential for these different types of changes to impact INSTI drug resistance in the clinic is also discussed. The unexpected observation that multiple non-integrase pathways can contribute to the generation of dolutegravir resistance highlights the remarkable plasticity of HIV-1 to circumvent challenge with a highly efficacious small molecule inhibitor. Given its current global use as a frontline anti-HIV inhibitor, this research informs regions of sequence surveillance for the continued safe and efficacious use of dolutegravir-based antiretroviral therapies.
BACKGROUND:The foamy virus (FV) glycoprotein complex (GPC) facilitates exceptionally broad species and tissue tropism. While cell surface heparan sulfate (HS) serves as a known attachment factor, it is not essential for viral entry. Recent high-resolution structures of GPCs from various FV species identified an evolutionarily conserved, positively charged surface patch (PCSP) on the receptor-binding domain (RBD) as a putative HS-binding site (HSBS). To date, only the gorilla FV (SFVggo) HSBS has been functionally characterized, demonstrating the role of basic PCSP residues in HS-dependent attachment. Experimental evidence supporting a universal role for the GPC PCSP across other FV species is currently lacking. RESULTS:The prototype FV (PFV) GPC PCSP consists of four central residues surrounded by five peripheral, positively charged residues. Using charge-switch mutagenesis, we investigated the functional role of eight PCSP residues. The central residues-K343, K355, R357, and K368-proved essential for HS-dependent attachment and infection across various target cells. Individual mutations of these residues reduced attachment and infectivity in HT1080 cells by 50- to 100-fold. Among peripheral residues, only K356 contributed significantly to these processes on different HS-expressing target cells. Notably, all mutant PFV GPCs maintained levels of attachment and infectivity in HS-deficient cells similar to those of the wild-type, though these levels were 10- to 30-fold lower than in HS-expressing parental cells but well above background. CONCLUSIONS:The minimal HSBS of the PFV GPC is defined by four central, evolutionarily conserved positively charged residues. Substituting these with negatively charged amino acids abolishes HS-dependent attachment and severely reduces specific infectivity. The minor impact of the peripheral residue mutation K356E, combined with the lack of evolutionary conservation among most peripheral positively charged residues in primate FV species, suggests these residues play only a secondary role in HS interaction. Furthermore, the residual infectivity of PCSP mutants in HS-deficient cells confirms that HS is an important attachment factor but not an essential entry receptor. The functional homology between PFV and SFVggo GPCs strongly suggests that this conserved PCSP constitutes a universal HS-binding site across all FV species.
Breast cancer is the most commonly diagnosed cancer globally. The potential role of oncogenic viruses, particularly Human Betaretrovirus (HBRV, formerly MMTV-LV/HMTV), in the pathogenesis of breast cancer has been a subject of research for decades. However, studies investigating this association have produced conflicting results. This systematic review and meta-analysis aim to assess the prevalence of HBRV in breast cancer cases and evaluate its potential association with breast cancer. A systematic literature search was conducted in MEDLINE, Web of Science, Scopus, and EMBASE following PRISMA guidelines. Studies assessing HBRV prevalence in breast cancer patients and case-control studies investigating its association with breast cancer risk were included. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality, and meta-analysis was performed using RevMan 5.1. Heterogeneity was assessed using the I² statistic, and subgroup analyses were conducted based on detection methods, sample types, and geographic regions. The literature search identified a total of 45 studies that were deemed suitable for inclusion in the systematic review. 26 studies were used in the subsequent meta-analysis. The initial meta-analysis revealed a significant association between HBRV and breast cancer (OR = 4.92, 95
Although HPV infection is obligatory for almost all cases of cervical cancer (CC), other risk factors can promote the progression of cervical cancer. In this context, the expression of human endogenous retroviruses (HERVs) in the development of CC has been investigated. In this study, the expression status of HERV-E env transcripts was analyzed in 111 cervical biopsies, including 35 cervical cancer samples, 20 precancerous lesions, and 56 normal samples. Real-time PCR with specific primers was used to quantify the relative expression of HERV-E env, HPV 16 and 18 E6/E7 genes, and GAPDH as a normalization control. Our results indicated an increase in the expression of HERV-E env, and the difference was statistically significant in the cancer group compared to the precancerous group (1.5-fold change) (P = 0.031). In HPV 16 or 18-infected patients, a higher mean value of HERV-E env mRNA was also found in the cancer group than in the precancerous group. ROC curve analysis showed a significant difference in env expression between precancerous and cancerous lesions in all patients analyzed (P = 0.015) and in a group of patients infected with HPV 16 or 18 genotypes (P = 0.023). In addition, there was a positive correlation between the higher expression of HERV-E env mRNA with E7 (R = 0.34, P = 0.016) and age (R = 0.35, p = 0.016) in HPV 16-infected patients. In conclusion, our study found a possible association between HERV-E env expression and cervical cancer, as HERV-E is actively transcribed during the progression of cervical lesions. Future studies on the potential interaction of HERV-E env with HPV 16 E7 oncoprotein are likely to elucidate common signaling pathways in the progression of cervical cancer and other HPV-related malignancies.
