Acute HIV Infection Research Articles

872 Osmotic demyelinating syndrome and acute hiv infection: a coincidence?

872 Osmotic demyelinating syndrome and acute hiv infection: a coincidence?

Point-of-care nucleic acid testing - a step forward in controlling the HIV epidemic: A review.

The HIV/AIDS epidemic, with 85.6 million infections and 40.4 million AIDS-related deaths globally, remains a critical public health challenge. Current diagnostic methods, primarily fourth-generation immunoassays, have limitations due to their long window periods, and most viral load assays require centralized testing protocols that result in delays, especially in remote regions. Point-of-care (POC) nucleic acid amplification testing (NAAT) presents a transformative approach by reducing the window period for detection to one week and significantly shortening turnaround times for viral load monitoring. This review highlights the clinical utility of POC NAAT for acute HIV infection diagnosis, its role in timely combination antiretroviral therapy adjustments, and its potential to reduce the basic reproduction number (R0), a critical threshold for suppressing the epidemic. By improving early detection and facilitating faster clinical decisions, POC NAAT enhances the effectiveness of HIV prevention and treatment programmes, particularly in high-risk and remote communities, and supports the global effort to achieve the ambitious UNAIDS 95-95-95 targets.

Cannabis Use and Self-Reported Bothersome Symptoms in People with HIV

Objective: While cannabis use is common among people with HIV (PWH), there have been few studies examining the association of use with health outcomes among PWH. We aimed to evaluate the association between cannabis use and bothersome physical and mental health symptoms using both self-report and a direct biomarker for cannabis use. Method: The Medications, Alcohol and Substance use in HIV Study (MASH) is a cross-cohort study focused on polypharmacy and substance use among PWH. Participants were enrolled from October 2018 to May 2022 in the Swiss HIV Cohort Study (SHCS), Kaiser Permanente Northern California (KPNC) HIV Cohort, and 7 sites (Atlanta, GA; Bronx, NY; Washington, DC; Houston, TX; Los Angeles, CA; New York, NY; and Nashville, TN) in the Veterans Aging Cohort Study - HIV (VACS-HIV). Participants submitted self-reported information on the presence/absence of symptoms in the prior 4 weeks, along with bothersome level, using the HIV Symptom Index, which is comprised of 20 symptoms commonly reported in PWH, including fatigue, diarrhea, fever, anxiety, and weight loss, among others. Concurrent self-reported substance use information was also collected, and participants provided nail clippings to be tested for cannabis use. We used logistic regression models, adjusted for age, sex, race/ethnicity, and cohort, to examine associations of self-report and biomarker-identified cannabis use with self-reported bothersome symptoms. Results: The analytic sample included 1,226 PWH who were predominantly male (85%), non-white (64%), with an average age of 57 years; 20% tested positive for cannabis use, and 23% reported recent cannabis use. Agreement between self-report and biomarker cannabis use was substantial (agreement 89%, kappa = 0.67). Put together, 27% either reported cannabis use or tested positive. Of the 20 symptoms included in the HIV Symptom Index, 19 were more prevalent at a bothersome level among those with cannabis use compared to those without. In adjusted models, the patterns of association remained for both self-reported and biomarker-confirmed cannabis use, and they were particularly substantial for memory, depression, anxiety, and nausea. Conclusions: Cannabis use was common among PWH and was associated with a number of bothersome symptoms. While cannabis use may be used to treat loss of appetite, nausea/vomiting, and weight loss, the associations of cannabis use with depression, anxiety, and memory loss are concerning and deserve investigation.

Updates to HIV transmission rate estimates along the HIV care continuum in the United States, 2019.

In 2019, there were an estimated 1.2 million persons with HIV (PWH) and 35,100 new infections in the United States. The HIV care continuum has a large influence on transmission dynamics. We updated Progression and Transmission of HIV 3.0, an agent-based simulation model, to estimate 2019 HIV transmission rates and distribution of transmissions by the HIV care continuum, race/ethnicity, transmission group, and age group. In 2019, the estimated transmission rate in the United States was 2.94 new infections per 100 person-years (inf /100p-y). Transmission rates decreased along the HIV care continuum; the highest transmission rate was associated with persons with acute HIV infection and unaware of their HIV status at 16.35 inf /100p-y, followed by persons with HIV (non-acute) and unaware of their HIV status (9.52), persons aware of their HIV status and not in care (5.96), persons receiving HIV care (on antiretroviral therapy) but not virally suppressed (4.53), and persons virally suppressed (0). The highest transmission rate by transmission group was among men who have sex with men at 3.68 inf /100p-y. Transmission rates decreased as age increased and are similar by race/ethnicity, after accounting for the HIV care continuum. Our results support a continued emphasis on helping PWH move along the care continuum through early diagnosis, linkage to care, and adherence to ART, resulting in viral suppression to reduce HIV transmissions. Further, efforts should focus on reducing disparities in the provision of HIV prevention and care services, particularly for populations disproportionally affected by HIV.

