Increased Prevalence of Neurocognitive Impairment in Aging People Living With Human Immunodeficiency Virus: The ANRS EP58 HAND 55-70 Study.

BACKGROUND: There are limited data on the comparative prevalence of neurocognitive impairment (NCI) in aging people living with human immunodeficiency virus (PLHIV) and people not living with HIV. METHODS: This was a cross-sectional study of PLHIV randomly matched by age (±4 years), gender, and education with 5 HIV-uninfected individuals from the CONSTANCES cohort. PLHIV were fluent in French and sequentially included during routine outpatient visits if aged 55-70 years, with HIV viral load <50 copies/mL, and lymphocyte T-CD4 level ≥200 cells/µL in the past 24 and 12 months, respectively. The primary outcome was NCI as defined by the Frascati criteria. Multivariate normative comparison (MNC) and -1.5 standard deviations in ≥2 neurocognitive domains were secondary outcomes of NCI. RESULTS: Two hundred PLHIV were matched with 1000 controls. Median age was 62 years, and 85% were men. In PLHIV, the median T-CD4 lymphocyte level was 650 cells/µL, and median nadir T-CD4 lymphocyte level was 176 cells/µL. NCI was found in 71 (35.5%) PLHIV and in 242 (24.2%) controls (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.25, 2.41). After adjusting for confounders, HIV remained significantly associated with NCI (OR, 1.50; 95% CI, 1.04, 2.16). Adjusted results were similar with NCI defined by MNC (ORMNC, 2.95; 95% CI, 1.13, 3.50) or -1.5 SD (OR-1.5, 2.24; 95% CI, 1.39, 3.62). CONCLUSIONS: In this matched study of aging individuals, HIV was significantly associated with an increased risk of NCI after adjusting for major confounders. Results were confirmed with more stringent NCI classifications. CLINICAL TRIALS REGISTRATION: NCT02592174.

The two human CXCR4 isoforms display different HIV receptor activities: consequences for the emergence of X4 strains.

CXCR4 is a chemokine receptor that plays key roles with its specific ligand, CXCL12, in stem cell homing and immune trafficking. It is also used as a coreceptor by some HIV-1 strains (X4 strains), whereas other strains (R5 strains) use an alternative coreceptor, CCR5. X4 strains mainly emerge at late stages of the infection and are linked to disease progression. Two isoforms of this coreceptor have been described in humans: CXCR4-A and CXCR4-B, corresponding to an unspliced and a spliced mRNA, respectively. In this study, we show that CXCR4-B, but not CXCR4-A, mediates an efficient HIV-1 X4 entry and productive infection. Yet, the chemotactic activity of CXCL12 on both isoforms was similar. Furthermore, HIV-R5 infection favored CXCR4-B expression over that of CXCR4-A. In vitro infection with an R5 strain increased CXCR4-B/CXCR4-A mRNA ratio in PBMCs, and this ratio correlated with HIV RNA plasma level in R5-infected individuals. In addition, the presence of the CXCR4-B isoform favored R5 to X4 switch more efficiently than did CXCR4-A in vitro. Hence, the predominance of CXCR4-B over CXCR4-A expression in PBMCs was linked to the ability of circulating HIV-1 strains to use CXCR4, as determined by genotyping. These data suggest that R5 to X4 switch could be favored by R5 infection-induced overexpression of CXCR4-B. Finally, we achieved a specific small interfering RNA-mediated knockdown of CXCR4-B. This represents a proof of concept for a possible gene-therapeutic approach aimed at blocking the HIV coreceptor activity of CXCR4 without knocking down its chemotactic activity.

Brief Report: Frailty in Aging People Living With HIV: A Matched Controlled Study.

BACKGROUND: We compared the prevalence of frailty among aging people living with HIV (PLHIV) with people without HIV from the ANS EP58 HAND 55-70 Study. METHODS: Cross-sectional multicentric study which consecutively included 200 PLHIV and 1000 people without HIV from the French national CONSTANCES cohort, matched on age, sex, and education level. PLHIV were aged 55-70 years, with a HIV viral load < 50 copies/mL and a lymphocyte T-CD4 level > 200 cells/µL for the last 24 and 12 months, respectively. We measured frailty (>2 items) and prefrailty (one or 2 items) using a proxy of the 5-item Fried score. Multivariate logistic regression was performed to assess the association between HIV and frailty/prefrailty, adjusting for demographic, social, behavioral, and comorbidity confounders. RESULTS: Outcome measures were available for 192 PLHIV and 822 people without HIV. The median age was 62 years, and 84.9% were men. Among PLHIV, the median CD4 cell count was 645.5 cells/µL. Prevalence of frailty/prefrailty was 5.73%/57.3% in PLHIV vs. 1.73%/52.2% in people without HIV, respectively. HIV was associated with prefrailty/frailty [odds ratio = 1.89; 95% confidence interval = 1.37 to 2.61), but after adjusting for social and behavioral factors and comorbidities, HIV was not significantly associated with prefrailty/frailty (odds ratio = 1.24; 95% confidence interval: = 0.84 to 1.81). In PLHIV only, frailty/prefrailty was associated with depressive symptomatology, kidney disease, and time since HIV infection. CONCLUSIONS: Prevalence of frailty is increased in aging PLHIV with well-controlled HIV disease, but other factors than HIV are predominant, particularly depression and comorbidities.

Residual Viremia Is Linked to a Specific Immune Activation Profile in HIV-1-Infected Adults Under Efficient Antiretroviral Therapy.

