HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections.

Upon infection, HIV disseminates throughout the human body within 1-2 weeks. However, its early cellular targets remain poorly characterized. We used a single-cell approach to retrieve the phenotype and TCR sequence of infected cells in blood and lymphoid tissue from individuals at the earliest stages of HIV infection. HIV initially targeted a few proliferating memory CD4+ T cells displaying high surface expression of CCR5. The phenotype of productively infected cells differed by Fiebig stage and between blood and lymph nodes. The TCR repertoire of productively infected cells was heavily biased, with preferential infection of previously expanded and disseminated clones, but composed almost exclusively of unique clonotypes, indicating that they were the product of independent infection events. Latent genetically intact proviruses were already archived early in infection. Hence, productive infection is initially established in a pool of phenotypically and clonotypically distinct T cells, and latently infected cells are generated simultaneously.

Adaptive NK Cells Rapidly Expand during Acute HIV Infection and Persist Despite Early Initiation of Antiretroviral Therapy.

HIV is associated with NK cell dysfunction and expansion of adaptive-like NK cells that persist despite antiretroviral therapy (ART). We investigated the timing of NK cell perturbations during acute HIV infection and the impact of early ART initiation. PBMCs and plasma were obtained from people with HIV (PWH; all men who have sex with men; median age, 26.0 y) diagnosed during Fiebig stages I, II, III, or IV/V. Participants initiated ART a median of 3 d after diagnosis, and immunophenotyping was performed at diagnosis and longitudinally after ART. Anti-CMV Abs were assessed by ELISA. Samples from matched HIV-uninfected males were also analyzed. Proportions of adaptive NK cells (A-NKs; defined as Fcε-Receptor-1γ-) were expanded at HIV diagnosis at all Fiebig stages (pooled median 66% versus 25% for controls; p < 0.001) and were not altered by early ART initiation. Abs to CMV immediate early protein were elevated in PWH diagnosed in Fiebig stages III and IV/V (p < 0.03 for both). Proportions of A-NKs defined as either Fcε-Receptor-1γ- or NKG2C+/CD57+ were significantly associated with HIV DNA levels at diagnosis (p = 0.046 and 0.029, respectively) and trended toward an association after 48 wk of ART. Proportions of activated HLA-DR+/CD38+ NK cells remained elevated in PWH despite early ART initiation. NK cell activation and A-NK expansion occur very early after HIV transmission, before T cell activation, and are not altered by ART initiation during acute infection. A-NKs may contribute to HIV control and thus be useful for HIV cure.

Safety and Immunogenicity of mRNA-1010, an Investigational Seasonal Influenza Vaccine, in Healthy Adults: Final Results From a Phase 1/2 Randomized Trial.

BACKGROUND: Seasonal influenza remains a global public health concern. A messenger RNA (mRNA)-based quadrivalent seasonal influenza vaccine, mRNA-1010, was investigated in a 3-part, first-in-human, phase 1/2 clinical trial. METHODS: In Parts 1-3 of this stratified, observer-blind study, adults aged ≥18 years old were randomly assigned to receive a single dose (6.25 µg to 200 µg) of mRNA-1010 or placebo (Part 1) or an active comparator (Afluria; Parts 2-3). Primary study objectives were assessment of safety, reactogenicity, and humoral immunogenicity of mRNA-1010, placebo (Part 1), or active comparator (Parts 2-3). Exploratory endpoints included assessment of cellular immunogenicity (Part 1) and antigenic breadth against vaccine heterologous (A/H3N2) strains (Parts 1-2). RESULTS: In all study parts, solicited adverse reactions were reported more frequently for mRNA-1010 than placebo or Afluria and most were grade 1 or 2 in severity. No vaccine-related serious adverse events or deaths were reported. In Parts 1-2, a single dose of mRNA-1010 (25 µg to 200 µg) elicited robust Day 29 hemagglutination inhibition (HAI) titers that persisted through 6 months. In Part 3, lower doses of mRNA-1010 (6.25 µg to 25 µg) elicited Day 29 HAI titers that were higher or comparable to Afluria for influenza A strains. Compared with Afluria, mRNA-1010 (50 µg) elicited broader A/H3N2 antibody responses (Part 2). mRNA-1010 induced greater T-cell responses than placebo at Day 8 that were sustained or stronger at Day 29 (Part 1). CONCLUSIONS: Data support the continued development of mRNA-1010 as a seasonal influenza vaccine. CLINICALTRIALS.GOV IDENTIFIER: NCT04956575 (https://clinicaltrials.gov/study/NCT04956575).

