HIV-seronegative Control Subjects Research Articles

Sonographic appearances of the kidneys and correlation with CD4 count and viral load in adult HIV/AIDS patients in a rural-based infectious disease hospital in sub-saharan Africa

Background: The management of HIV infection is often challenging as it can affect every organ in the body including the kidneys. Determination of the Resistivity Indices (RI) of the intra-renal arteries is an emerging non-invasive tool that could predict renal disease. Aims & objectives: To determine the renal volume, parenchymal pattern, as well as the RI of the intra-renal arteries by Doppler ultrasonography in adult HIV/AIDS patients and correlate findings with CD4 count, viral load and serum creatinine. Materials & methods: This is a comparative cross-sectional descriptive study that involved sonographic assessment of the renal dimensions, parenchymal echogenicity, and Doppler velocimetry of the segmental intra-renal arteries in 100 apparently healthy confirmed HIV-seronegative control subjects and an equal number of confirmed HIV-seropositive adult patients at Retroviral (RV) clinic of our hospital. A Doppler ultrasound machine with a 3.5MHz Curvilinear probe was used. Data analysis: Data obtained was analyzed and presented as means which were compared using Student’s t - test, and p values < 0.05 at 95% intervals were considered significant. Pearson’s correlation coefficient was used to assess correlation. Results: The renal volumes were larger in the HIV/AIDS subjects (right: 125.94 ± 34.02 cm3 and left: 138.99 ± 33.29cm3) than in controls (p = < 0.01) with the left also larger than the right in both HIV/AIDS and control subjects (p = < 0.01, < 0.01) respectively. There were significantly more individuals with abnormal renal echogenicity in the HIV/AIDS subjects than in the controls. The RI was significantly greater in the HIV/AIDS than in control subjects. Both renal volumes showed a weak negative correlation with CD4, viral load, and serum creatinine which was not statistically significant. There was a statistically significant weak negative correlation between renal echogenicity and CD4 but a positive correlation with viral load and serum creatinine. RI showed weak negative correlations with serum creatinine and weak positive correlations with CD4 count. Conclusion: There is a significant difference in renal volume, echogenicity, and RI in HIV/AIDS patients compared to the controls. Renal echogenicity is a better predictor of serum creatinine levels than renal volume and RI. Thus, renal volume and RI do not provide sufficient correlation to be used as a means of monitoring HIV/AIDS patients with renal impairment.

Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy.

Background: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). Methods: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. Results: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased β-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and β-oxidation of long-chain fatty acids remained abnormal. Conclusion: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.

Does plantar lipoatrophy affect dynamic balance in HIV infected persons?

BackgroundChronic inflammation in HIV infection and antiretroviral therapy have been shown to cause balance disorders due to neuromusculoskeletal damage, sensorimotor deficits, failure of foot mechanoreceptors and/or plantar lipoatrophy. However, despite evidence of plantar lipoatrophy in HIV patients, there is a dearth of information on how this relates to walking balance. This study sought to investigate how plantar fat thickness affects dynamic balance in HIV infected persons. Research QuestionCan plantar lipoatrophy significantly affect walking balance in HIV infected persons? MethodsThis is a cross sectional study of 367 persons (106 HIV seronegative control subjects, 211 HIV seropositive subjects on antiretroviral therapy (HIV_ART) and 50 HIV ART naïve subjects (HIV_NonART)). Plantar fat thickness (PFT) was measured using diagnostic ultrasound. Subjects were asked to walk at 5 self-selected speeds, from very slow to very fast on a level 15-meter walkway. Average number of steps and time taken to complete the study distance were obtained, used to calculate gait parameters and plot the velocity field diagram for gait analysis. ResultsFindings from this study showed significant reduction in plantar fat thickness, velocity of travel, stride frequency and a significant increase in stride and double support duration (p < 0.01) in HIV-seropositive individuals compared to healthy controls but none were observed between HIV_ART and NonART groups. ConclusionHIV infection significantly affects dynamic balance and increases the risk of falls, fracture and mobility impairment in this patient population. SignificanceThis study will help clinicians to recognize plantar lipoatrophy as a significant cause of gait pathology in HIV infected persons and thus, make targeted interventions to minimize deformity and impairment, promote functional independence and improve quality of life.

