Activation In HIV Disease Research Articles

Viral Rebound Kinetics Correlate with Distinct HIV Antibody Features.

Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy (ART) is interrupted. The kinetics of viral rebound, specifically the time until plasma virus becomes detectable, differ quite substantially between individuals, and associations with virological and immunological factors have been suggested. Standard clinical measures, like CD4 T-cell counts and plasma HIV RNA levels, however, are poor predictive markers. Antibody features, including Fc functionality and Fc glycosylation have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we analyzed HIV-specific antibody quantities and qualitative differences like antibody-mediated functions, Fc gamma receptor (FcγR) binding, and IgG Fc glycosylation as well as cytokine profiles and cellular HIV DNA and RNA levels in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders (≤4 weeks versus >4 weeks) and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. Specifically, individuals with early viral rebound exhibited higher levels of total HIV-specific IgGs carrying inflammatory Fc glycans, while delayed rebounders showed an enrichment of highly functional antibodies. Overall, only four features, including enhanced antibody-mediated NK cell activation in delayed rebounders, were necessary to discriminate the groups. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future ATI studies.IMPORTANCE Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy is interrupted, and interindividual differences in the kinetics of viral rebound have been associated with virological and immunological factors. Antibody features, including Fc functionality and Fc glycosylation, have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we systematically analyzed HIV-specific antibody quantities and qualitative differences in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future HIV eradication studies.

A-104 Gender and Neurocognitive Impairment among HIV Infected Individuals in Nigeria

Background: Neurocognitive impairment (NCI) in HIV infection occurs as a frequent complication of HIV infection and, among HIV infected individuals in Nigeria, can be detected during the early stages of infection. The presence and severity of NCI can correlate with elevation of plasma levels of monocyte activation markers. In this study was examined the potential role of gender in the occurrence of NCI and associations between NCI and levels markers of HIV disease activity. Methods: One hundred thirty-three antiretroviral-naive seropositive (SP; 94 women and 59 men) and 56 seronegative (SN; 38 women and 18 men) participants received neuropsychological testing in 7 ability domains with calculation of demographically adjusted domain scores and a global deficit score (GDS). Also measured were plasma HIV RNA levels and plasma levels of the monocyte activation markers soluble CD163 and soluble CD14. Results: SP women in the study were younger than SP men, and SP women and men were less educated than their SN counterparts. CD4+ T cell counts, which were lower SP than for SN individuals, were higher for SN woman and SP women than for their male counterparts. Within the various ability domains, SP women scored worse than SN women with respect to verbal fluency and motor function and had higher overall mean GDS scores. In addition, SP women scored worse than SP men with respect to learning and memory. Mean log HIV viral load was higher and the frequency of non-detectable virus was lower for SP women than for SP men. Among SP women there was a borderline statistically significant correlation between sCD163 levels and GDS, and sCD14 levels were higher for impaired SP women than for non-impaired SP women. Viral load was higher for impaired SP men than non-impaired men and did not differ for impaired versus non-impaired SP women. Conclusions: Gender can have a significant impact on the occurrence of NCI among HIV infected individuals in Nigeria. This association appears to be linked to specific immune and viral factors, which require further study.

Ultrasonographic measures of cardiovascular disease risk in antiretroviral treatment-naive individuals with HIV infection

To evaluate associations between traditional cardiovascular disease (CVD) risk factors, inflammatory markers and markers of HIV disease activity with ultrasonographic measures of CVD risk in patients with HIV who are not receiving antiretroviral therapy (ART). Cross-sectional, baseline evaluation of ART-naive HIV-infected individuals without known CVD or diabetes mellitus enrolled in a randomized ART treatment trial. Prior to ART initiation, carotid artery intima-media thickness (CIMT) and brachial artery flow-mediated dilation (FMD) were measured. Additional parameters included CD4 cell count, HIV viral load, body composition, lipoproteins and inflammatory markers. Associations with common CIMT, bifurcation CIMT, presence of carotid artery lesions and brachial artery FMD were evaluated. The 331 enrolled individuals were a median (first-third quartile) of 36 (28-45) years old. Common and bifurcation CIMT values were higher and lesions more prevalent with older age (P < 0.001). FMD was lower with older age (P = 0.009). Those with a Framingham Risk Score of at least 6% per 10 years (N = 44) had higher common and bifurcation CIMT (P < 0.001), carotid lesion prevalence (P < 0.001) and lower FMD (P = 0.035). Independent associations with common CIMT were identified for increasing age, height, weight, small low-density lipoprotein (LDL) particles and black race; these were similar for bifurcation CIMT. Presence of carotid artery lesions was associated with increasing age, presence of metabolic syndrome, interleukin-6 and lower HIV-1 RNA. In a contemporary cohort of ART-naive HIV-infected individuals, ultrasonographic measures of CVD risk were more strongly associated with traditional risk factors than CD4 cell counts, HIV replication or inflammatory markers.