Preferential and persistent impact of acute HIV-1 infection on CD4+ iNKT cells in colonic mucosa.

Acute HIV-1 infection (AHI) results in the widespread depletion of CD4+ T cells in peripheral blood and gut mucosal tissue. However, the impact on the predominantly CD4+ immunoregulatory invariant natural killer T (iNKT) cells during AHI remains unknown. Here, iNKT cells from peripheral blood and colonic mucosa were investigated during treated and untreated AHI. iNKT cells in blood were activated and rapidly depleted in untreated AHI. At the time of peak HIV-1 viral load, these cells showed the elevated expression of cell death-associated transcripts compared to preinfection. Residual peripheral iNKT cells suffered a diminished responsiveness to in vitro stimulation early into chronic infection. Additionally, HIV-1 DNA, as well as spliced and unspliced viral RNA, were detected in iNKT cells isolated from blood, indicating the active infection of these cells in vivo. The loss of iNKT cells occurred from Fiebig stage III in the colonic mucosa, and these cells were not restored to normal levels after initiation of ART during AHI. CD4+ iNKT cells were depleted faster and more profoundly than conventional CD4+ T cells, and the preferential infection of CD4+ iNKT cells over conventional CD4+ T cells was confirmed by in vitro infection experiments. In vitro data also provided evidence of latent infection in iNKT cells. Strikingly, preinfection levels of peripheral blood CD4+ iNKT cells correlated directly with the peak HIV-1 load. These findings support a model in which iNKT cells are early targets for HIV-1 infection, driving their rapid loss from circulation and colonic mucosa.

Immunological, Cognitive, and Psychiatric Outcomes After Initiating Efavirenz- and Dolutegravir-based Antiretroviral Therapy During Acute Human Immunodeficiency Virus Infection.

BACKGROUND: Efavirenz (EFV)- and dolutegravir (DTG)-based antiretroviral therapy (ART) is the former and current recommended regimen for treatment-naive individuals with human immunodeficiency virus type 1 (HIV-1). Whether they impact the immunological and neuropsychiatric profile differentially remains unclear. METHODS: This retrospective analysis included 258 participants enrolled during acute HIV-1 infection (AHI). Participants initiated 1 of 3 ART regimens during AHI: EFV-based (n = 131), DTG-based (n = 92), or DTG intensified with maraviroc (DTG/MVC, n = 35). All regimens included 2 nucleoside reverse-transcriptase inhibitors and were maintained for 96 weeks. CD4+ and CD8+ T-cell counts, mood symptoms, and composite score on a 4-test neuropsychological battery (NPZ-4) were compared. RESULTS: At baseline, the median age was 26 years, 99% were male, and 36% were enrolled during Fiebig stage I-II. Plasma viral suppression at weeks 24 and 96 was similar between the groups. Compared with the EFV group, the DTG group showed greater increments of CD4+ (P < .001) and CD8+ (P = .015) T-cell counts but a similar increment of CD4/CD8 ratio at week 96. NPZ-4 improvement was similar between the 2 groups at week 24 but greater in the DTG group at week 96 (P = .005). Depressive mood and distress symptoms based on the Patient Health Questionnaire and distress thermometer were similar between the 2 groups at follow-up. Findings for the DTG/MVC group were comparable to those for the DTG group vs the EFV group. CONCLUSIONS: Among individuals with AHI, 96 weeks of DTG-based ART was associated with greater increments of CD4+ and CD8+ T-cell counts and improvement in cognitive performance.

Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection.

