ALVAC-HIV and AIDSVAX B/E vaccination induce improved immune responses compared with AIDSVAX B/E vaccination alone.

The RV144 phase III vaccine trial demonstrated that ALVAC-HIV and AIDSVAX B/E administration over 6 months resulted in 31% efficacy in preventing HIV acquisition, while administration of AIDSVAX B/E alone in both VAX003 and VAX004 studies failed to show efficacy. In this study, we aimed to understand the impact of ALVAC-HIV on the development of cellular, humoral, and functional immune responses compared to the administration of AIDSVAX B/E alone. ALVAC-HIV in combination with 3 doses of AIDSVAX B/E significantly increased CD4+ HIV-specific T cell responses, polyfunctionality, and proliferation compared with 3 doses of AIDSVAX B/E alone. Additionally, Env-specific plasmablasts and A244-specific memory B cells were identified with a significantly higher magnitude in the group that received ALVAC-HIV. Subsequently, data revealed increased magnitude of plasma IgG binding to and avidity for HIV Env in participants who received ALVAC-HIV compared with 3 doses of AIDSVAX B/E alone. Lastly, levels of the Fc-mediated effector functions antibody-dependent cellular cytotoxicity, NK cell activation, and trogocytosis were significantly increased in participants who received ALVAC-HIV compared with those receiving AIDSVAX B/E alone. Taken together, these results suggest that ALVAC-HIV plays an essential role in developing cellular and humoral immune responses to protein-boosted regimens relative to protein alone.

Brain volumetrics differ by Fiebig stage in acute HIV infection.

OBJECTIVE: People with chronic HIV exhibit lower regional brain volumes compared to people without HIV (PWOH). Whether imaging alterations observed in chronic infection occur in acute HIV infection (AHI) remains unknown. DESIGN: Cross-sectional study of Thai participants with AHI. METHODS: One hundred and twelve Thai males with AHI (age 20-46) and 18 male Thai PWOH (age 18-40) were included. Individuals with AHI were stratified into early (Fiebig I-II; n  = 32) and late (Fiebig III-V; n  = 80) stages of acute infection using validated assays. T1-weighted scans were acquired using a 3 T MRI performed within five days of antiretroviral therapy (ART) initiation. Volumes for the amygdala, caudate nucleus, hippocampus, nucleus accumbens, pallidum, putamen, and thalamus were compared across groups. RESULTS: Participants in late Fiebig stages exhibited larger volumes in the nucleus accumbens (8% larger; P  = 0.049) and putamen (19%; P  < 0.001) when compared to participants in the early Fiebig. Compared to PWOH, participants in late Fiebig exhibited larger volumes of the amygdala (9% larger; P  = 0.002), caudate nucleus (11%; P  = 0.005), nucleus accumbens (15%; P  = 0.004), pallidum (19%; P  = 0.001), and putamen (31%; P  < 0.001). Brain volumes in the nucleus accumbens, pallidum, and putamen correlated modestly with stimulant use over the past four months among late Fiebig individuals ( P s < 0.05). CONCLUSIONS: Findings indicate that brain volume alterations occur in acute infection, with the most prominent differences evident in the later stages of AHI. Additional studies are needed to evaluate mechanisms for possible brain disruption following ART, including viral factors and markers of neuroinflammation.

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.

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8+ T cells.

BACKGROUND: Harnessing CD8+ T cell responses is being explored to achieve HIV remission. Although HIV-specific CD8+ T cells become dysfunctional without treatment, antiretroviral therapy (ART) partially restores their function. However, the extent of this recovery under long-term ART is less understood. METHODS: We analyzed the differentiation status and function of HIV-specific CD8+ T cells after long-term ART initiated in acute or chronic HIV infection ex vivo and upon in vitro recall. FINDINGS: ART initiation in any stage of acute HIV infection promoted the persistence of long-lived HIV-specific CD8+ T cells with high expansion (P<0·0008) and cytotoxic capacity (P=0·02) after in vitro recall, albeit at low cell number (P=0·003). This superior expansion capacity correlated with stemness (r=0·90, P=0·006), measured by TCF-1 expression, similar to functional HIV-specific CD8+ T cells found in spontaneous controllers. Importanly, TCF-1 expression in these cells was associated with longer time to viral rebound ranging from 13 to 48 days after ART interruption (r =0·71, P=0·03). In contrast, ART initiation in chronic HIV infection led to more differentiated HIV-specific CD8+ T cells lacking stemness properties and exhibiting residual dysfunction upon recall, with reduced proliferation and cytolytic activity. INTERPRETATION: ART initiation in acute HIV infection preserves functional HIV-specific CD8+ T cells, albeit at numbers too low to control viral rebound post-ART. HIV remission strategies may need to boost HIV-specific CD8+ T cell numbers and induce stem cell-like properties to reverse the residual dysfunction persisting on ART in people treated after acute infection prior to ART release. FUNDING: U.S. National Institutes of Health and U.S. Department of Defense.