HIV Disease Activity as a Modulator of Lipoprotein(a) and Allele-Specific Apolipoprotein(a) Levels

Mechanisms underlying the cardiovascular risk of lipoprotein(a) are poorly understood. We investigated the relationship of apolipoprotein(a) (apo(a)) size, lipoprotein(a), and allele-specific apo(a) levels with HIV disease activity parameters in a biethnic population. Lipoprotein(a) and allele-specific apo(a) levels were determined in 139 white and 168 black HIV-positive patients. Plasma HIV RNA viral load and CD4+ T-cell count were used as surrogates for disease activity. Lipoprotein(a) and allele-specific apo(a) levels were higher in blacks than whites (for both P<0.001). Apo(a) allele size distribution was similar between the 2 ethnic groups, with a median apo(a) size of 28 kringle 4 repeats. Allele-specific apo(a) levels were positively associated with CD4+ T-cell count (P=0.027) and negatively with plasma HIV RNA viral load (P<0.001). Further, allele-specific apo(a) levels associated with smaller (<28 kringle 4) atherogenic apo(a) sizes were higher in subjects with CD4+ T-cell counts of ≥350 (P=0.002). Allele-specific apo(a) levels were higher in subjects with high CD4+ T-cell count or low plasma HIV RNA viral load. The findings suggest that HIV disease activity reduced allele-specific apo(a) levels. Higher allele-specific apo(a) levels associated with atherogenic small apo(a) sizes might contribute to increased cardiovascular risk in HIV-positive subjects with improved disease status.

HIV interferes with SOCS‐1 and ‐3 expression levels driving immune activation

HIV infection is characterized by sustained immune activation, which is reflected by activated T cells and, in particular, by increased levels of phosphorylated STAT proteins. Here, we hypothesized that T-cell activation in HIV infection is partially due to the inability of SOCS-1 and SOCS-3 to control the JAK/STAT pathway. We found higher levels of SOCS-1/3 mRNA levels in CD4(+) T cells of HIV-infected patients than in healthy controls. However, SOCS protein levels were lower, explaining the lack of attenuation of the JAK/STAT pathway. Infection of CD4(+) T cells alone did not activate STATs, while ex vivo infection of PBMC did, indicating that non-T cells critical for shaping the immune response, e.g. DC were responsible for the STAT-1 activation. Supernatants from ex vivo-infected PBMC transferred to CD4(+) T cells induced JAK/STAT activation, pointing to a central role of soluble factors. Notably, over-expression of SOCS-1/3 in CD4(+) T cells prevented JAK/STAT activation. Thus, HIV infection interferes with SOCS-1/3 expression driving immune activation. Sustained immune activation disrupts the lymphoid system and favors HIV replication since HIV preferentially infects activated cells. We speculate that regulating SOCS may be a potential way to counteract immune activation in HIV disease.

Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation

AbstractHIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV+ patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.

The influence of HIV infection on the correlation between plasma concentrations of monocyte chemoattractant protein-1 and carotid atherosclerosis

Background Monocyte chemoattractant protein-1 (MCP-1) plays a crucial role in atherosclerosis and it has been recently proposed as a surrogate biomarker of long-term clinical outcomes in patients with acute myocardial infarction. Little is known of the factors that may influence plasma MCP-1 concentrations. Methods We studied 384 healthy volunteers and 226 HIV-infected patients as a model of chronic inflammatory condition that predisposes to sub-clinical atherosclerosis. Results In healthy participants there were significant associations between plasma MCP-1 concentration and age, smoking status, and serum triglyceride concentrations that were not observed in the HIV-infected patients. The plasma concentration of MCP-1 was significantly associated with the polymorphism at position –2518 of the MCP-1 gene and, in patients, with the carotid artery intima–media thickness. There were also significant correlations indicating a close association between MCP-1 and HIV disease activity. However, in a multiple regression model, only age, the MCP-1 genotype and smoking status showed significant, and independent, associations with plasma MCP-1 concentrations. Conclusion Plasma MCP-1 concentration is genetically determined and associated with age and smoking habit and it also correlates with subclinical atherosclerosis in HIV-infected patients.

The effect of combination antiretroviral therapy on CD5 B‐ cells, B‐cell activation and hypergammaglobulinaemia in HIV‐1‐infected patients

This study assessed B-cell activation, CD5 B-cells and circulating immunoglobulin levels in HIV-infected patients treated with combination antiretroviral therapy (CART). Measurement of plasma immunoglobulin levels and electrophoresis of plasma proteins, and analyses of total numbers of B-cells and B-cells expressing CD 38 and CD5 in whole blood, were undertaken in 47 consecutive HIV-1-infected patients attending an out-patient clinic. All HIV-infected patients had similar percentages and numbers of B-cells. Proportions of CD5 B-cells in all HIV-infected patients were significantly lower than those in HIV-negative controls. Aviraemic HIV-infected patients on CART had lower percentages of CD5, CD 38 and CD5 CD 38 B-cell subsets and lower plasma levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) than viraemic HIV-infected patients (untreated or on CART). However, 33-37% of aviraemic HIV-infected patients had IgG and IgA levels above the 95th percentile of the normal range defined in HIV-seronegative donors. In aviraemic HIV-infected patients, plasma IgA levels correlated only with proportions of activated (CD 38) B-cells. IgG levels did not correlate with the proportions of B-cell subsets or any marker of HIV disease activity. Monoclonal immunoglobulins were not detected in any plasma sample. Aviraemic HIV-infected patients on CART have lower plasma levels of IgG and IgA than viraemic HIV-infected patients, but levels are often above the normal range. CD5 B-cell numbers are depressed, so these cells are unlikely to contribute to hypergammaglobulinaemia in HIV-infected patients.

N400 detects the impairment in semantic activation in HIV disease more sensitively than behavioral measures

N400 detects the impairment in semantic activation in HIV disease more sensitively than behavioral measures

Melanocytic activation in HIV disease: HMB-45 positivity in oral melanotic macules

Melanocytic activation in HIV disease: HMB-45 positivity in oral melanotic macules