Predictors of Clinical Outcomes among People with HIV and Tuberculosis Symptoms after Rapid Treatment Initiation in Haiti

Predictors of Clinical Outcomes among People with HIV and Tuberculosis Symptoms after Rapid Treatment Initiation in Haiti

Comparing acute versus AIDS ART initiation on HIV-1 integration sites and clonal expansion

Early antiretroviral therapy (ART) initiation is known to limit the establishment of the HIV reservoir, with studies suggesting benefits such as a reduced number of infected cells and a smaller latent reservoir. However, the long-term impact of early ART initiation on the dynamics of the infected cell pool remains unclear, and clinical evidence directly comparing proviral integration site counts between early and late ART initiation is limited. In this study, we used Linear Target Amplification-PCR (LTA-PCR) and Next Generation Sequencing to compare unique integration site (UIS) clonal counts between individuals who initiated ART during acute HIV infection stage (Acute-ART group) and those in the AIDS stage (AIDS-ART group). Our analysis revealed distinct clonal distribution patterns, with greater UIS heterogeneity in Acute-ART group and more homogeneity in AIDS-ART group. Monoclonal UIS accumulation, predominantly in-gene regions, was influenced by ART timing and duration, with early treatment delaying this process. Host cell genes integrated by HIV provirus as monoclonal types were enriched in cell cycle and lymphocyte activation pathways. Tumor suppressor genes (TSGs) were more frequently integrated as monoclonal types in AIDS-ART group, suggesting potential risk factors. Overall, we introduced a sequencing method to assess provirus size in human peripheral blood and identified the widespread presence of monoclonal distribution of UIS in AIDS-ART group after long-term treatment. The early intervention helps slow the progress of clonal expansion of infected cells, reducing the formation of stable and persistent reservoirs, and ultimately posing fewer barriers to achieving a functional cure.

Effectiveness, safety, and patient-reported outcomes of bictegravir/emtricitabine/tenofovir alafenamide in routine clinical care in Italy: 12-Month results from the BICSTaR cohort.

BICSTaR is a multi-national, observational cohort evaluating the effectiveness, safety, and patient-reported outcomes (PROs) in treatment-naïve (TN) and -experienced (TE) people with HIV-1 receiving bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in routine clinical care. We present the 12-month (M12) outcomes of the Italian BICSTaR cohort. Participants initiating B/F/TAF in routine care were prospectively followed. Outcomes included virological and immunologic effectiveness, drug-related adverse events (DRAEs), treatment persistence, and PROs using the HIV Symptom Index (HIV-SI) and the HIV Treatment Satisfaction Questionnaires (HIVTSQ). N = 201 were included (29TN, 172TE), 83% male, median age 38 years in TN, 48 years in TE. At baseline, 94% of TE had an HIV-1 RNA <50 cp/mL, 92% switched to B/F/TAF for simplification. Overall, 69% reported comorbidities (TN: 59%, TE: 70%). At M12, 88% (23/26) of TN and 96% (152/159) of TE had an HIV-1 RNA <50 cp/mL in the discontinuation = failure analysis (without emergence of resistance to B/F/TAF). Median CD4 count changes were +296 cells/µL (interquartile range [IQR], 118, 383) in TN, and +23 cells/µl (-137, 114) in TE. DRAEs were reported for 5% and led to discontinuation in 1%. M12 persistence on B/F/TAF was 97%. TN had a median HIV-SI bothersome symptom count decrease of -1.5 (IQR, -5.0, 0.0). Median treatment satisfaction change score was +29.0 (21, 30) in TE indicating an improvement. In this real-world Italian cohort of mostly treatment-experienced people switching for simplification, B/F/TAF demonstrated high effectiveness and persistence over 12 months and confirmed the favourable safety profile shown in clinical trials. European cohort: EUPAS22185.