JC virus infection of meningeal and choroid plexus cells in patients with progressive multifocal leukoencephalopathy

JC virus (JCV) can cause a lytic infection of oligodendrocytes and astrocytes in the central nervous system (CNS) leading to progressive multifocal leukoencephalopathy (PML). JCV can also infect meningeal and choroid plexus cells causing JCV meningitis (JCVM). Whether JCV also infects meningeal and choroid plexus cells in PML patients and other immunosuppressed individuals with no overt symptoms of meningitis remains unknown. We therefore analyzed archival formalin-fixed, paraffin-embedded brain samples from PML patients, and HIV-seropositive and seronegative control subjects by immunohistochemistry for the presence of JCV early regulatory T Ag and JCV VP1 late capsid protein. In meninges, we detected JCV T Ag in 11/48 (22.9%) and JCV VP1 protein in 8/48 (16.7%) PML patients. In choroid plexi, we detected JCV T Ag in 1/7 (14.2%) and JCV VP1 protein in 1/8 (12.5%) PML patients. Neither JCV T Ag nor VP1 protein could be detected in meninges or choroid plexus of HIV-seropositive and HIV-seronegative control subjects without PML. In addition, examination of underlying cerebellar cortex of PML patients revealed JCV-infected cells in the molecular layer, including GAD 67+ interneurons, but not in HIV-seropositive and HIV-seronegative control subjects without PML. Our findings suggest that productive JCV infection of meningeal cells and choroid plexus cells also occurs in PML patients without signs or symptoms of meningitis. The phenotypic characterization of JCV-infected neurons in the molecular layer deserves further study. This data provides new insight into JCV pathogenesis in the CNS.

ASSESSMENT OF KIDNEY FUNCTION, ESTIMATED GLOMERULAR FILTRATION RATE AND BODY MASS INDEX IN HIV SEROPOSITIVE SUBJECTS ON ANTIRETROVIRAL THERAPY IN NNEWI

Objective: Antiretroviral therapy (ART) is anticipated to result in an increase in long-term survival in human immunodeficiency virus (HIV) infected individuals, but may present with the development of associated complications including kidney damage. The present study aimed at assessing the kidney function estimated glomerular filtration (eGFR) rate and body mass index (BMI) of HIV seropositive subjects with or without HAART at Nnewi, Nigeria.Methods: A total of 90 subjects were recruited comprising of 30 HIV-seropositive on highly antiretroviral therapy (HAART), 30 HIV-seropositive drug naive, and 30 HIV-seronegative (control subjects). Anthropometric parameters of the subjects were assessed using a well-structured questionnaire. Five millilitres of blood sample was collected from the patients and used for the estimation of urea, creatinine, uric acid, serum total protein and cluster of differentiation (CD4) T-cell counts using diacetyl monoxime method, Jaffe-slot method, Caraway phosphotungstic acid method, refractometry and flow cytometric method respectively.Results: The result shows significantly higher mean serum urea, creatinine and uric acid levels in HIV seropositive drug-naive subjects and HIV seropositive subjects on HAART when compared with control (p&lt;0.05). Similar observation were made with same parameters between HIV seropositive drug-naive subjects and HIV subjects on HAART (p&lt;0.05). However, total protein and CD4 T-cells counts were significantly lower in HIV seropositive drug-naive subjects compared with HIV subjects on HAART and controls (p&lt;0.05). Based on the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, 6 (20.0%) of HIV seropositive subjects on antiretroviral therapy had a mild renal impairment, while 2 (6.6%) had a moderate renal impairment. Based on the modification of diet in renal disease (MDRD) equation, 7 (23.3%) of HIV subjects on therapy had mild renal impairment while 2 (6.6%) had a moderate renal impairment. Among the HIV drug naïve subjects, 8(26.7%) had mild renal impairment based on both equations. However, there were no significant differences in BMI and eGFR between HIV seropositive subjects on therapy and HIV seropositive drug-naive subjects.Conclusion: The present study shows evidence of significant alterations in serum urea, creatinine, and uric acid levels with mild and moderate state of renal impairment in HIV infected subjects with or without therapy. The significantly lower CD4 count and serum total protein in HIV naive subjects compared with HIV on HAART and control indicates reduced cellular immunity. Routine kidney function test using longitudinal study and more sensitive predictors for renal damage are recommended to ascertain the clearer picture of renal disease burden among HIV subjects in this environment.

