Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurological and clinical manifestations that do not meet diagnostic criteria for HAM. These conditions may later progress to HAM or constitute an intermediate clinical form: intermediate syndrome (IS), a mid-point between asymptomatic HTLV-1 carriers and those with full myelopathy. Thus, we determined the incidence of HAM cases in the HTLV-1-asymptomatic and IS patients, and the clinical/laboratory associated markers. A total of 204 HTLV-1-positive patients were included in this study, divided into two groups: Group 1, including 145 asymptomatic HTLV-1 subjects (ASY), and Group 2, including 59 patients with inflammatory clinical symptoms in more than three systems and a high proviral load (PVL). During a 60-month follow-up time, with the age ranging from 47 to 79 years, ten patients of the fifty-nine initially diagnosed as IS developed HAM (iHAM), and two patients of the initial 145 ASY developed HAM directly. Women were more prevalent in all groups. For the iHAM patients, the age ranged from 20 to 72 years, with a mean of 53 (±15 SD). Older age was associated with the development of HAM, higher PVL and IS; however, there was no any specific symptom or clinical sign, that was associated with risk for iHAM. In conclusion, IS cases could be an early phase of development of HAM. These findings show the presence of higher incidence probabilities in our cohort than previously reported.

Despite care and the availability of effective antiretroviral treatment, some people living with HIV (PLHIV) suffer from neurocognitive disorders associated with the human immunodeficiency virus (HAND) that is a major problem in their quality of life. The different types of HAND can be characterized into asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and the most severe form known as HIV-associated dementia (HAD). Little is known about the mechanisms of HAND, but it is accepted that it is correlated with the infection of astrocytes, microglial cells and macrophages in the human brain. The formation of a viral reservoir that remains dormant as a provirus in resting CD4+ T lymphocytes, and of refuge tissues, such as the brain is a major contributor to HIV eradication. In recent years, a new set of tools has emerged: gene editing based on the CRISPR/Cas9 system, which can alter genomic segments by insertion, deletion, and replacement and has great therapeutic potential. This technology has been used in research to treat HIV and appears to offer hope for a possible cure for HIV infection and perhaps the prevention of HAND. This approach has the potential to directly impact the quality of life of HIV-infected individuals, which is a very important topic to be known and discussed.

The human T-cell lymphotropic virus type 1 (HTLV-1) is a single-stranded positive-sense RNA virus that belongs to the Retroviridae family, genus Deltaretro, and infects approximately five to 10 million people worldwide. Although a significant number of individuals living with HTLV-1 remain asymptomatic throughout their lives, some develop one or more severe clinical conditions, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive and debilitating disease, and/or a subtype of non-Hodgkin’s lymphoma with a more threatening course known as adult T-cell leukemia/lymphoma (ATLL). Moreover, current therapeutic options are limited and focus primarily on treating symptoms and controlling viral latency. CRISPR-Cas9 gene editing is proposed as a promising tool to address the intricate links associated with HTLV-1. By targeting or silencing key genes during initial infection and dysregulating immune signaling pathways, CRISPR-Cas9 offers potential intervention opportunities. In this review, we address the therapeutic potential of CRISPR-Cas9 gene editing, as well as examine the primary mechanisms involved in editing potential target genes and discuss the existing evidence in the current scientific literature.