Detecting and measuring HIV reservoirs, neutralizing antibodies, and restriction factors are important for HIV cure research and the development of new therapeutics and vaccines. Here we describe the development and validation of several HIV Rev-dependent indicator cell lines for these purposes. These reporter cells derive from different T-lymphoblast cell lines, including Molt4-CCR5, SupT1-CCR5, CEM-SS, A3R5, and from the adherent TZM cell platform based on HeLa clone JC53. These cells express CD4, CXCR4, and various levels of CCR5. We compared these cell lines for responsiveness to both X4 and R5-tropic viruses, and confirmed that reporter expression in these cells is not affected by stimulation from mitogens but is responsive to HIV Tat and Rev, reducing non-specific reporter induction from the leaky LTR promoter. To validate the sensitivity of the Rev-dependent reporter cell systems, we conducted a viral dilution assay with three primary HIV-1 clade C swarms from an adult in Malawi. We also validated the systems for quantifying antibody neutralization and screening restriction factors; these systems are also sensitive for viral outgrowth assays for quantifying viral reservoirs in clinical and basic research settings. Given that the systems can measure HIV accurately in complex environments with mitogens or other substances, they can be used for versatile applications, such as quantifying latent reservoirs, testing inhibitory compounds, conducting neutralizing antibody assays, and identifying new restriction factors.
Variation in the level of cell-associated HIV-1 RNA is an important parameter followed in clinical trials focusing on HIV-1 infection, latency or reactivation. In addition to sense products, HIV-1 also expresses antisense products that can modulate HIV-1 replication, either positively through the antisense protein ASP or negatively through repressive noncoding antisense RNAs. Therefore, quantification of both sense and antisense HIV-1 products could provide key information for monitoring the dynamics of viral replication in vivo. While the ASP protein is difficult to detect even in vitro, antisense RNAs can be detected both in vitro and in vivo. The aim of this study was therefore to establish protocols for the specific quantification of sense and antisense transcription that can be applied in clinical studies. To this end, we developed strand-specific RT-PCR protocols allowing us to quantify individually sense and antisense RNAs in PLWH with B and non-B viruses. We show that the two RTqPCR protocols can quantify standard HIV-1 sequences with good analytical parameters. We also demonstrate the strand specificity of the two protocols by showing that RNAs of the other orientation do not contaminate RNAs of one orientation during the PCR step and that the sense and antisense RT-qPCR protocols detect distinct populations of HIV-1 RNAs. We then compared the sensitivity of RT-qPCR and RT-ddPCR to quantify HIV-1 cell-associated RNAs and found that RT-ddPCR results in lower inter-sample variation or higher levels of detection than RT-qPCR. Finally, we show that the RT-ddPCR protocols efficiently quantify cell-associated HIV-1 sense and antisense RNAs not only in HIV-1-infected primary CD4 + T cells but also in spleen and blood samples from untreated HIV-1-infected individuals. This study demonstrates that HIV-1 antisense RNAs are expressed in spleen and blood of untreated HIV-1-infected individuals, of at least B and CRF02 subtypes, and that the level of antisense transcription can be significant and even predominant, as compared to sense transcription. These data, along with the protocols we described, will enable a more thorough analysis of HIV-1 sense and antisense expression dynamics in vivo, which could pave the way for novel strategies to control HIV-1 infection.