Cluster of differentiation and renal assessment of reactive HIV subjects in Akure Nigeria

Background: HIV/AIDS is a rapidly growing epidemic in sub-Saharan Africa, Nigeria in particular. The report of the 2012 National Reproductive Health Survey Plus indicated that the prevalence of HIV/AIDS in Nigeria, that is, Nigerians currently living with HIV/AIDS is about 3.4% while Ondo State has a prevalence of 4.3%. HIV is a retrovirus that primarily infects components of the human immune system such as CD4 T-cells, macrophages and dendritic cells. Objectives: To evaluate the CD4+ T cell count, sodium, potassium, urea and creatinine in adult HIV seropositive subjects on Highly Active Antiretroviral Therapy (HAART) and those yet to be started on HAART as well as HIV seronegative control subjects. Materials and Methods: Serum levels of CD4+ count of adult HIV seropositive subjects on HAART, yet to start HAART and seronegative controls were determined using flow cytometry while their serum sodium, potassium, urea and creatinine were determined using enzymatic spectrophotometric method. All data were expressed as Mean ± Standard Deviation (SD) and analysed with Analysis of Variance (ANOVA) while multiple comparisons were done using Post Hoc test. Results: The serum sodium is significantly lower in the subjects in HAART group as compared with that of the other two groups. No significant difference in urea & creatinine was found in the three groups. Conclusion: Despite the fact that it appears the drugs did not have adverse effect on the kidneys, there is need for close monitoring of patients on antiretroviral medications as various drugs over time have adverse effects on various organs.

In vivo effect of statins on the expression of the HIV co-receptors CCR5 and CXCR4

BackgroundDuring the HIV-1 replication cycle, several molecules including chemokine receptors and cholesterol are crucial, and are therefore potential targets for therapeutic intervention. Indeed statins, compounds that inhibit cellular synthesis of cholesterol and have anti-inflammatory and immunomodulatory properties were shown to inhibit HIV-1 infection by R5 tropic strains but not by X4 strains in vitro, mainly by altering the chemokine receptor/ligands axes. Therefore, the objective of this study was to characterize in vivo, the capacity of statins to modulate in HIV seronegative and chronically HIV-1-infected adults the expression of CCR5 and CXCR4, of their ligands and the tropism of circulating HIV-1 strains.MethodsSamples from asymptomatic HIV-1-infected adults enrolled in a clinical trial aimed at evaluating the antiretroviral activity of lovastatin were used to evaluate in vivo the modulation by lovastatin of CCR5, CXCR4, their ligands, and the shift in plasma viral tropism over one year of intervention. In addition, ten HIV negative adults received a daily oral dose of 40 mg of lovastatin or 20 mg of atorvastatin; seven other HIV negative individuals who received no treatment were followed as controls. The frequency and phenotype of immune cells were determined by flow-cytometry; mRNA levels of chemokine receptors and their ligands were determined by real-time PCR. Viral tropism was determined by PCR and sequencing, applying the clonal and clinical model of analyses.ResultsOur study shows that long-term administration of lovastatin in HIV-infected individuals does not induce a shift in viral tropism, or induce a significant modulation of CCR5 and CXCR4 on immune cells in HIV-infected patients. Similar results were found in HIV seronegative control subjects, treated with lovastatin or atorvastatin, but a significant increase in CCL3 and CCL4 transcription was observed in these individuals.ConclusionsThese findings suggest that long-term administration of statins at therapeutic doses, does not significantly affect the expression of HIV-1 co-receptors or of their ligands. In addition it is important to point out that based on the results obtained, therapeutic administration of statins in HIV-infected patients with lipid disorders is safe in terms of selecting X4 strains.