Chronic immune activation persists in persons living with HIV-1 even though they are aviremic under antiretroviral therapy, and fuels comorbidities. In previous studies, we have revealed that virologic responders present distinct profiles of immune activation, and that one of these profiles is related to microbial translocation. In the present work, we tested in 140 HIV-1-infected adults under efficient treatment for a mean duration of eight years whether low-level viremia might be another cause of immune activation. We observed that the frequency of viremia between 1 and 20 HIV-1 RNA copies/mL (39.5 ± 24.7% versus 21.1 ± 22.5%, p = 0.033) and transient viremia above 20 HIV-1 RNA copies/mL (15.1 ± 16.9% versus 3.3 ± 7.2%, p = 0.005) over the 2 last years was higher in patients with one profile of immune activation, Profile E, than in the other patients. Profile E, which is different from the profile related to microbial translocation with frequent CD38+ CD8+ T cells, is characterized by a high level of CD4+ T cell (cell surface expression of CD38), monocyte (plasma concentration of soluble CD14), and endothelium (plasma concentration of soluble Endothelial Protein C Receptor) activation, whereas the other profiles presented low CD4:CD8 ratio, elevated proportions of central memory CD8+ T cells or HLA-DR+ CD4+ T cells, respectively. Our data reinforce the hypothesis that various etiological factors shape the form of the immune activation in virologic responders, resulting in specific profiles. Given the type of immune activation of Profile E, a potential causal link between low-level viremia and atherosclerosis should be investigated.

Microbial Translocation Is Linked to a Specific Immune Activation Profile in HIV-1-Infected Adults With Suppressed Viremia.

Persistent immune activation in virologically suppressed HIV-1 patients, which may be the consequence of various factors including microbial translocation, is a major cause of comorbidities. We have previously shown that different profiles of immune activation may be distinguished in virological responders. Here, we tested the hypothesis that a particular profile might be the consequence of microbial translocation. To this aim, we measured 64 soluble and cell surface markers of inflammation and CD4+ and CD8+ T-cell, B cell, monocyte, NK cell, and endothelial activation in 140 adults under efficient antiretroviral therapy, and classified patients and markers using a double hierarchical clustering analysis. We also measured the plasma levels of the microbial translocation markers bacterial DNA, lipopolysaccharide binding protein (LBP), intestinal-fatty acid binding protein, and soluble CD14. We identified five different immune activation profiles. Patients with an immune activation profile characterized by a high percentage of CD38+CD8+ T-cells and a high level of the endothelial activation marker soluble Thrombomodulin, presented with higher LBP mean (± SEM) concentrations (33.3 ± 1.7 vs. 28.7 ± 0.9 µg/mL, p = 0.025) than patients with other profiles. Our data are consistent with the hypothesis that the immune activation profiles we described are the result of different etiological factors. We propose a model, where particular causes of immune activation, as microbial translocation, drive particular immune activation profiles responsible for particular comorbidities.

One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study.

Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, using a panel of 68 soluble and cell surface markers, we measured the level of activation in circulating CD4+ and CD8+ T cells, B cells, monocytes, NK cells, polynuclear and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45years of age. As compared with age- and sex-matched uninfected individuals, we observed a persistence of activation in all the cell subpopulations analyzed, together with marks of inflammation and fibrinolysis. Two independent hierarchical clustering analyses allowed us to identify five clusters of markers that varied concurrently, and five patient groups, each with the same activation profile. The five groups of patients could be characterized by a marker of CD4+ T cell, CD8+ T cell, NK cell, monocyte activation or of inflammation, respectively. One of these profiles was strongly associated with marks of metabolic syndrome, particularly with hyperinsulinemia (OR 12.17 [95% CI 1.79-82.86], p=0.011). In conclusion, our study unveils biomarkers linked to metabolic syndrome that could be tested as predictive markers, and opens the way to new therapeutic approaches tailored to each patient group.

Maraviroc intensification of stable antiviral therapy in HIV-1-infected patients with poor immune restoration: MARIMUNO-ANRS 145 study.

OBJECTIVE: To address the ability of a 24-week Maraviroc (MVC) intensification of a stable antiretroviral therapy (cART) to significantly increase the CD4 cell count slope. METHODS: Patients were eligible if they had CD4 <350 cells/mm, a CD4 slope <50 cells/mm per year, and sustained plasma HIV-RNA <50 copies/mL over the last 2 years, while receiving a stable cART. Patients harboring pure X4-using viruses by a phenotypic tropism assay were excluded. MVC was added to cART for 24 weeks, at the recommended dosage per drug-drug interactions. The primary endpoint was a significant positive difference in CD4 slopes (with MVC- pre-MVC, paired t test). RESULTS: Sixty patients (55 men), with median age 51 years, baseline CD4 238 cells/mm, and slope before intensification +14.1 cells/mm per year were included. CD4 nadir was <50/mm in 47% of the population. The full set of patients (N = 57) completed week 24, and the on-treatment patients (N = 48) did not discontinue MVC. The median CD4 slope difference from baseline was +22.6 cells/mm per year (P = 0.08) in full set and +22.6 cells/mm per year (P = 0.04) in on-treatment. Slope evolution was not different according to baseline tropism, CD4 nadir, or ongoing cART regimen. No drug-related severe adverse events were recorded during intensification. MVC plasma concentrations were significantly different depending on drug-drug interaction with ongoing cART regimen and tended to be correlated with CD4 cells increase. CONCLUSION: In this study, MVC intensification of stable cART over 24 weeks was able to enhance CD4 cell slopes in patients with prior insufficient immune restoration despite long-term virological control.