The evolutionary history of retroviruses and their impact on vertebrate evolution remains poorly understood, particularly in non-mammalian hosts. In this study, we explore retroviruses associated with Amphibia through analysis of 169 RNA sequencing datasets from 102 amphibian species. Using a BLAST-based approach, we identified retroviral transcripts from assembled transcriptomes and phylogenetically characterise both their pol and env regions to elucidate their evolutionary history. We identified the transcription of 18 novel and two previously described retroviruses with closest relatives in gammaretrovirus, epsilonretrovirus, betaretrovirus and spumaretrovirinae. Despite their differing pol phylogenies, we found that all amphibian retroviruses belong to the gamma-type envelope group (GTE). This suggests a common selection pressure for amphibian retroviruses to retain GTEs. Within these GTEs we also observed a new clade of alpharetrovirus-like envelopes in amphibians which form a sister clade to avian alpharetrovirus envelopes. Furthermore, we observe correlations between amphibian taxonomical order and retroviral diversity, with Gymnophiona (caecilians) harbouring the widest diversity of retroviruses whilst Anura (frogs and toads) harbour the fewest. Through mapping these transcribed retroviruses to their respective genomes (seven available) supplemented with observing ORF intactness, we determined that 14 of the 20 retroviruses are likely endogenous in origin yet are still transcribed in many amphibian tissues. These amphibian endogenous retroviruses (ERVs) have high genomic copy numbers: most (5/7) ERVs investigated have > 100 copies, and one of which has 9,219 integrations within the Ichthyophis bannanicus caecilian genome. This high retroviral load in amphibian genomes may suggest that these retroviruses have low pathogenicity, or may reflect a lack of transposon control mechanisms in amphibian cells. Through the characterisation of metatranscriptomic and genomic data from retroviruses in this study, we provide insights into their evolution in amphibians and exemplify the diversity of Retroviridae in vertebrate genomes. The identification of novel retroviral clades, widespread transcription of endogenous retroviruses in amphibians and abundance of ERV copies suggests that Retroviridae have played a significant role in amphibian evolution.
Human T-cell leukemia virus type 1 (HTLV-1) infects mainly CD4+ T lymphocytes and causes both malignant and inflammatory diseases: the aggressive malignancy known as Adult T-cell leukemia/lymphoma (ATL) and several chronic inflammatory syndromes. HTLV-1 infection is established by integration of proviral DNA ( 9000 bp) into the host genome. In HTLV-1, two viral genes, tax and HBZ, play critical roles in viral transcription and promotion of T-cell proliferation, respectively. The present study was undertaken to test the hypothesis that the higher-order structure of proviral chromatin regulates its transcription on both the plus strand and the minus strand. ATAC-seq analysis identified an open chromatin region in the pol gene of proviral DNA, which we name IPOR, in many ATL cases. Using reporter assays, it was found that the sequence of IPOR suppresses the transcription of the plus strand and activates that of the minus strand. Binding motifs of Eomes and TEAD proteins were predicted in this region, and we confirmed recruitment of the transcription factors to their respective motifs by ChIP-qPCR. A mutant of IPOR which cannot bind the transcription factors weakened the transcriptional activating effects compared with the wild type, suggesting that the IPOR and those transcription factors suppress the 5' long terminal repeat (LTR) but activate the 3'LTR. In addition, a mutant HTLV-1 molecular clone, which possesses the IPOR mutant, produced a higher titer of virus than the wild type. RNA-seq analysis of HTLV-1-infected cell lines, in which Tax expression can be traced after induction, revealed that EOMES expression decreases during the tax transcriptional burst and resumes following termination of the burst. These findings suggested that the expression dynamics of Eomes affect the transient expression of Tax. The IPOR sequence appears to regulate the transcription from both LTRs, suppressing the 5'LTR but activating the 3'LTR. Recruitment of Eomes to the IPOR is likely to influence the expression of Tax and HBZ. Since both viral genes are involved in diverse mechanisms for viral replication, cellular proliferation, and immune regulation, the IPOR may play a role in fine-tuning the modes of viral persistence in vivo.