HIV-1 replication within the central nervous system (CNS) impairs neurocognitive function and has the potential to establish persistent, compartmentalized viral reservoirs. The origins of HIV-1 detected in the CNS compartment are unknown, including whether cells within the cerebrospinal fluid (CSF) produce virus. We measured viral RNA+ cells in CSF from acutely infected macaques longitudinally and people living with early stages of acute HIV-1. Active viral transcription (spliced viral RNA) was present in CSF CD4+ T cells as early as four weeks post-SHIV infection, and among all acute HIV-1 specimens (N = 6; Fiebig III/IV). Replication-inactive CD4+ T cell infection, indicated by unspliced viral RNA in the absence of spliced viral RNA, was even more prevalent, present in CSF of >50% macaques and human CSF at ~10-fold higher frequency than productive infection. Infection levels were similar between CSF and peripheral blood (and lymph nodes in macaques), indicating comparable T cell infection across these compartments. In addition, surface markers of activation were increased on CSF T cells and monocytes and correlated with CSF soluble markers of inflammation. These studies provide direct evidence of HIV-1 replication in CD4+ T cells and broad immune activation in peripheral blood and the CNS during acute infection, likely contributing to early neuroinflammation and reservoir seeding. Thus, early initiation of antiretroviral therapy may not be able to prevent establishment of CNS viral reservoirs and sources of long-term inflammation, important targets for HIV-1 cure and therapeutic strategies.

Paradoxically Greater Persistence of HIV RNA-Positive Cells in Lymphoid Tissue When ART Is Initiated in the Earliest Stage of Infection.

Starting antiretroviral therapy (ART) in Fiebig 1 acute HIV infection limits the size of viral reservoirs in lymphoid tissues, but does not impact time to virus rebound during a treatment interruption. To better understand why the reduced reservoir size did not increase the time to rebound we measured the frequency and location of HIV RNA+ cells in lymph nodes from participants in the RV254 acute infection cohort. HIV RNA+ cells were detected more frequently and in greater numbers when ART was initiated in Fiebig 1 compared to later Fiebig stages and were localized to the T-cell zone compared to the B-cell follicle with treatment in later Fiebig stages. Variability of virus production in people treated during acute infection suggests that the balance between virus-producing cells and the immune response to clear infected cells rapidly evolves during the earliest stages of infection. Clinical Trials Registration: NCT02919306.

Randomized Study of Rivaroxaban vs Placebo on Disease Progression and Symptoms Resolution in High-Risk Adults With Mild Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection may be associated with a prothrombotic state, predisposing patients for a progressive disease course. We investigated whether rivaroxaban, a direct oral anticoagulant factor Xa inhibitor, would reduce coronavirus disease 2019 (COVID-19) progression. METHODS: Adults (N = 497) with mild COVID-19 symptoms and at high risk for COVID-19 progression based on age, body mass index, or comorbidity were randomized 1:1 to either daily oral rivaroxaban 10 mg (N = 246) or placebo equivalent (N = 251) for 21 days and followed to day 35. Primary end points were safety and progression. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method. RESULTS: The study was terminated after 497 of the target 600 participants were enrolled due to a prespecified interim analysis of the first 200 participants that crossed the futility boundary for the primary efficacy end point in the intent-to-treat population. Enrollees were 85% aged <65 years; 60% female; 27% Hispanic, Black, or other minorities; and 69% with ≥2 comorbidities. Rivaroxaban was well tolerated. Disease progression rates were 46 of 222 (20.7%) in rivaroxaban vs 44 of 222 (19.8%) in placebo groups, with a risk difference of -1.0 (95% confidence interval, -6.4 to 8.4; P = .78). CONCLUSIONS: We did not demonstrate an impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19. There remains a critical public health gap in identifying scalable effective therapies for high-risk people in the outpatient setting to prevent COVID-19 progression.

Time to Viral Rebound After Interruption of Modern Antiretroviral Therapies.