Increased Frequency of Regulatory T Cells Accompanies Increased Immune Activation in Rectal Mucosae of HIV-Positive Noncontrollers

Gut-associated lymphoid tissue (GALT) is a major site of HIV replication and CD4(+) T cell depletion. Furthermore, microbial translocation facilitated by mucosal damage likely contributes to the generalized immune activation observed in HIV infection. Regulatory T cells (Treg) help maintain homeostasis and suppress harmful immune activation during infection; however, in the case of persistent viral infections such as HIV, their role is less clear. Although a number of studies have examined Treg in blood during chronic infection, few have explored Treg in the gastrointestinal mucosa. For this study, paired blood and rectal biopsy samples were obtained from 12 HIV noncontrollers (viral load of >10,000 copies/ml plasma), 10 HIV controllers (viral load of <500 copies/ml plasma for more than 5 years), and 12 HIV seronegative control subjects. Noncontrollers had significantly higher percentages of Treg in rectal mononuclear cells (RMNC), but not in blood, compared to seronegative subjects (P = 0.001) or HIV controllers (P = 0.002). Mucosal Treg positively correlated with viral load (P = 0.01) and expression of immune activation markers by CD4(+) (P = 0.01) and CD8(+) (P = 0.07) T cells. Suppression assays indicated that mucosal and peripheral Treg of noncontrollers and controllers maintained their capacity to suppress non-Treg proliferation to a similar extent as Treg from seronegative subjects. Together, these findings reveal that rather than experiencing depletion, mucosal Treg frequency is enhanced during chronic HIV infection and is positively correlated with viral load and immune activation. Moreover, mucosal Treg maintain their suppressive ability during chronic HIV infection, potentially contributing to diminished HIV-specific T cell responses and viral persistence.

Packed cell volume and serum iron in subjects with HIV-malaria co-infection in Nnewi, South-Eastern Nigeria

The present study was designed to assess the PCV and serum iron in HIV-malaria co-infected subjects in Nnewi, South Eastern Nigeria. 207 participants aged between 16-72 (44 ± 28) years were recruited andclassified as follows based on standard screening and WHO criteria: (i) Asymptomatic HIV stage I subjects with or without malaria. (ii) Symptomatic HIV stage II subjects with or without malaria and not on (ART). (iii) HIV/AIDS subjects with or without malaria and on ART. (vi) HIV seronegative control subjects with or without malaria. Blood sample from these participants were analyzed for HIV seroreactivity, Plasmodium falciparum antigen, parasite density, serum iron concentrations and PCV using Standard Laboratory methods. The result showed that serum iron and PCV were significantly reduced amongst all the groups studied when compared with the control (p

Obesity and Dyslipidemia in Behaviorally HIV‐Infected Young Women: Adolescent Trials Network Study 021