Over the past two decades, the global HIV/AIDS pandemic has emerged as one of the most pressing health concerns worldwide. In low-income countries, where resources are scarce, both the prevalence of HIV and the associated mortality rates have been steadily increasing. According to the national AIDS control program, approximately 74,619 individuals in Pakistan are living with HIV/AIDS, with cases distributed across various provinces and autonomous territories. The country's low literacy rate poses a significant barrier to understanding preventive measures, thereby facilitating the uncontrolled transmission of HIV through sexual intercourse, blood transfusions, and the use of contaminated medical equipment. Vulnerable populations include persons engaged in sex work, transgender individuals, males who have sex with men, and those who inject drugs. The movement and relocation of people, particularly in Karachi, are significant factors in the high prevalence of HIV. In Pakistan, where 20% of drug users are HIV positive the HIV positive population and is still spreading among injection drug users (IDUs). Male sex workers and transgender people who engage in sexual interactions with intravenous drug users are experiencing new outbreaks in some locations. HIV risk behaviors are influenced by limited awareness, social stigma, and inadequate harm reduction programs. The HIV/AIDS epidemic is spreading rapidly throughout Pakistan. This review article aims to identify the various factors that are involved in HIV epidemiology in Pakistan.
BACKGROUND:In the early phase of HIV infection, as studied in vitro, high levels of unintegrated (both linear and circular) and integrated (provirus) forms of viral DNA are seen, and cells produce high levels of virus. In time, the level of unintegrated DNA declines, followed by a progressive decline in virus expression. Extensive studies of the proviral landscape in people living with HIV (PLWH) on antiretroviral therapy (ART) show that only about 2% of proviruses are intact; the remainder are characterized as defective and contain numerous deletions of proviral DNA segments and hypermutations. In the current study, we investigated the decline of viral expression in infected T cells in search of mechanisms involved in proviral inactivation. RESULTS:We derived clonal lines from Jurkat cells infected with HIV MN and monitored them for viral expression over time in culture. In a subset of clones that displayed a decline in expression, we found provirus containing large deletions and the integration of a retrotranscribed molecule of tRNAGly adjacent to the 3'-end of the proviral DNA. We provide evidence linking the proviral deletions to the insertion of a reverse transcribed tRNAGly molecule and propose a mechanism for its self-primed reverse transcription. CONCLUSIONS:Large deletions of proviral DNA have been reported in PLWH on ART and attributed to errors that occurred in the synthesis of the minus strand during the reverse transcription of the viral genome. Our results support an additional mechanism for proviral deletions, mediated by tRNAGly, in the inactivation of the provirus.
BACKGROUND:Among the many CRFs, CRF55_01B was the first CRF01_AE and subtype B recombinant strain identified around 2013 among men who have sex with men (MSM) in Shenzhen, China. With rapid spreading throughout the country, CRF55_01B has attracted much attention in recent years. This study aimed to analyze its prevalence of drug resistance and transmission characteristics in people living with HIV/AIDS (PLWHA) in Henan province, China so as to pay particular attention to this group of individuals to reduce the incidence of drug resistance. RESULTS:Two hundred and forty-five CRF55_01B-infected individuals, including 141 treatment-naïve and 104 treatment-experienced individuals, were enrolled. In treatment-naïve individuals, 6.38% (9/141) of them harboured NRTI DRMs and 19.15% (27/141) of them harboured NNRTI DRMs except V179E/D. In treatment-experienced individuals, 2.00% (2/100) harboured INSTI DRMs, 82.69% (86/104) of them harboured NRTI DRMs, and 88.46% (92/104) of them harboured NNRTI DRMs except V179E/D. The overall prevalence of ADR was 89.42% (93/104), while the prevalence of PDR was 19.86% (28/141). A total of 23 transmission clusters, accounting for 37.55% (92/245) of the total sequences, were identified. The clusters ranged in size from 2 to 19, and 15 (65.22%) had 3 or more sequences. CONCLUSIONS:High prevalence of DRMs and drug resistance were observed in CRF55_01B in both treatment-naïve and treatment-experienced individuals, particular attention should be paid to this group of individuals to reduce the incidence of drug resistance.