Missed and Delayed Diagnoses of Acute Human Immunodeficiency Virus (HIV) Infection in a Southern Opt-Out HIV Testing Environment Without Reflex HIV RNA Testing.

Prompt confirmation of human immunodeficiency virus (HIV) is critical. We examined 10 years of discordant results without reflex HIV RNA. Of patients with acute HIV infection, 43.9% (95% confidence interval, 36.2%-52.0%) had confirmation delays >30 days or were never confirmed, indicating a need for reflex RNA to facilitate diagnosis.

Viral and Immune Risk Factors of HIV Rebound after Interruption of Antiretroviral Therapy.

Identifying risk factors for HIV rebound after treatment interruption is crucial for designing effective remission strategies. Peripheral blood mononuclear cells from participants in the Zurich HIV Primary Infection Cohort (ZPHI, N=73) and ACTG study A5345 (N=44) were analyzed before ART interruption. We measured cell-associated HIV RNA, total HIV DNA, and proviral diversity (env gene). Immune phenotyping was conducted by flow cytometry. Cox proportional hazards (PH) models and penalized Cox PH models with an adaptive LASSO penalty identified risk factors for time to rebound (HIV RNA >1,000 copies/mL). Late ART initiation was associated with higher rebound risk (shorter time to rebound), as compared to early ART. Higher pre-ART HIV RNA, total HIV DNA, and increased cellular HIV transcription at the time of ART interruption were associated with higher rebound risk. Higher proviral diversity was associated with higher rebound risk but only among male participants and those enrolled in the ZPHI cohort. Less CD4+ T cells at ART interruption, higher proportions of effector and terminally differentiated T cells, and more activated and exhausted T cells were associated with higher rebound risk, primarily in early treated participants. No significant immunological risk factors were found in participants treated during chronic HIV. In the combined cohort, total HIV DNA and terminally differentiated CD8+ T Cells appeared to be the most relevant risk factors for time to rebound. These findings underscore the importance of early ART initiation and suggest that tailored interventions based on virologic, immunologic, and demographic factors may help achieve sustained viral suppression.

Correlates of Using Medically-Authorized Cannabis in a Large Cohort of People Living with HIV Who Use Cannabis.

Many people living with HIV (PLWH) use cannabis to manage symptoms, but a large proportion do so without medical cannabis authorization and use cannabis obtained outside the medical stream. In jurisdictions where non-medical cannabis use is legal, PLWH who hold medical cannabis authorization may represent a unique subgroup; yet, research on the correlates of using medical cannabis (authorized by a healthcare provider) in the context of non-medical cannabis legalization is lacking. Thus, this study examined the cannabis- and health-related correlates of medical cannabis use among PLWH in Ontario, Canada, where non-medical cannabis is legal. PLWH (N = 868; 85.37% men, mean age 51.34years [SD = 12.25]) who were enrolled in the Ontario HIV Treatment Network Cohort Study in 2022 and who reported past-year cannabis use completed an assessment of sociodemographic characteristics, HIV-related variables, cannabis and other substance use, and health-related quality of life. Relatively few participants (n = 122; 14.06%) reported any medical cannabis use, with most (n = 746; 85.94%) reporting exclusive use of non-medical cannabis. Logistic regression analyses showed that greater HIV symptom distress, poorer physical-health-related quality of life, more frequent cannabis use, and using smokeless forms of cannabis were each uniquely associated with increased likelihood of using medical cannabis relative to exclusively using non-medical cannabis. Results suggest that even in jurisdictions where non-medical cannabis is legal, a subset of PLWH continue to access cannabis through the medical stream, and these individuals report distinct patterns of cannabis use and poorer physical health. Findings may inform cannabis policy and clinical care for PLWH who use cannabis.

Dynamics of the blood plasma proteome during hyperacute HIV-1 infection

The complex dynamics of protein expression in plasma during hyperacute HIV-1 infection and its relation to acute retroviral syndrome, viral control, and disease progression are largely unknown. Here, we quantify 1293 blood plasma proteins from 157 longitudinally linked plasma samples collected before, during, and after hyperacute HIV-1 infection of 54 participants from four sub-Saharan African countries. Six distinct longitudinal expression profiles are identified, of which four demonstrate a consistent decrease in protein levels following HIV-1 infection. Proteins involved in inflammatory responses, immune regulation, and cell motility are significantly altered during the transition from pre-infection to one month post-infection. Specifically, decreased ZYX and SCGB1A1 levels, and increased LILRA3 levels are associated with increased risk of acute retroviral syndrome; increased NAPA and RAN levels, and decreased ITIH4 levels with viral control; and increased HPN, PRKCB, and ITGB3 levels with increased risk of disease progression. Overall, this study provides insight into early host responses in hyperacute HIV-1 infection, and present potential biomarkers and mechanisms linked to HIV-1 disease progression and viral load.