The goal of this study was to determine the nature and prevalence of abnormalities in lipids, glucose metabolism, and body composition in behaviorally human immunodeficiency virus (HIV)-infected young women and the relationship of these abnormalities to different classes of antiretroviral therapy regimens. We conducted a cross-sectional, multicenter study involving 173 behaviorally HIV-infected women aged 14-24 years and 61 HIV-seronegative control subjects. HIV-infected women were categorized as follows: antiretroviral therapy naive (n=85), receiving a regimen containing a nonnucleoside reverse-transcriptase inhibitor (NNRTI; n=33), receiving a regimen containing a protease inhibitor (PI; n=36), or receiving a regimen not containing an NNRTI or a PI (n=19). Measurements included fasting lipid levels, glucose and insulin levels before and 2 hours after an oral glucose challenge, high-sensitivity C-reactive protein (hsCRP) levels, anthropometry, fat distribution (measured by dual energy X-ray absorptiometry), and antiretroviral therapy and medical histories. Race-adjusted results were compared across groups and within HIV-infected groups. The median age of participants was 20 years. Of HIV-infected subjects, 77% were African American, 35% smoked cigarettes, and 32% reported exercising regularly. More than 40% had a body mass index > or =25. Triglycerides; total, high-density lipoprotein (HDL), and non-HDL cholesterol; and hsCRP levels differed significantly among groups, with higher levels being most common among those receiving antiretroviral therapy. Indices of glucose metabolism did not differ among groups. In general, cholesterol levels, hsCRP levels, and indices of glucose metabolism worsened as body mass index increased. Obesity, dyslipidemia, and inflammation were prominent among HIV-infected adolescent women and, coupled with other risk factors, may accelerate the lifetime risk of cardiovascular disease and other adverse events. These results underscore the need for a multifaceted approach to addressing risk reduction in this population.

Neutrophil Ingestion Rate Of Nitroblue Tetrazolium In Subjects With Malaria-Hiv Co-Morbidity

Objectives: This study was designed to assess the WBC count, absolute neutrophil count, CD4 +T cell count and neutrophil ingestion rate of nitroblue tetrazolium in subjects with Malaria and HIV Co-morbidity. Method and materials: 134 participants were recruited and group as follow: Symptomatic HIV infected participants (n=63), 32 of these participants had malaria co-infection; Asymptomatic HIV infected participants (n=42), 17 of these participants had malaria co-infection; and HIV seronegative Control subjects (n=27), 15 of these subjects had malaria parasitaemia. Blood samples collected from the participants were used to determine the WBC count, absolute neutrophil count, CD4 + T cell count and the rate of reduction of NBT to formazan by the neutrophils in vitro. Result: The result showed that the rate of reduction of NBT to formazan (fmol/phagocyte) was significantly reduced in both Symptomatic and asymptomatic HIV participants with or without malaria parasitaemia compared with the corresponding values in the HIV seronegative control participants with or without malaria respectively. There was no significant difference in WBC and absolute neutrophil counts. This was also true for the CD4 = T cell count amongst participants with malaria but not with those without malaria. Conclusion: This study suggests that inhibition of phagocytic function may be an early sign in HIV infection. This has grave consequences in malaria endemic area where phagocytosis is important in the clearance of malaria parasites. Keywords: HIV, Malaria, NBT, phagocytes and participants.Tropical Journal of Medical Research Vol. 12 (1) 2008: pp. 1-5

Urinary ascorbic acid and serum concentrations of circulating immune complexes and albumin in HIV infected subjects.

The aim of the present study was to determine the presence or absence of ascorbic acid in urine and serum levels of circulating immune complexes (CIC) and albumin in HIV infected subjects. A total of 90 participants (30 Symptomatic HIV infected subjects on antiretroviral therapy (ART), 30 Symptomatic HIV infected subjects not yet on ART and 30 HIV seronegative control subjects) were recruited for the study. Urine samples from participants were used to assess for ascorbic acid while blood samples were used to determine the serum CIC and albumin levels. The result showed that the mean serum concentration of CIC (mg/dl) of Symptomatic HIV subjects on ART was 693±606, for the symptomatic HIV subjects was 535±305 and 84±28 for control subjects (f=19.492; p Keywords : HIV; ART; ascorbic acid; albumin and CIC. Journal of Biomedical Investigation Vol. 4 (2) 2006 pp.54-59

Serum Levels of anti-BCG, Albumin and Packed Cell Volume and White Blood Cell Count in Subjects with HIV and Malaria Co-morbidity