Prototype foamy virus (PFV) is a complex retrovirus that can maintain latent infection for life after viral infection of the host. However, the mechanism of latent infection with PFV remains unclear. Our previous studies have shown that PFV promotes autophagy flux, but whether PFV causes mitophagy remains unclear. In this study, we demonstrated that PFV infection damages mitochondria, increases mitochondria reactive oxygen species (mtROS) production, and induces mitophagy in a time-dependent manner. Further investigation revealed that PFV Gag is a crucial protein responsible for triggering mitophagy. The overexpression of Gag leads to mitochondrial damage and stimulates mitophagy in a dose-dependent manner. Additionally, overexpression of Gag activates the PINK1-Parkin signaling pathway, while the knockdown of Parkin inhibits Gag-induced mitophagy. Furthermore, Rab5a was significantly upregulated in cells overexpressed Gag, and the inhibition of Rab5a reversed the effects of Gag-induced mitophagy. Our data suggested that PFV can induce mitophagy and Gag induces Parkin-dependent mitophagy by upregulating Rab5a. These findings not only enhance a better understanding of the foamy virus infection mechanisms but also provide critical insights into novel virus-host cell interactions.
Background The retrovirus Human T-lymphotropic virus type 1 is classified into different subtypes, and due to its low evolutionary rates, it can be used to explore geographic patterns of origin and dispersion of human populations. In Brazil, Transcontinental and Japanese subgroups, from the Cosmopolitan subtype, are the more common lineages, with prevalence rates notably higher among Japanese immigrants and their descendants. The study aimed to trace the history and circulation of the Japanese subgroup in Brazil using phylogenetic and populational analyses. Methods A total of 381 HTLV-1 long terminal repeat region sequences were retrieved from the GenBank database. Phylogenetic and molecular clock analysis were performed using Maximum Likelihood and Bayesian Inference methods. A median-joining network was constructed to assess the relationships among the haplotypes of the Japanese subgroup. Results This study found that the HTLV-1 LTR sequences from Japanese immigrants and their descendants in Brazil formed two major clades, Transcontinental (HTLV-1aTC) and Japanese (HTLV-1aJpn). Seventy-four haplotypes were identified in the haplotype network and the estimate of Japanese clade divergence dates 18,748 years ago (95% CI13,348 to 24,767 years). Conclusion Our study corroborates the recent migratory movements as the potential mechanism for HTLV-1aJpn introduction in Brazil.
People living with HIV (PLWH) who experience low-level viremia (LLV) face unique challenges in disease management, particularly when diagnosed with concurrent malignancies. Albuvirtide (ABT), a long-acting HIV fusion inhibitor approved in China, has shown promise in clinical trials for treatment-experienced individuals. However, its efficacy in managing LLV in the context of concurrent malignancies remains under-explored. We report two cases of PLWH with LLV who developed non-AIDS-defining cancers(NADCs). The first individual developed lung squamous cell carcinoma, and the second was diagnosed with breast cancer. Both patients received ABT as part of their optimized antiretroviral therapy (ART) regimen during their cancer treatment course. After treatment optimization, both cases achieved viral suppression (HIV-1 RNA < 50 copies/mL) with improvements in CD4 + T cell counts. Both patients received appropriate cancer treatments according to clinical practice guidelines. The patient diagnosed with lung cancer required an adjustment to his PD-1 inhibitor monotherapy due to intolerance to chemotherapy, whereas the breast cancer patient successfully completed her planned multimodal treatment regimen. These cases suggest potential benefits of ABT-containing ART regimens in PLWH who have LLV and concurrent NADCs. While two cases cannot establish definitive conclusions, they highlight the need for larger studies investigating the role of ABT in this complex clinical scenario.