BACKGROUND: Development of human immunodeficiency virus (HIV) remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty regarding whether modern antiretroviral therapy (ART) regimens and timing of ART initiation may affect this outcome. METHODS: AIDS Clinical Trials Group (ACTG) A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon 2 successive viral loads ≥1000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies. RESULTS: Thirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of the chronic-treated and none of the early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens, whereas 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at posttreatment interruption week 12 (chronic vs early: 2% vs 9%, P = .0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants resuppressed after ART reinitiation. CONCLUSIONS: Early ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission.

A qualitative study of the impact of coronavirus disease (COVID-19) on psychological and financial wellbeing and engagement in care among men who have sex with men living with HIV in Thailand.

OBJECTIVES: The coronavirus disease (COVID-19) pandemic is an unprecedented event with massive global health and socio-economic impacts on vulnerable populations, especially people living with HIV. The epidemic has severely affected Thailand's economy and potentially impacted the financial and psychological wellbeing of Thai HIV-positive men who have sex with men (MSM). METHODS: Between 15 June and 10 December 2020, we conducted qualitative interviews with 26 MSM living with HIV in Thailand who participate in an Adam's Love We Care Study. We intentionally recruited individuals who may have experienced a greater impact of COVID-19. Interviews explored worry, stigma and stress surrounding COVID-19, and multiple domains of potential COVID-19 impact: financial/employment, HIV service delivery and antiretroviral (ART) adherence during the first 10 months of the COVID-19 pandemic. RESULTS: Participants perceived themselves as immunocompromised and susceptible, and feared contracting COVID-19. Participants worried that contracting COVID-19 would lead to HIV status disclosure and stigmatization. Participants had considerable worry about job loss as a result of the economic downturn, and some shared challenges associated with relocation and re-engaging with HIV care. Financial stress and lack of basic necessities caused by job losses were commonly reported. Participants reported optimal ART adherence as a consequence of local HIV service delivery responses, convenient ART refills and Adam's Love online support interventions. CONCLUSIONS: Our study highlights that the COVID-19 pandemic produced high levels of anxiety and concerns about additional stigma among MSM living with HIV. It had a significant negative effect on the daily lives of our participants. These findings indicate a need for the provision of confidential COVID-19 diagnosis and care, relief programmes, vaccination roll-out equity, and addressing employment needs of vulnerable populations.

Individual Differences in CD4/CD8 T-Cell Ratio Trajectories and Associated Risk Profiles Modeled From Acute HIV Infection.

OBJECTIVE: We examined individual differences in CD4/CD8 T-cell ratio trajectories and associated risk profiles from acute HIV infection (AHI) through 144 weeks of antiretroviral therapy (ART) using a data-driven approach. METHODS: A total of 483 AHI participants began ART during Fiebig I-V and completed follow-up evaluations for 144 weeks. CD4+, CD8+, and CD4/CD8 T-cell ratio trajectories were defined followed by analyses to identify associated risk variables. RESULTS: Participants had a median viral load (VL) of 5.88 copies/ml and CD4/CD8 T-cell ratio of 0.71 at enrollment. After 144 weeks of ART, the median CD4/CD8 T-cell ratio was 1.3. Longitudinal models revealed five CD4/CD8 T-cell ratio subgroups: group 1 (3%) exhibited a ratio >1.0 at all visits; groups 2 (18%) and 3 (29%) exhibited inversion at enrollment, with normalization 4 and 12 weeks after ART, respectively; and groups 4 (31%) and 5 (18%) experienced CD4/CD8 T-cell ratio inversion due to slow CD4+ T-cell recovery (group 4) or high CD8+ T-cell count (group 5). Persistent inversion corresponded to ART onset after Fiebig II, higher VL, soluble CD27 and TIM-3, and lower eosinophil count. Individuals with slow CD4+ T-cell recovery exhibited higher VL, lower white blood cell count, lower basophil percent, and treatment with standard ART, as well as worse mental health and cognition, compared with individuals with high CD8+ T-cell count. CONCLUSIONS: Early HIV disease dynamics predict unfavorable CD4/CD8 T-cell ratio outcomes after ART. CD4+ and CD8+ T-cell trajectories contribute to inversion risk and correspond to specific viral, immune, and psychological profiles during AHI. Adjunctive strategies to achieve immune normalization merit consideration.