Acute HIV-1 infection viremia associate with rebound upon treatment interruption.

BACKGROUND: Analytic treatment interruption (ATI) studies evaluate strategies to potentially induce remission in people living with HIV-1 but are often limited in sample size. We combined data from four studies that tested three interventions (vorinostat/hydroxychloroquine/maraviroc before ATI, Ad26/MVA vaccination before ATI, and VRC01 antibody infusion during ATI). METHODS: The statistical validity of combining data from these participants was evaluated. Eleven variables, including HIV-1 viral load at diagnosis, Fiebig stage, and CD4+ T cell count were evaluated using pairwise correlations, statistical tests, and Cox survival models. FINDINGS: Participants had homogeneous demographic and clinical characteristics. Because an antiviral effect was seen in participants who received VRC01 infusion post-ATI, these participants were excluded from the analysis, permitting a pooled analysis of 53 participants. Time to viral rebound was significantly associated with variables measured at the beginning of infection: pre-antiretroviral therapy (ART) viral load (HR = 1.34, p = 0.022), time to viral suppression post-ART initiation (HR = 1.07, p < 0.001), and area under the viral load curve (HR = 1.34, p = 0.026). CONCLUSIONS: We show that higher viral loads in acute HIV-1 infection were associated with faster viral rebound, demonstrating that the initial stage of HIV-1 infection before ART initiation has a strong impact on viral rebound post-ATI years later. FUNDING: This work was supported by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of the Army (W81XWH-18-2-0040). This research was funded, in part, by the US National Institute of Allergy and Infectious Diseases (AAI20052001) and the I4C Martin Delaney Collaboratory (5UM1AI126603-05).

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.

Safety and immunogenicity of Ad26 and MVA vaccines in acutely treated HIV and effect on viral rebound after antiretroviral therapy interruption.

We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306).

Infrequent HIV Infection of Circulating Monocytes during Antiretroviral Therapy.

Whereas human immunodeficiency virus (HIV) persists in tissue macrophages during antiretroviral therapy (ART), the role of circulating monocytes as HIV reservoirs remains controversial. Three magnetic bead selection methods and flow cytometry cell sorting were compared for their capacity to yield pure CD14+ monocyte populations. Cell sorting by flow cytometry provided the purest population of monocytes (median CD4+ T-cell contamination, 0.06%), and the levels of CD4+ T-cell contamination were positively correlated with the levels of integrated HIV DNA in the monocyte populations. Using cell sorting by flow cytometry, we assessed longitudinally the infection of monocytes and other cell subsets in a cohort of 29 Thai HIV-infected individuals. Low levels of HIV DNA were detected in a minority of monocyte fractions obtained before and after 1 year of ART (27% and 33%, respectively), whereas HIV DNA was readily detected in CD4+ T cells from all samples. Additional samples (2 to 5 years of ART) were obtained from 5 individuals in whom monocyte infection was previously detected. Whereas CD4+ T cells were infected at high levels at all time points, monocyte infection was inconsistent and absent in at least one longitudinal sample from 4/5 individuals. Our results indicate that infection of monocytes is infrequent and highlight the importance of using flow cytometry cell sorting to minimize contamination by CD4+ T cells.IMPORTANCE The role of circulating monocytes as persistent HIV reservoirs during ART is still controversial. Several studies have reported persistent infection of monocytes in virally suppressed individuals; however, others failed to detect HIV in this subset. These discrepancies are likely explained by the diversity of the methods used to isolate monocytes and to detect HIV infection. In this study, we show that only flow cytometry cell sorting yields a highly pure population of monocytes largely devoid of CD4 contaminants. Using this approach in a longitudinal cohort of HIV-infected individuals before and during ART, we demonstrate that HIV is rarely found in monocytes from untreated and treated HIV-infected individuals. This study highlights the importance of using methods that yield highly pure populations of cells as flow cytometry cell sorting to minimize and control for CD4+ T-cell contamination.

Normalization of Soluble CD163 Levels After Institution of Antiretroviral Therapy During Acute HIV Infection Tracks with Fewer Neurological Abnormalities.