The present study was designed to determine anti-BCG titres, serum albumin, packed cell volume, white blood cell count and malaria parasite density in HIV infected subjects in a malaria endemic area with stable transmission. For this study 75 participants aged between 17 and 70 years (females=45; males=30) were enlisted and grouped into: (I) HIV⁄AIDS subjects (n=21) on anti-retroviral therapy (ART), 12 of these subjects had malaria co-infection; (ii) HIV seropositive subjects (n=29) not on ART, 13 of whom had malaria co-infection, and (iii) HIV seronegative control subjects (n=25), 15 of whom had malaria parasiteamia. Serum albumin, anti-BCG and PCV, WBC and malaria parasite density were determined in all participants. The results showed that all participants had detectable anti-BCG, but the titre was lowest in HIV⁄AIDS on ART followed by HIV seropositives and control subjects (f=16.878; pI0.001). The results also showed that serum albumin (g⁄l) was significantly different among the HIV seropositives, HIV⁄AIDS and control subjects (f=8.043; pI0.001). This pattern was also true for the PCV (f=17.505; pI0.001). When the above parameters were considered for subjects with malaria co-infection, a similar pattern of results was observed. There was no within-group difference in those with or without malaria for the respective groups except for WBC count, which was significantly reduced in HIV⁄AIDS subjects with malaria, compared with those without malaria. The positive association between WBC count and malaria parasite density was consistent in all groups. The present study thus indicates that, although there is evidence of prior exposure to bacterial infection, serum anti-BCG, serum albumin and PCV are mostly impaired by HIV infection even in cases of malaria co-morbidity in endemic areas.

Prevalence and Impact of Diarrhea on Health-related Quality of Life in HIV-infected Patients in the Era of Highly Active Antiretroviral Therapy

Before the introduction of highly active antiretroviral therapy (HAART), the majority of HIV-infected patients experienced diarrhea. The aims of this study were to compare the prevalence of diarrhea among HIV-infected and uninfected patients in the HAART era, and to evaluate the impact of diarrhea on health-related quality of life (HRQOL). Diarrheal symptoms experienced by 163 consecutive HIV-infected patients and 253 HIV-seronegative control subjects were ascertained using a validated questionnaire. The HRQOL of these patients was assessed using the Medical Outcomes Study (MOS) SF-36 and MOS-HIV Health surveys. Among the 163 HIV-infected patients, the median CD4 cell count was 370 cells/mm and 150 individuals were taking HAART. Significantly, more HIV-infected subjects reported having 3 or more bowel movements daily within the past 7 days than did HIV-seronegative subjects (28.2% vs. 7.1%, P<0.001), even after adjusting for potential confounding variables (odds ratios=6.65; 95% confidence intervals, 3.36-13.17). In addition, diarrhea was significantly more common in HIV-infected patients than in control subjects when assessed by several other criteria. HIV-infected patients reported significantly worse HRQOL across all domains of the MOS SF-36 as compared with control subjects. Among HIV-infected patients, individuals with diarrhea had significantly worse HRQOL in nearly all domains of the MOS-HIV as compared with those without diarrhea. Diarrhea remains an important clinical problem in HIV-infected patients and is associated with significant impairments in HRQOL. It is important that healthcare providers specifically evaluate their HIV-infected patients for diarrhea so that these symptoms may be optimally managed.

Experimental Infection withHaemophilus ducreyiin Persons Who Are Infected with HIV Does Not Cause Local or Augment Systemic Viral Replication

We infected 11 HIV-seropositive volunteers whose CD4(+) cell counts were >350 cells/ microL (7 of whom were receiving antiretrovirals) with Haemophilus ducreyi. The papule and pustule formation rates were similar to those observed in HIV-seronegative historical control subjects. No subject experienced a sustained change in CD4(+) cell count or HIV RNA level. The cellular infiltrate in biopsy samples obtained from the HIV-seropositive and HIV-seronegative subjects did not differ with respect to the percentage of leukocytes, neutrophils, macrophages, or T cells. The CD4(+):CD8(+) cell ratio in biopsy samples from the HIV-seropositive subjects was 1:3, the inverse of the ratio seen in the HIV-seronegative subjects (P<.0001). Although CD4(+) cells proliferated in lesions, in situ hybridization and reverse-transcription polymerase chain reaction for HIV RNA was negative. We conclude that experimental infection in HIV-seropositive persons is clinically similar to infection in HIV-seronegative persons and does not cause local or augment systemic viral replication. Thus, prompt treatment of chancroid may abrogate increases in viral replication associated with natural disease.