PP4.5 – 00144 Unveiling Cellular Phenotypes and Transcriptional Dynamics in Early Treated Acute HIV Infection

PP4.5 – 00144 Unveiling Cellular Phenotypes and Transcriptional Dynamics in Early Treated Acute HIV Infection

Revealing the Magnitude of HIV Prevalence and Unraveling Its Risk Factors in The Enclave of District DG Khan

The risk is amplified by poverty, lack of education and social stigma. Transmission occurs mainly by unprotected sex, needle sharing, or mother-to-child - either during birth or breastfeeding. HIV's pathogenic life cycle begins within the body, from initial CD4/co-receptor binding and cell entry to proviral DNA integration, host cell machinery replication, and immune response evasion. This chronic immune activation and CD4+ T cell depletion over time leads to immunodeficiency (AIDS) if left untreated. Antibody and viral load testing can confirm infection. Acute HIV symptoms resemble the flu, while later stages see opportunistic infections when immunity is compromised. Screening is essential for epidemiological research and exposure risk evaluation. In closing, this study aimed to evaluate HIV prevalence and associated factors among residents of DG Khan District, Pakistan, to help address challenges and better focus local prevention/treatment programs.

Rapid viral suppression using integrase inhibitors during acute HIV-1 infection.

Antiretroviral therapy (ART) is recommended for all individuals with HIV infection, including those with acute HIV-1 infection (AHI). While recommendations are similar to those for chronic infection, efficacy data regarding treatment of acute HIV is limited. This was a single arm, 96-week study of a once-daily integrase inhibitor (INSTI)-based regimen using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) in AHI. Primary endpoint was proportion of participants with HIV-1 RNA <200 copies/mL and <50 copies/mL by treatment weeks 24 and 48, respectively. We also examined time to viral suppression and weight gain after treatment initiation. Outcomes and characteristics were compared with a historical AHI cohort using a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). Thirty-three participants with AHI were enrolled with 31 available for analyses. Most were African American (61%) and men who have sex with men (73%). Median age was 26 (IQR 22-42). Demographics were similar between the two AHI cohorts. By Week 24, 100% in the INSTI and 99% in the NNRTI cohort were <200 copies/mL; by Week 48, 100% in both cohorts were <50 copies/mL. Time to viral suppression was shorter in the INSTI cohort (median 54 versus 99 days). Mean weight change was similar with a 3.6 kg increase in the INSTI cohort and 2.4 kg in the NNRTI cohort at 96 weeks. INSTI-based ART during AHI resulted in rapid and sustained viral suppression. Over 96 weeks, weight increased in the INSTI-based cohort but was similar to weight increase in a historical NNRTI-based AHI cohort.

Fourth-Generation HIV Rapid Tests: Enhanced Sensitivity and Reduced Diagnostic Window for HIV-1 Primary Infection Screening.

As most HIV rapid tests (HRT) detect only HIV-1/2 antibodies, their performance during primary HIV infection is poor. Determine HIV Early detect (Abbott) (Determine) is the only HRT with an HIV-1 p24-antigen detection, but the impact of this addition in shortening the diagnostic window remains unclear. A total of 183 HIV-1 primary infection samples were tested using the HRTs Determine and ONE STEP anti-HIV (1&2) Test (InTec Products) (One-Step). The pre-seroconversion subgroup was defined as p24-antigen positivity without Western blot nor Liaison XL (fouth generation enzyme immunoassay with distinct signal for p24-antigen and HIV-1 antibody) HIV-1 antibodies. Global sensitivity (95% CI) was 95% (91-97) for Determine versus 80% (74%-85%) for One-Step (difference p = 1.38e-06). Pre-seroconversion subgroup sensitivity was lower, at 71.9 (54.6%-84.4%) for Determine and 9.7% (3.3%-24.9%) for One-Step. Among the 45 samples with an HIV-1 infection date, no HRT was reactive up to 2 weeks. Between 2 and 3 weeks, Determine sensitivity was 78% (45%-95%) versus 56% (27%-81%) for One-Step. From 3 weeks to 1 month Determine sensitivity was 90% (62%-98%) and One-Step 45% (21%-72%). The last negative sample occurred at 3 weeks for Determine versus 70-90 days for One-Step. HRT with p24-antigen detection significantly shortens the diagnostic window from approximatively 3 months to 1 month. HRTs should be used with caution in the first month after HIV infection.

