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Objectives: Chemokine receptor CCR5 is the principal co-receptor for entry of M-tropic HIV virus into immune cells. It is expressed in the central nervous system and may contribute to neuro-inflammation. The CCR5 antagonist maraviroc (MVC) has been suggested to improve HIV-associated neurocognitive impairment (NCI)., Design: A double-blind, placebo-controlled, 48-week, randomized study of MVC vs. placebo in people with HIV (PWH) on stable antiretroviral therapy (ART) for more than one year in Hawaii and Puerto Rico with plasma HIV RNA less than 50 copies/ml and at least mild NCI defined as an overall or domain-specific neuropsychological z (NPZ) score less than -0.5., Methods: Study participants were randomized 2 : 1 to intensification of ART with MVC vs. placebo. The primary endpoint was change in global and domain-specific NPZ modeled from study entry to week 48. Covariate adjusted treatment comparisons of average changes in cognitive outcome were performed using winsorized NPZ data. Monocyte subset frequencies and chemokine expression as well as plasma biomarker levels were assessed., Results: Forty-nine participants were enrolled with 32 individuals randomized to MVC intensification and 17 to placebo. At baseline, worse NPZ scores were seen in the MVC arm. Comparison of 48-week NPZ change by arm revealed no differences except for a modest improvement in the Learning and Memory domain in the MVC arm, which did not survive multiplicity correction. No significant changes between arms were seen in immunologic parameters., Conclusion: This randomized controlled study found no definitive evidence in favor of MVC intensification among PWH with mild cognitive difficulties., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

While the protective role of neutrophil extracellular traps (NETs) in limiting human immunodeficiency virus (HIV) spread to susceptible cells has been documented, there is comparatively little insight into whether NET formation is harmful in people living with HIV (PLWH). To gain insight into neutrophil dysregulation and the pathological role of NETs in HIV, we examined expressions of NET-associated markers [cell-free DNA (cfDNA) and citrullinated histone H3 (CitH3)] in the plasmas from a cohort of the Hawaii Aging with HIV-cardiovascular and HIV-seronegative (HIV-) individuals. In a subset of participants, circulating low-density granulocyte (LDG) levels and their maturation and activation status were analyzed via flow cytometry. We demonstrated higher plasma levels of CitH3 in PLWH compared to HIV- individuals. LDGs from PLWH had heightened CD66b, but reduced CD16 expression. The percentages and counts of CD10 + LDGs were significantly decreased in PLWH. In addition, the CD16 Lo LDG subsets were enriched in PLWH, compared to HIV- group, indicating that immature LDGs are increased in PLWH. Moreover, LDGs from PLWH exhibited significantly higher NET forming capacity. In summary, our study presents evidence that LDGs from PLWH on ART display an immature and altered phenotype with increased NET formation. Among PLWH, plasma NET levels as well as LDG parameters correlated with blood markers for inflammation and coagulation, suggesting that neutrophil activation and NETs may exert proinflammatory and coagulation effects. Our data provide insights into the pathologic role of LDGs at least in part mediated through NET formation in PLWH., (© 2023. Springer Nature Limited.)

We previously reported that galectin-9 (Gal-9), a soluble lectin with immunomodulatory properties, is elevated in plasma during HIV infection and induces HIV transcription. The link between Gal-9 and compromised neuronal function is becoming increasingly evident; however, the association with neuroHIV remains unknown. We measured Gal-9 levels by ELISA in cerebrospinal fluid (CSF) and plasma of 70 HIV-infected (HIV+) adults stratified by age (older > 40 years and younger < 40 years) either ART suppressed or with detectable CSF HIV RNA, including a subgroup with cognitive assessments, and 18 HIV uninfected (HIV-) controls. Gal-9 tissue expression was compared in necropsy brain specimens from HIV- and HIV+ donors using gene datasets and immunohistochemistry. Among older HIV+ adults, CSF Gal-9 was elevated in the ART suppressed and CSF viremic groups compared to controls, whereas in the younger group, Gal-9 levels were elevated only in the CSF viremic group (p < 0.05). CSF Gal-9 positively correlated with age in all groups (p < 0.05). CSF Gal-9 tracked with CSF HIV RNA irrespective of age (β = 0.33; p < 0.05). Higher CSF Gal-9 in the older viremic HIV+ group correlated with worse neuropsychological test performance scores independently of age and CSF HIV RNA (p < 0.05). Furthermore, CSF Gal-9 directly correlated with myeloid activation (CSF-soluble CD163 and neopterin) in both HIV+ older groups (p < 0.05). Among HIV+ necropsy specimens, Gal-9 expression was increased in select brain regions compared to controls (p < 0.05). Gal-9 may serve as a novel neuroimmuno-modulatory protein that is involved in driving cognitive deficits in those aging with HIV and may be valuable in tracking cognitive abnormalities.