The Impact of Cirrhosis on CD4+ T Cell Counts in HIV-Seronegative Patients

Studies of the progression liver fibrosis in human immunodeficiency virus (HIV) and hepatitis C virus-coinfected patients suggest that cirrhosis is associated with immunosuppression, as measured by low absolute CD4(+) T cell counts. However, we hypothesized that, in patients with advanced liver disease, low CD4(+) T cell counts may occur secondary to portal hypertension and splenic sequestration, regardless of the presence or absence of HIV infection. Sixty HIV-seronegative outpatients with cirrhosis were enrolled during the period 2001-2003 in a prospective, cross-sectional study of the association between liver disease and CD4(+) T cell counts and percentages. Demographic characteristics, liver disease-related characteristics, and laboratory results--including CD4(+) T cell parameters--were collected. A total of 39 patients (65%) had a low CD4(+) T cell count; 26 patients (43%) and 4 patients (7%) had CD4(+) T cell counts <350 and <200 cells/mm(3), respectively. Abnormal CD4(+) T cell counts were associated with splenomegaly (P=.03), thrombocytopenia (P=.002), and leukopenia (P<.001). The percentage of CD4(+) T cells was normal in 95% of patients who had a low absolute CD4(+) T cell count. CD4(+) T cell counts were significantly lower among cirrhotic patients than among 7638 HIV-seronegative historic control subjects without liver disease. Cirrhosis is associated with low CD4(+) T cell counts in the absence of HIV infection. Discordance between low absolute CD4(+) T cell counts and normal CD4(+) T cell percentages may be attributable to portal hypertension and splenic sequestration. Our findings have significant implications for the use and interpretation of absolute CD4(+) T cell counts in HIV-infected patients with advanced liver disease.

Whole-Body Proteolysis Rate Is Elevated in HIV-Associated Insulin Resistance

Type 2 diabetes is characterized by impaired glucose tolerance (IGT) and insulin resistance with respect to glucose metabolism but not amino acid metabolism. We examined whether whole-body leucine and protein metabolism are dysregulated in HIV-infected individuals with IGT. Glucose and leucine kinetics were measured under fasting insulin conditions and during euglycemic hyperinsulinemia using primed-constant infusions of 2H2-glucose and 13C-leucine in 10 HIV-seronegative control subjects, 16 HIV+ subjects with normal glucose tolerance, and 21 HIV+IGT subjects. Glucose disposal rate during hyperinsulinemia was lower in HIV+IGT than the other two groups. Absolute plasma leucine levels and rate of appearance (whole-body proteolysis) were higher in HIV+IGT at all insulin levels but declined in response to hyperinsulinemia in parallel to those in the other two groups. HIV+IGT had greater visceral adiposity, fasting serum interleukin (IL)-8 and free fatty acid levels, and higher lipid oxidation rates during the clamp than the other two groups. These findings implicate several factors in the insulin signaling pathway, which may be further dysregulated in HIV+IGT, and support the notion that insulin signaling pathways for glucose and leucine metabolism may be disrupted by increased proinflammatory adipocytokines (IL-8) and increased lipid oxidation. Increased proteolysis may provide amino acids for gluconeogenesis, exacerbating hyperglycemia in HIV.