Attitudes About Analytic Treatment Interruption (ATI) in HIV Remission Trials with Different Antiretroviral Therapy (ART) Resumption Criteria.

HIV remission trials often require temporary stopping of antiretroviral therapy (ART)-an approach called analytic treatment interruption (ATI). Trial designs resulting in viremia raise risks for participants and sexual partners. We conducted a survey on attitudes about remission trials, comparing ART resumption criteria (lower-risk "time to rebound" and higher-risk "sustained viremia") among participants from an acute HIV cohort in Thailand. Analyses included Wilcoxon-Ranks and multivariate logistic analysis. Most of 408 respondents supported ATI trials, with slightly higher approval of, and willingness to participate in, trials using time to rebound versus sustained viremia criteria. Less than half of respondents anticipated disclosing trial participation to partners and over half indicated uncertainty or unwillingness about whether partners would be willing to use PrEP. Willingness to participate was higher among those who rated higher trial approval, lower anticipated burden, and those expecting to make the decision independently. Our findings support acceptability of ATI trials among most respondents. Participant attitudes and anticipated behaviors, especially related to transmission risk, have implications for future trial design and informed consent.

An Inflammatory Composite Score Predicts Mycobacterial Immune Reconstitution Inflammatory Syndrome in People with Advanced HIV: A Prospective International Cohort Study.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is a common cause of morbidity among people with human immunodeficiency virus (PWH) who initiate antiretroviral therapy (ART) with severe lymphopenia. Easily accessible tools that reliably predict emergence and elucidate pathogenesis of IRIS are needed to facilitate improved clinical management. METHODS: Plasma levels of biomarkers were measured before ART initiation in a large multinational cohort of ART-naive PWH with severe immunosuppression (CD4+ count <100 cells/mm3) in United States, Kenya, and Thailand. We performed a series of multiparametric analyses of inflammatory and clinical biomarkers and developed a composite score merging relevant biomarkers for use in a prediction model. RESULTS: We identified a distinct baseline inflammatory profile and changes in inflammatory networks among biomarkers in participants who subsequently developed mycobacterial or viral IRIS. We also developed a composite score incorporating biomarkers associated with IRIS (interleukin-6 [IL-6], IL-10, IL-27, sCD14, interferon-γ, tumor necrosis factor-α, hyaluronic acid, D-dimer, body mass index, and hemoglobin) that accurately predicted mycobacterial IRIS and death in this cohort. CONCLUSIONS: Systemic inflammatory profiles in PWH with severe immunosuppression are predictive of IRIS. Composite scores for the prediction of mycobacterial IRIS and death could be useful for risk stratification in PWH and lymphopenia initiating ART. CLINICAL TRIALS REGISTRATION: NCT00286767.

Novel Criteria for Diagnosing Acute and Early Human Immunodeficiency Virus Infection in a Multinational Study of Early Antiretroviral Therapy Initiation.

BACKGROUND: Antiretroviral therapy (ART) initiation during acute and early human immunodeficiency virus infection (AEHI) limits HIV reservoir formation and may facilitate post-ART control but is logistically challenging. We evaluated the performance of AEHI diagnostic criteria from a prospective study of early ART initiation. METHODS: AIDS Clinical Trials Group A 5354 enrolled adults at 30 sites in the Americas, Africa, and Asia who met any 1 of 6 criteria based on combinations of results of HIV RNA, HIV antibody, Western blot or Geenius assay, and/or the signal-to-cutoff (S/CO) ratio of the ARCHITECT HIV Ag/Ab Combo or GS HIV Combo Ag/Ab EIA. HIV status and Fiebig stage were confirmed by centralized testing. RESULTS: From 2017 through 2019, 195 participants were enrolled with median age of 27 years (interquartile range, 23-39). Thirty (15.4%) were female. ART was started by 171 (87.7%) on the day of enrollment and 24 (12.3%) the next day. AEHI was confirmed in 188 (96.4%) participants after centralized testing, 4 (2.0%) participants were found to have chronic infection, and 3 (1.5%) found not to have HIV discontinued ART and were withdrawn. Retrospectively, a nonreactive or indeterminate HIV antibody on the Geenius assay combined with ARCHITECT S/CO ≥10 correctly identified 99 of 122 (81.2%) Fiebig II-IV AEHI cases with no false-positive results. CONCLUSIONS: Novel AEHI criteria that incorporate ARCHITECT S/CO facilitated rapid and efficient ART initiation without waiting for an HIV RNA result. These criteria may facilitate AEHI diagnosis, staging, and immediate ART initiation in future research studies and clinical practice. CLINICAL TRIALS REGISTRATION: NCT02859558.