Background: Myeloid activation contributes to cognitive impairment in chronic human immunodeficiency virus (HIV) infection. We explored whether combination antiretroviral therapy (cART) initiation during acute HIV infection impacts CD163 shedding, a myeloid activation marker, and in turn, implications on the central nervous system (CNS). Methods: We measured soluble CD163 (sCD163) levels in plasma and cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay in Thais who initiated cART during acute HIV infection (Fiebig stages I-IV). Examination of CNS involvement included neuropsychological testing and analysis of brain metabolites by magnetic resonance spectroscopy. Chronic HIV-infected or uninfected Thais served as controls. Results: We examined 51 adults with acute HIV infection (Fiebig stages I-III; male sex, >90%; age, 31 years). sCD163 levels before and after cART in Fiebig stage I/II were comparable to those in uninfected controls (plasma levels, 97.9 and 93.6 ng/mL, respectively, vs 99.5 ng/mL; CSF levels, 6.7 and 6.4 ng/mL, respectively, vs 7.1 ng/mL). In Fiebig stage III, sCD163 levels were elevated before cART as compared to those in uninfected controls (plasma levels, 135 ng/mL; CSF levels, 10 ng/mL; P < .01 for both comparisons) before normalization after cART (plasma levels, 90.1 ng/mL; CSF levels, 6.5 ng/mL). Before cART, higher sCD163 levels during Fiebig stage III correlated with poor CNS measures (eg, decreased N-acetylaspartate levels), but paradoxically, during Fiebig stage I/II, this association was linked with favorable CNS outcomes (eg, higher neuropsychological test scores). After cART initiation, higher sCD163 levels during Fiebig stage III were associated with negative CNS indices (eg, worse neuropsychological test scores). Conclusion: Initiation of cART early during acute HIV infection (ie, during Fiebig stage I/II) may decrease inflammation, preventing shedding of CD163, which in turn might lower the risk of brain injury.

Characterization of Cellular Immune Responses in Thai Individuals With and Without HIV-Associated Neurocognitive Disorders.

HIV-associated neurocognitive disorder (HAND) remains a challenge despite antiretroviral therapy (ART), and has been linked to monocyte/macrophage (M/M) migration to the brain. Due to the potential impact of T cell effector mechanisms in eliminating activated/HIV-infected M/M, T cell activation may play a role in the development of HAND. We sought to investigate the relationship between cognition and both CD8+ T cell activation (HLA-DR+/CD38+) and HIV-specific CD8+ T cell responses at the time of HIV diagnosis and 12 months postinitiation of ART. CD8+ T cell activation was increased in HAND compared to cognitive normal (NL) individuals and correlated directly with plasma viral load and inversely with the cognitive status. In addition, Gag-specific cytolytic activity (CD107a/b+) was decreased in HAND compared with NL individuals and correlated with their neurological testing, suggesting a potential role of cytotoxic CD8+ T cells in the mechanism of HAND development.

Brief Report: CD14+ Enriched Peripheral Cells Secrete Cytokines Unique to HIV-Associated Neurocognitive Disorders.

Monocytes play a vital role in HIV-associated neurocognitive disorder (HAND), postulated to transport HIV into the brain and secrete pro-inflammatory cytokines. We analyzed cytokines released by cultured peripheral blood mononuclear cells enriched with the CD14 marker isolated from HIV-infected individuals with HAND and normal cognition (NC) in combination antiretroviral therapy naive and after 1 year on treatment. Interleukin-8 and monocyte chemoattractant protein-1 levels were higher in HAND compared with NC at baseline (P = 0.002 and P < 0.0001). These cytokines remained higher in HAND patients 1 year after combination antiretroviral therapy and were significant when NC patients who were initially HAND were excluded (P = 0.012 and P = 0.002). Both correlated with baseline CD14 peripheral blood mononuclear cell HIV DNA levels supporting the role of HIV DNA reservoir size and monocyte cytokines in HAND persistence.

High Number of Activated CD8+ T Cells Targeting HIV Antigens Are Present in Cerebrospinal Fluid in Acute HIV Infection.