Effectiveness, safety, and patient-reported outcomes of emtricitabine/tenofovir alafenamide-based regimens for the treatment of HIV-1 infection: Final 24-month results from the prospective German TAFNES cohort study.

Tenofovir alafenamide (TAF) was introduced in the European Union in 2015 as a novel prodrug of tenofovir showing similar efficacy in clinical trials and a more favorable safety profile than tenofovir disoproxil fumarate (TDF). The German TAFNES cohort study (2016-2019) was conducted to generate real-world evidence. Treatment-naïve (TN) and treatment-experienced (TE) people with HIV (PWH) receiving elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF), rilpivirine/F/TAF (R/F/TAF) or F/TAF + 3rd agent were included. Month (M) 24 outcomes included virologic effectiveness (HIV RNA <50 copies/mL), treatment persistence, adverse drug reactions (ADRs) and patient-reported outcomes, using the HIV Symptom Index (HIV-SI), 36-Item Short Form Health Survey (SF-36) and HIV Treatment Satisfaction (HIVTSQ) questionnaires. The study included 767 PWH (92% men, median age 46 years; 301 TN, 466 TE; E/C/F/TAF [n = 318], R/F/TAF [n = 192], F/TAF + 3rd agent [n = 257]). Among TN, 35% had late HIV diagnosis (CD4 < 350/μL and/or AIDS). Of TE, 95% were on suppressive antiretroviral therapy (ART) before switching. D:A:D (Data Collection on Adverse Effects of Anti-HIV Drugs) 5-year risks for chronic kidney disease were high for about 1 in 10 TN and 4 in 10 TE. Overall treatment persistence at M24 was 81% (E/C/F/TAF: 88%; R/F/TAF: 86%; F/TAF + 3rd agent: 70%, with ART simplification of multiple-tablet regimens in 13%). M24 viral suppression (missing = excluded) was 96% (479/501). Discontinuations due to virologic failure or ADRs were rare, 2% (12/767) and 4% (30/767), respectively. HIV-SI and SF-36 summary scores improved in TN; HIVTSQ change scores showed an improvement in treatment satisfaction in TE. Real-world data confirmed a favorable safety profile and high virologic effectiveness with high treatment satisfaction on F/TAF-based ART.

Death and survival of gut CD4 T cells following HIV-1 infection ex vivo.

The gastrointestinal tract is ground zero for the massive and sustained CD4 T cell depletion during acute HIV-1 infection. To date, the molecular mechanisms governing this fundamental pathogenic process remain unclear. HIV-1 infection in the gastrointestinal tract is associated with chronic inflammation due to a disrupted epithelial barrier that results in microbial translocation. Here, we utilized the lamina propria aggregate culture model to demonstrate that the profound induction of granzyme B by bacteria in primary gut CD4 T cells ex vivo significantly contributes to HIV-1-mediated CD4 T cell death. Counterintuitively, a substantial fraction of gut granzyme B+ CD4 T cells harboring high levels of HIV-1 infection survive via a pathway linked to CD120b/TNFR2. Our findings underscore previously undescribed mechanisms governing the death and survival of gut CD4 T cells during HIV-1 infection that could inform strategies to counter HIV-1 pathogenesis and persistence in this critical tissue compartment.

A new perspective on risk factors for progressive liver fibrosis in patients with HIV, HBV, HCV superinfection