Continuous Prophylactic Antiretrovirals/Antiretroviral Therapy Since Birth Reduces Seeding and Persistence of the Viral Reservoir in Children Vertically Infected With Human Immunodeficiency Virus.

BACKGROUND: Early antiretroviral therapy (ART) restricts the size of the human immunodeficiency virus (HIV) reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown. METHODS: We measured total and integrated HIV DNA, as well as the frequency of CD4 T cells producing multiply spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically infected Thai infants. Eighty-five infants were followed longitudinally for up to 3 years. We compared the size of the reservoir in children who received continuous ARV prophylaxis since birth vs those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings. RESULTS: Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous ARV prophylaxis since birth compared to those in whom ARV prophylaxis was discontinued or never initiated (P < .020 and P < .001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (P < .01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during 3 years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARVs before starting ART and those who delayed ART initiation without receiving prior prophylaxis. CONCLUSIONS: Neonatal ARV prophylaxis with direct transition to ART durably limits the size of the HIV reservoir.

Central Nervous System Safety During Brief Analytic Treatment Interruption of Antiretroviral Therapy Within 4 Human Immunodeficiency Virus Remission Trials: An Observational Study in Acutely Treated People Living With Human Immunodeficiency Virus.

BACKGROUND: The central nervous system (CNS) is a likely reservoir of human immunodeficiency virus (HIV), vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission. METHODS: Thirty participants who started ART during acute HIV infection underwent CNS assessments across 4 ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). RESULTS: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART before ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in 6 of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes. CONCLUSION: No adverse CNS effects were observed with brief, closely monitored ATI in participants with acutely treated HIV, except an MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.

Increased Burden of Concordant and Sequential Anogenital Human Papillomavirus Infections Among Asian Young Adult Women With Perinatally Acquired HIV Compared With HIV-Negative Peers.

BACKGROUND: Youth with perinatally acquired HIV (YPHIV) are at higher risk for anogenital human papillomavirus (HPV) infection. METHODS: We enrolled a cohort of YPHIV and HIV-negative youth in Thailand and Vietnam, matched by age and lifetime sex partners, and followed them up for 144 weeks (to 2017). Participants had annual pelvic examinations with samples taken for HPV genotyping. Concordant infection was simultaneous HPV detection in multiple anogenital compartments (cervical, vaginal, anal); sequential infection was when the same type was found in successive compartments (cervicovaginal to/from anal). Generalized estimating equations were used to assess factors associated with concordant infection, and Cox regression was used to assess factors associated with sequential infection. RESULTS: A total of 93 YPHIV and 99 HIV-negative women were enrolled, with a median age of 19 years (interquartile range, 18-20 years). High-risk anogenital HPV infection was ever detected in 76 (82%) YPHIV and 66 (67%) HIV-negative youth during follow-up. Concordant anogenital high-risk HPV infection was found in 62 (66%) YPHIV versus 44 (34%) HIV-negative youth. Sequential cervicovaginal to anal high-risk HPV infection occurred in 20 YPHIV versus 5 HIV-negative youth, with an incidence rate of 9.76 (6.30-15.13) versus 2.24 (0.93-5.38) per 100 person-years. Anal to cervicovaginal infection occurred in 4 YPHIV versus 0 HIV-negative women, with an incidence rate of 1.78 (0.67-4.75) per 100 person-years. Perinatally acquired HIV was the one factor independently associated with both concordant and sequential high-risk HPV infection. CONCLUSIONS: Children and adolescents with perinatally acquired HIV should be prioritized for HPV vaccination, and cervical cancer screening should be part of routine HIV care for sexually active YPHIV.