Cerebrospinal fluid interferon-γ-inducible protein 10 (IP-10, CXCL10) in HIV-1 infection

Interferon-γ-inducible protein (IP-10 or CXCL10) is a potent chemoattractant and has been suggested to enhance retrovirus infection and mediate neuronal injury. In order to assess this chemokine in central nervous system (CNS) HIV infection, we measured the cerebrospinal fluid (CSF) and plasma concentrations of CXCL10 by immunoassay in samples derived from 97 HIV-infected subjects across a spectrum of immunological progression and CNS complications and from 16 HIV seronegative control subjects studied at three clinical centers between 1994 and 2001. We also examined changes in the CSF and plasma CXCL10 concentrations in 30 subjects starting and three stopping antiretroviral therapy. CSF CXCL10 concentrations: (1) correlated with CSF HIV RNA and white blood cell (WBC) counts, but not with blood CXCL10, HIV RNA, or CD4 counts; (2) were increased in subjects with primary and asymptomatic HIV infections and AIDS dementia complex, but less frequently in those with more advanced infection, with or without CNS opportunistic diseases except cytomegalovirus encephalitis; (3) decreased in subjects starting antiretroviral in association with decreases in CSF and plasma HIV RNA and CSF WBCs; and (4) conversely, increased in subjects stopping treatment in parallel with CSF HIV RNA and WBCs. These results confirm that CSF CXCL10 associates closely with both CSF HIV and WBCs and suggest that this chemokine may be both a response to and contributing determinant of local infection. High CSF levels may be useful in the diagnosis of ADC in subjects with advanced immunosuppression in whom CMV encephalitis has been ruled out, though this issue requires further study.

Characteristics of hepatitis C virus infection in HIV-infected people.

Knowledge pertaining to hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection is currently incomplete or conflicting. Several points are well studied, however. Plasma HCV RNA levels are higher in matched HIV-infected people than in HIV-seronegative control subjects and are inversely correlated with CD4(+) T lymphocyte counts. HCV genotype does not appear to influence this value. Co-infected individuals develop histological and clinical features of HCV liver disease more rapidly than HIV-seronegative patients. Co-infected individuals appear to respond to interferon-alpha therapy equally as well as HIV-seronegative HCV-infected adults, but minimal information exists regarding the efficacy and toxicity of combination HCV therapy (interferon-alpha plus ribavirin) in this population. Adverse consequences of highly active antiretroviral therapy in co-infected patients include hepatic toxicity and, in a minority of patients, an 'immune restoration syndrome'. It is unclear whether long term, highly active antiretroviral therapy positively or negatively influences the natural history of HCV infection.

Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia.

The pathogenesis of HIV-associated dementia (HIVD) has been postulated to be due to the indirect effects of HIV infection, including the aberrant central nervous system production of cytokines and other neurotoxins. A correlation between the severity of dementia and production of neurotoxins in HIVD has been demonstrated. We have previously identified nonproductive HIV infection of astrocytes. Because astrocytes participate in the inactivation of neurotoxins, we hypothesize that HIV nonproductive infection of astrocytes may lead to an environment in which there is a significant level of astrocyte apoptosis and a consequent increase in the levels of neurotoxins and that this results in more rapidly progressing dementia. Postmortem brain tissue was examined from clinically well-characterized HIV-positive demented patients, HIV-positive nondemented patients, and HIV-seronegative nondemented control subjects. The HIVD group was further categorized into subjects with rapid and those with slow progression of dementia. Tissue was paraformaldehyde fixed and paraffin embedded, and 6-microm sections from the basal ganglia and mid-frontal gyrus were processed to detect apoptosis by in situ transferase dUTP nick end labeling. Astrocytes were co-localized using immunohistochemical techniques. In situ polymerase chain reaction (PCR) techniques were utilized to detect HIV DNA in astrocytes. The density of apoptotic astrocytes was significantly greater in the HIV-positive groups than in the HIV-negative group (p < 0.01). The HIVD rapid progressors had a significantly greater number of apoptotic astrocytes in the basal ganglia than did the HIVD slow progressors (p < 0.05). In addition, there were a greater number of HIV DNA-positive astrocytes, as demonstrated by in situ PCR, in the HIVD rapid progressors than in the slow progressor and HIV-nondemented groups. These data suggest that there is an increased rate of astrocyte loss in the subjects with rapidly progressive dementia, in association with an increased number of HIV DNA-positive astrocytes. The results emphasize the importance of understanding more completely the role of HIV infection of astrocytes in the neuropathogenesis of HIVD.