Topicality. One of the risk factors for the progression of the fibrotic process in the liver in triple superinfection with HIV/HBV/HCV may be the order of entry of viral pathogens into the human body, as well as the time interval between the entry of different pathogens. The aim of the study was to assess the effect on the course of liver fibrosis in HIV/HBV/HCV superinfection of the sequence of pathogens entering the human body and the time between superinfection.Materials and methods. 97 people with a verified diagnosis of HIV/HBV/HCV superinfection were subjected to a retrospective analysis depending on the timing of pathogen intake, the severity of liver fibrosis and antiviral therapy. Among the examined, 80% were men. The age category of 18-44 years included 84% and the remaining patients were in the category of 45–49 years. All patients received antiviral therapy. Liver fibrosis was assessed using dynamic liver elastography.Outcomes. The most favorable from the point of view of the progression of liver fibrosis was the primary HIV infection with an interval of 1–5 years between infection with hepatitis B and C viruses. The predominance of the progressive course of the fibrotic process in the liver occurred in cases where the first pathogen was HBV, and the interval between superinfection with another virus (HIV, HCV) exceeded 10 years. In cases not included in this category of patients, a HCV viral load above 1,700,000 copies/ml may be a risk factor for triple superinfection.Findings. 1. In HIV/HBV/HCV superinfection, a high risk of progressive liver fibrosis is associated with situations when: the first superinfecting pathogen is HIV at an interval of 1–5 years before superinfection with hepatitis B and/or C viruses; the first superinfecting pathogen is HBV with an interval of more than 10 years prior to HIV and/or HCV superinfection. 2. In HIV/HBV/HCV superinfection, in the absence of a priority for superinfection, a HCV viral load of more than 1700000 copies/ml may be a risk factor for advanced liver fibrosis. A rational regimen for antiretroviral therapy in triple superinfection with HIV/HBV/HCV is a combination of nucleotide inhibitors of HIV and HBV reverse transcriptase and HIV protease inhibitors.

Effect of HIV on Lung Function and Structure: A Systematic Review and Meta-analysis.

Obstructive lung disease (OLD) pathogenesis includes inhalational (e.g., smoking) and non-inhalational mechanisms (e.g., infections). HIV has been suggested as a novel OLD risk factor. Substantial data have recently emerged about its effects on lung function and structure, especially in low-to-middle-income countries and regarding longitudinal lung function. To assess the association of HIV infection with OLD, impaired gas exchange, and emphysema. In this systematic review and meta-analysis, we searched PubMed, EMBASE, CENTRAL, CDSR, WoS, Scopus, CINAHL, and GIM through April 2023 for controlled and observational studies of people living with and without HIV reporting pulmonary function and/or emphysema. Primary outcomes were OLD by spirometry, gas exchange impairment by diffusing capacity for carbon monoxide, and visual emphysema by computed tomography. We performed random-effects meta-analyses using odds ratios (OR) with 95% confidence intervals (CIs). This study was registered in PROSPERO (CRD42021268498). We included 95 publications pertaining to 43 unique studies. HIV was associated with OLD (OR 1.29; 95% CI 1.02-1.63), impaired gas exchange (OR 2.63; 95% CI 0.96-7.24), emphysema (OR 1.46; 95% CI 1.02-2.09), and faster lung function decline. OLD risk was greatest in Africans with HIV. There were no gas exchange or emphysema data from Africa. Certainty of evidence was low to very low, primarily due to studies' observational design. People living with HIV have increased risk for OLD, gas exchange impairment, faster lung function decline, and emphysema. OLD risk in HIV varies regionally. We recommend both spirometry and DLCO be measured in people living with HIV and respiratory symptoms. Future studies should develop and validate HIV-specific screening and case-finding strategies for chronic lung disease.

Double-Negative T-Cells during Acute Human Immunodeficiency Virus and Simian Immunodeficiency Virus Infections and Following Early Antiretroviral Therapy Initiation.

HIV infection significantly affects the frequencies and functions of immunoregulatory CD3+CD4-CD8- double-negative (DN) T-cells, while the effect of early antiretroviral therapy (ART) initiation on these cells remains understudied. DN T-cell subsets were analyzed prospectively in 10 HIV+ individuals during acute infection and following early ART initiation compared to 20 HIV-uninfected controls. In this study, 21 Rhesus macaques (RMs) were SIV-infected, of which 13 were assessed during acute infection and 8 following ART initiation four days post-infection. DN T-cells and FoxP3+ DN Treg frequencies increased during acute HIV infection, which was not restored by ART. The expression of activation (HLA-DR/CD38), immune checkpoints (PD-1/CTLA-4), and senescence (CD28-CD57+) markers by DN T-cells and DN Tregs increased during acute infection and was not normalized by ART. In SIV-infected RMs, DN T-cells remained unchanged despite infection or ART, whereas DN Treg frequencies increased during acute SIV infection and were not restored by ART. Finally, frequencies of CD39+ DN Tregs increased during acute HIV and SIV infections and remained elevated despite ART. Altogether, acute HIV/SIV infections significantly changed DN T-cell and DN Treg frequencies and altered their immune phenotype, while these changes were not fully normalized by early ART, suggesting persistent HIV/SIV-induced immune dysregulation despite early ART initiation.