BACKGROUND: Central nervous system (CNS) infiltration by CD8 T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8 T cells in the CNS during acute HIV infection (AHI) is unknown. METHODS: We analyzed the phenotype, gene expression, T cell receptor (TCR) repertoire, and HIV specificity of CD8 T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of AHI (n = 26), chronic (n = 23), and uninfected (n = 8). RESULTS: CSF CD8 T cells were elevated in AHI compared with uninfected controls. The frequency of activated CSF CD8 T cells positively correlated to CSF HIV RNA and to markers of CNS inflammation. In contrast, activated CSF CD8 T cells during chronic HIV infection were associated with markers of neurological injury and microglial activation. CSF CD8 T cells in AHI exhibited increased functional gene expression profiles associated with CD8 T cells effector function, proliferation, and TCR signaling, a unique restricted TCR Vbeta repertoire and contained HIV-specific CD8 T cells directed to unique HIV epitopes compared with the periphery. CONCLUSIONS: These results suggest that CSF CD8 T cells in AHI expanding in the CNS are functional and directed against HIV antigens. These cells could thus play a beneficial role protective of injury seen in chronic HIV infection if combination antiretroviral therapy is initiated early.

HIV DNA Set Point is Rapidly Established in Acute HIV Infection and Dramatically Reduced by Early ART.

HIV DNA is a marker of HIV persistence that predicts HIV progression and remission, but its kinetics in early acute HIV infection (AHI) is poorly understood. We longitudinally measured the frequency of peripheral blood mononuclear cells harboring total and integrated HIV DNA in 19 untreated and 71 treated AHI participants, for whom 50 were in the earliest Fiebig I/II (HIV IgM-) stage, that is ≤2weeks from infection. Without antiretroviral therapy (ART), HIV DNA peaked at 2weeks after enrollment, reaching a set-point 2weeks later with little change thereafter. There was a marked divergence of HIV DNA values between the untreated and treated groups that occurred within the first 2weeks of ART and increased with time. ART reduced total HIV DNA levels by 20-fold after 2weeks and 316-fold after 3years. Therefore, very early ART offers the opportunity to significantly reduce the frequency of cells harboring HIV DNA.

Virologic failure is uncommon after treatment initiation during acute HIV infection.

OBJECTIVE: In chronic HIV infection, initiation of antiretroviral therapy (ART) typically induces swift HIV RNA declines and virologic suppression within 24 weeks. The objective of this study was to investigate viral dynamics and common criteria for treatment success after ART initiation during acute HIV infection (AHI). METHODS: Participants were prospectively enrolled and offered ART during AHI from May 2009-June 2015 in Bangkok, Thailand. Regimens included tenofovir, lamivudine or emtricitabine, and efavirenz with or without raltegravir and maraviroc. Participants were monitored for several HIV RNA end points: one-log reduction at week 2; two-log reduction at week 4; less than 1000 copies/ml at week 24; and less than 200 copies/ml at week 24. Factors associated with each end point, time to suppression, and virologic blips were explored. RESULTS: Two hundred and sixty-four Thai participants initiated ART during AHI. Their median age was 27 years and 96% were men. At 2 weeks, 6.5% had not achieved a one-log reduction in HIV RNA. At 4 weeks, 11.0% had not achieved a two-log reduction. At 24 weeks, 1.1% had not achieved HIV RNA less than 1000 copies/ml and 1.5% had not achieved HIV RNA less than 200 copies/ml. Participants who initiated ART during Fiebig I demonstrated a shorter median time to virologic suppression than did all other stages combined, [4 (interquartile range 2-8) vs. 8 (interquartile range 4-12) weeks, P < 0.001] and 7.3% had subsequent blips (16.1% in other stages, P = 0.23). CONCLUSION: Virologic failure is uncommon in individuals who initiate ART during AHI. ART initiation during AHI is efficacious and clinicians can monitor for virologic failure after 24 weeks of therapy.

Sex differences in soluble markers vary before and after the initiation of antiretroviral therapy in chronically HIV-infected individuals.