Preferential Infection of α4ß7+ Memory CD4+ T Cells During Early Acute Human Immunodeficiency Virus Type 1 Infection.

BACKGROUND: Establishment of persistent human immunodeficiency virus type 1 (HIV-1) reservoirs occurs early in infection, and biomarkers of infected CD4+ T cells during acute infection are poorly defined. CD4+ T cells expressing the gut homing integrin complex α4ß7 are associated with HIV-1 acquisition, and are rapidly depleted from the periphery and gastrointestinal mucosa during acute HIV-1 infection. METHODS: Integrated HIV-1 DNA was quantified in peripheral blood mononuclear cells obtained from acutely (Fiebig I-III) and chronically infected individuals by sorting memory CD4+ T-cell subsets lacking or expressing high levels of integrin ß7 (ß7negative and ß7high, respectively). HIV-1 DNA was also assessed after 8 months of combination antiretroviral therapy (cART) initiated in Fiebig II/III individuals. Activation marker and chemokine receptor expression was determined for ß7-defined subsets at acute infection and in uninfected controls. RESULTS: In Fiebig I, memory CD4+ T cells harboring integrated HIV-1 DNA were rare in both ß7high and ß7negative subsets, with no significant difference in HIV-1 DNA copies. In Fiebig stages II/III and in chronically infected individuals, ß7high cells were enriched in integrated and total HIV-1 DNA compared to ß7negative cells. During suppressive cART, integrated HIV-1 DNA copies decreased in both ß7negative and ß7high subsets, which did not differ in DNA copies. In Fiebig II/III, integrated HIV-1 DNA in ß7high cells was correlated with their activation. CONCLUSIONS: ß7high memory CD4+ T cells are preferential targets during early HIV-1 infection, which may be due to the increased activation of these cells.

Viral Blips After Treatment Initiation During Acute Human Immunodeficiency Virus Infection.

Transient viral blips ≥20 copies/mL were observed in 16.9% of acutely treated adults with HIV. Blip incidence increased from 0.0 (95% CI, 0.0-2.9)/100 person-years after ART in Fiebig I to 15.9 (7.6-29.2) in Fiebig V. Increasing viral load and Fiebig stage at ART initiation were independently predictive of blips.

Prospective International Study of Incidence and Predictors of Immune Reconstitution Inflammatory Syndrome and Death in People Living With Human Immunodeficiency Virus and Severe Lymphopenia.

BACKGROUND: Patients living with human immunodeficiency virus (PLWH) with low CD4 counts are at high risk for immune reconstitution inflammatory syndrome (IRIS) and death at antiretroviral therapy (ART) initiation. METHODS: We investigated the clinical impact of IRIS in PLWH and CD4 counts <100 cells/µL starting ART in an international, prospective study in the United States, Thailand, and Kenya. An independent review committee adjudicated IRIS events. We assessed associations between baseline biomarkers, IRIS, immune recovery at week 48, and death by week 48 with Cox models. RESULTS: We enrolled 506 participants (39.3% were women). Median age was 37 years, and CD4 count was 29 cells/µL. Within 6 months of ART, 97 (19.2%) participants developed IRIS and 31 (6.5%) died. Participants with lower hemoglobin at baseline were at higher IRIS risk (hazard ratio [HR], 1.2; P = .004). IRIS was independently associated with increased risk of death after adjustment for known risk factors (HR, 3.2; P = .031). Being female (P = .004) and having a lower body mass index (BMI; P = .003), higher white blood cell count (P = .005), and higher D-dimer levels (P = .044) were also significantly associated with increased risk of death. Decision-tree analysis identified hemoglobin <8.5 g/dL as predictive of IRIS and C-reactive protein (CRP) >106 µg/mL and BMI <15.6 kg/m2 as predictive of death. CONCLUSIONS: For PLWH with severe immunosuppression initiating ART, baseline low BMI and hemoglobin and high CRP and D-dimer levels may be clinically useful predictors of IRIS and death risk.