HTLV-1 is an enigmatic retrovirus triggering a debilitating neuroinflammatory disease, HTLV-1-associated myelopathy (HAM), with unknown pathogenesis. Both HTLV-1 infection and HAM predominantly affect women and non-white neglected populations. HAM is lacking disease-modifying treatment, as current treatment is mostly symptomatic and inspired by either HIV-1 or multiple sclerosis therapeutic strategies. We used systems biology analyses of novel and publicly available data comprising (epi)genomics, transcriptomics, metabolomics and proteomics of multi-ancestry cohorts from a total of > 2500 People Living with HTLV-1 from 5 countries (Brazil, Peru, Japan, UK, US). Leveraging an unique admixed Brazilian cohort, genome-wide association study (GWAS) revealed African-specific variants in inflammasome sensor AIM2 with genome-wide significance (p < 5x10^− 8). Suggestive loci (p > 5x10^− 8) corresponding to metabolic, immune and neuronal genes were validated using published Japanese GWAS. Polygenic risk score and proviral load were independent disease predictors across ancestries. Systems biology analysis revealed neuronal/synaptic signaling, monocyte count, glucose/lipid metabolism, and neurocognition/depression as genetically linked to HAM. In silico drug screening identified estrogen blocker Fulvestrant as the top hit, while also confirming existing (pre)clinical data for HDAC inhibitors and immunosuppressants. Validated GWAS genes were overexpressed in HAM patients’ whole blood and CD4 T-cells, as well as in spinal cord astrocytes, oligodendrocytes, and microglia by single-cell RNAseq. We experimentally confirmed decreased ApoA1/lipid/cholesterol levels, higher monocyte levels and lower neurocognitive scores in multi-ancestry cohorts. We found striking biological similarities between retroviral Hbz/Tax overexpression, Hbz interactome and HAM multi-omics findings: enrichment for lipid/cholesterol metabolism, estrogen signaling, neurodegenerative diseases, and viral pathways including EBV, recently identified as the major driver of multiple sclerosis. In conclusion, our data-driven approach uncovers novel disease mechanisms and therapeutic targets, and a validated polygenic risk score allowing targeted surveillance for high-risk individuals. A strong molecular overlap to other neurodegenerative/neuroinflammatory diseases reveals shared neuropathogenic pathways between unrelated viruses.

Tuberculosis (TB) is the most common comorbidity in people living with HIV/AIDS (PLWH), including those under antiretroviral treatment. PLWH are 28 times more likely to develop TB in Brazil, the leading cause of HIV-related deaths globally, with approximately 161,000 reported deaths worldwide in 2023. Early diagnosis of latent tuberculosis infection (LTBI) and prophylactic therapy can reduce TB cases, prevent disease progression, and decrease transmission in high-risk populations. This study assessed the prevalence of LTBI in PLWH using the interferon-gamma release assay (IGRA) and the impact of the 3HP regimen (isoniazid [INH]/rifapentine [RPT]) as prophylactic treatment. Blood samples from 335 PLWH (78% of the 427 in the cohort) were tested for IGRA; 50 PLWH (15%) tested positive and were treated with 3HP. Treatment included 900 mg of INH and 900 mg of RPT in 12 weekly doses according to the Brazilian health guidelines. No specific risk factors, including nadir CD4+T count, age, gender, or antiretroviral therapy (ART), were more frequently observed in the PLWH with LTBI compared to the PLWH without LTBI. All PLWH with LTBI received treatment and no cases of active TB were observed. Our findings highlight the need for wider LTBI screening and treatment among PLWH in the latent phase, emphasizing more stringent approaches for implementing 3HP prophylaxis.

Introduction: Simian T-cell leukemia virus type 1 (STLV-1) and human T-lymphotropic virus type 1 (HTLV-1) are homologous viruses with high genetic identity. STLV-1 infections in non-human primates serve as valuable models to study HTLV-1 pathogenesis.Methods: This study investigated STLV-1 infection in captive green monkeys (Chlorocebus aethiops) in Brazil. Blood samples from 52 animals were collected and analyzed for viral presence, genetic characterization, and pathological manifestations.Results: STLV-1 infection was detected in seven animals, corresponding to a seroprevalence of 13.4%. Phylogenetic analysis showed that the STLV-1 strains identified are more closely related to baboon STLV-1 strains and human African HTLV-1 isolates than to other STLV-1 variants, suggesting a shared evolutionary history and possible cross-species transmission. Clinically and hematologically, STLV-1 infection in C. aethiops presented parallels to HTLV-1 infection in humans, including the presence of characteristic “flower cells” and similar lymphoproliferative disorders.Discussion: These findings reinforce the relevance of C. aethiops as a natural model for studying HTLV-1 infection and pathogenesis. The genetic and clinical similarities indicate potential mechanisms of viral evolution and transmission, providing insights that may aid in understanding HTLV-1-associated diseases in humans.