OBJECTIVE: To evaluate differences in soluble inflammatory markers between chronically HIV-infected men and women, with or without cognitive impairment, and in response to treatment. DESIGN: Soluble biomarkers were measured in cryopreserved plasma and cerebrospinal fluid (CSF) of 60 treatment-naïve individuals (25 men and 35 women) with chronic HIV infection and 18 HIV-uninfected controls (9 men and 9 women) from Thailand. Following enrollment, participants began combination antiretroviral therapy and were evaluated for expression of these markers after 48 weeks. METHODS: Plasma and CSF levels of 19 soluble biomarkers (IFN-γ, TNFα, TNF-RII, IL-1α, IL-1ß, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-15, MCP-1, t-Tau, IP-10, neopterin, IFNα, I-FABP, and sCD14) were measured using either a multiparameter or standard ELISA assay. RESULTS: Prior to combination antiretroviral therapy, women with impaired cognition had elevated levels of neopterin and TNF-RII compared with women with normal cognition in both the plasma and CSF; however, levels did not differ between cognitively impaired or normal men. In a secondary outcome-hypothesis generating analysis, sex differences were also pronounced in plasma levels of MCP-1, IL-10, I-FABP, and sCD14 in response to treatment. Neopterin, IP-10, TNFα, TNF-RII, IFNα, MCP-1, IL-8, I-FABP, and sCD14 plasma levels remained elevated following 48 weeks of therapy in both sexes compared with uninfected controls. CONCLUSION: We provide evidence of sustained immune activation after 48 weeks of treatment and identify possible sex differences in biomarkers previously linked to cognitive impairment, chronic inflammation, and gut integrity that may contribute to immunological differences between sexes in relationship to disease progression and response to therapy.

Neuronal-Glia Markers by Magnetic Resonance Spectroscopy in HIV Before and After Combination Antiretroviral Therapy.

OBJECTIVE: Combination antiretroviral therapy (cART) can suppress plasma HIV RNA to undetectable levels; yet reports indicate persistent HIV-associated neurocognitive disorders (HAND) among treated individuals. We sought to investigate imaging correlates of incomplete cognitive recovery among individuals with chronic HIV. METHODS: We used single voxel proton magnetic resonance spectroscopy in 4 regions of the brain to measure changes in neuronal and glia biomarkers in cART-naive subjects before (n = 59, 27 with HAND) and after 12 months of cART. RESULTS: At baseline, we observed elevated total choline (CHO) in the basal ganglia (BG, P = 0.002) and in the posterior cingulate gyrus (PCG, P = 0.022) associated with HIV infection. Myo-inositol (MI) was elevated in the frontal white matter (FWM, P = 0.040). N-acetylaspartate was elevated in the BG (P = 0.047). Using a mixed model approach among all HIV-infected individuals, at 6 months, we observed decreased n- acetylaspartate in FWM (P = 0.031), decreased creatine in PCG (P = 0.026) and increased MI in frontal gray matter (FGM, P = 0.023). At 12 months, we observed an increase in BG MI (P = 0.038) and in FGM (P = 0.021). Compared to those with normal cognition, HAND cases had higher FGM MI (P = 0.014) at baseline. At 12 months, individuals that remained cognitively impaired compared with those without HAND exhibited elevated CHO in the PCG (P = 0.018) and decreased glutamate in both FWM (P = 0.027) and BG (P = 0.013). CONCLUSIONS: cART started during chronic HIV is associated with reduced neuronal-glia and inflammatory markers. Alterations in CHO are noted among individuals who remain impaired after 12 months of cART.

Loss of CCR2 expressing non-classical monocytes are associated with cognitive impairment in antiretroviral therapy-naïve HIV-infected Thais.

HIV DNA in monocytes has been linked to HIV-associated neurocognitive disorders (HAND), however, characterization of monocyte subsets associated with HAND remains unclear. We completed a prospective study of antiretroviral therapy-naïve, HIV-infected Thais, with varying degrees of cognitive impairment, compared to HIV-uninfected controls. Monocyte subsets' CCR2, CCR5 and CD163 expression were profiled and inflammatory markers in plasma and cerebrospinal fluid (CSF), measured. Lower numbers of CCR2(+)non-classical monocytes were associated with worse neuropsychological test performance (r=0.43, p=0.024). CCR2(+)non-classical monocyte count inversely correlated with CSF neopterin (r=-0.43, p=0.035) and plasma TNF-α levels (r=-0.40, p=0.041). These data benchmark CCR2(+)non-classical monocytes as an independent index of cognitive impairment.

Neuropsychological Impairment in Acute HIV and the Effect of Immediate Antiretroviral Therapy.

OBJECTIVE: To investigate neuropsychological performance (NP) during acute HIV infection (AHI) before and after combination antiretroviral therapy (cART). DESIGN: Prospective study of Thai AHI participants examined at 3 and 6 months after initiation of cART. METHODS: Thirty-six AHI participants were evaluated pre-cART at median 19 days since HIV exposure and 3 and 6 months after cART with the Grooved Pegboard test, Color Trails 1 & 2 (CT1, CT2), and Trail Making Test A. Raw scores were standardized to 251 age- and education-matched HIV-uninfected Thais. To account for learning effects, change in NP performance was compared with that of controls at 6 months. Analyses included multivariable regression, nonparametric repeated measures analysis of variance, and Mann-Whitney U test. RESULTS: Baseline NP scores for the AHI group were within normal range (z-scores range: -0.26 to -0.13). NP performance improved on CT1, CT2, and Trail Making Test A in the initial 3 months (P < 0.01) with no significant change during the last 3 months. Only improvement in CT1 was greater than that seen in controls at 6 months (P = 0.018). Participants who performed >1 SD below normative means on ≥2 tests (n = 8) exhibited higher baseline cerebrospinal fluid HIV RNA (P = 0.047) and had no improvement after cART. CONCLUSIONS: Most AHI individuals had normal NP performance, and early cART slightly improved their psychomotor function. However, approximately 25% had impaired NP performance, which correlated with higher cerebrospinal fluid HIV RNA, and these abnormalities were not reversed by early cART possibly indicating limited reversibility of cognitive impairment in a subset of AHI individuals.

Association between brain volumes and HAND in cART-naïve HIV+ individuals from Thailand.

This study aimed to determine the effects of human immunodeficiency virus (HIV) on brain structure in HIV-infected individuals with and without HIV-associated neurocognitive disorders (HAND). Twenty-nine HIV-uninfected controls, 37 HIV+, treatment-naïve, individuals with HAND (HIV+HAND+; 16 asymptomatic neurocognitive impairment (ANI), 12 mild neurocognitive disorder (MND), and 9 HIV-associated dementia HAD), and 37 HIV+, treatment-naïve, individuals with normal cognitive function (HIV+HAND-) underwent magnetic resonance imaging (MRI) and neuropsychological assessment. The HIV-infected participants had a mean (SD) age of 35 (7) years, mean (interquartile range (IQR)) CD4 count of 221 (83-324), and mean (IQR) log10 plasma viral load of 4.81 (4.39-5.48). Six regions of interest were selected for analyses including total and subcortical gray matter, total white matter, caudate, corpus callosum, and thalamus. The HIV+/HAND+ group exhibited significantly smaller brain volumes compared to the HIV-uninfected group in subcortical gray and total gray matter; however, there were no statistically significant differences in brain volumes between the HIV+HAND+ and HIV+HAND- groups or between HIV+/HAND- and controls. CD4 count at time of combination antiretroviral therapy (cART) initiation was associated with total and subcortical gray matter volumes but not with cognitive measures. Plasma viral load correlated with neuropsychological performance but not brain volumes. The lack of significant differences in brain volumes between HIV+HAND+ and HIV+HAND- suggests that brain atrophy is not a sensitive measure of HAND in subjects without advanced immunosuppression. Alternatively, current HAND diagnostic criteria may not sufficiently distinguish patients based on MRI measures of brain volumes.

HIV DNA in CD14+ reservoirs is associated with regional brain atrophy in patients naive to combination antiretroviral therapy.

OBJECTIVE: To examine associations between regional brain volumes and HIV DNA in peripheral CD14 cells (monocytes) among HIV-infected individuals naive to combination antiretroviral therapy (cART). DESIGN: A prospective study of HIV-infected Thai individuals who met Thai national criteria for cART initiation. Enrolment was stratified by HIV DNA in a blinded fashion. METHODS: CD14 cells were isolated from peripheral mononuclear cells to high purity (median 91.4% monocytes by flow cytometry), and HIV DNA was quantified by multiplex real-time PCR. Baseline regional brain volumes obtained by T1-weighted 1.5-Tesla MRI were compared between HIV DNA groups using analysis of covariance (ANCOVA). RESULTS: We studied 60 individuals with mean (SD) age of 34.7 (7.0) years, CD4 T-lymphocyte count of 232 (137) cells/µl and log10 plasma HIV RNA of 4.8 (0.73). Median (interquartile range, IQR) HIV DNA copy number per 10 CD14 cells was 54 (102). Using our previously determined optimal cut-point of 45 copies/10 cells for this cohort, a threshold value above which CD14 HIV DNA identified HIV-associated neurocognitive disorders (HANDs), we found that CD14 HIV DNA  ≥ 45 copies/10 cells was associated with reduced volumes of the nucleus accumbens (P=0.021), brainstem (P=0.033) and total gray matter (P=0.045) independently of age, CD4 cell count and intracranial volume. CONCLUSION: HIV DNA burden in CD14 monocytes is directly linked to brain volumetric loss. Our findings implicate peripheral viral reservoirs in HIV-associated brain atrophy and support their involvement in the neuropathogenesis of HAND, underscoring the need for therapies that target these cells.