Background: Chronic inflammation and immune dysfunction occur in human immunodeficiency virus (HIV)-infection despite stable antiretroviral therapy (ART). Red blood cell distribution width (RDW) has been shown to correlate with markers of inflammation in non-HIV conditions. The study objective was to determine associations between RDW with cellular markers of immune activation and immune dysfunction including soluble inflammatory mediators in ART treated HIV infection., Methods: We performed a cross-sectional analysis of the Hawaii Aging with HIV-Cardiovascular study. RDW was defined as one standard deviation of RBC size divided by mean corpuscular volume multiplied by 100%. Correlations were analyzed between RDW, soluble inflammatory biomarkers and T cell activation (CD38 + HLA-DR+), senescence (CD28-CD57+), and immune exhaustion (PD-1, TIGIT, TIM-3 expression)., Results: Of 158 participants analyzed, median age was 50 years, duration of ART 12.6 years, virally suppressed 84.4%, and CD4 count 503 cells/mm3. Significant positive correlations were identified between RDW and soluble biomarkers including sICAM, IL-8, IL-6, SAA, TNF-α, sE-selection, fibrinogen, D-dimer, CRP, CD4/CD8 ratio, and frequency of multiple CD8 T-cell populations such as CD38 + HLA-DR + T-cells, single TIGIT+, and dual expressing of TIGIT + PD1+, TIGIT + TIM3+, and TIM3 + PD1+ CD8+ T-cell subsets (p < .05). Frequencies of CD38 + HLA-DR + CD8+ T-cells and TIGIT + CD8+ T-cells remained significant adjusting for baseline variables (p < .01)., Conclusion: Our study revealed correlations between RDW with systemic inflammatory biomarkers and CD8+ T-cell populations related to immune activation and exhaustion in HIV-infected individuals on ART. Further studies are warranted to determine the utility of RDW as a marker of immune dysregulation in HIV.

Plasminogen activator inhibitor type 1 (PAI-1), a key negative regulator of fibrinolysis, has been investigated to be one of the potential mechanisms of the development of impaired insulin sensitivity, insulin resistance, and diabetes mellitus. Because chronically stable HIV-infected individuals frequently develop abnormal glucose metabolism, including insulin resistance and diabetes mellitus, we postulated that PAI-1 could be one of the multifactorial pathogenic roles in the development of impaired insulin sensitivity and insulin resistance among chronic HIV-infected individuals. From our longitudinal cohort study, we selectively recruited chronically stable HIV-infected individuals without diagnosis of diabetes mellitus at baseline (N = 62) to analyze the correlation of baseline inflammatory cytokines, including PAI-1 and whole-body insulin sensitivity, with 2-year follow-up, as measured by Matsuda Index. We found a negative correlation between baseline PAI-1 and Matsuda Index (r = -0.435, p = .001) and a negative correlation between baseline PAI-1 and Matsuda Index at 2 years (r = -0.377, p = .005). In a linear regression model that included age, total body fat mass percentage, serum amyloid A, and family history of diabetes mellitus, PAI-1 still remained significantly associated with Matsuda Index at 2-year follow-up (β = -.397, p = .002). Our longitudinal study suggests that PAI-1 is an independent predictor of impaired insulin sensitivity among chronic HIV-infected individuals.

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.

Unlabelled: HIV infection treatment strategies have historically defined effectiveness through measuring patient plasma HIV RNA. While combined antiretroviral therapy (cART) can reduce plasma viral load (pVL) to undetectable levels, the degree that HIV is eliminated from other anatomical sites remains unclear. We investigated the HIV DNA levels in 229 varied autopsy tissues from 20 HIV-positive (HIV(+)) cART-treated study participants with low or undetectable plasma VL and cerebrospinal fluid (CSF) VL prior to death who were enrolled in the National Neurological AIDS Bank (NNAB) longitudinal study and autopsy cohort. Extensive medical histories were obtained for each participant. Autopsy specimens, including at least six brain and nonbrain tissues per participant, were reviewed by study pathologists. HIV DNA, measured in tissues by quantitative and droplet digital PCR, was identified in 48/87 brain tissues and 82/142 nonbrain tissues at levels >200 HIV copies/million cell equivalents. No participant was found to be completely free of tissue HIV. Parallel sequencing studies from some tissues recovered intact HIV DNA and RNA. Abnormal histological findings were identified in all participants, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. All brain tissues demonstrated some degree of pathology. Ninety-five percent of participants had some degree of atherosclerosis, and 75% of participants died with cancer. This study assists in characterizing the anatomical locations of HIV, in particular, macrophage-rich tissues, such as the central nervous system (CNS) and testis. Additional studies are needed to determine if the HIV recovered from tissues promotes the pathogenesis of inflammatory diseases, such as HIV-associated neurocognitive disorders, cancer, and atherosclerosis., Importance: It is well-known that combined antiretroviral therapy (cART) can reduce plasma HIV to undetectable levels; however, cART cannot completely clear HIV infection. An ongoing question is, "Where is HIV hiding?" A well-studied HIV reservoir is "resting" T cells, which can be isolated from blood products and succumb to cART once activated. Less-studied reservoirs are anatomical tissue samples, which have unknown cART penetration, contain a comparably diverse spectrum of potentially HIV-infected immune cells, and are important since <2% of body lymphocytes actually reside in blood. We examined 229 varied autopsy specimens from 20 HIV(+) participants who died while on cART and identified that >50% of tissues were HIV infected. Additionally, we identified considerable pathology in participants' tissues, especially in brain, spleen, lung, lymph node, liver, aorta, and kidney. This study substantiates that tissue-associated HIV is present despite cART and can inform future studies into HIV persistence., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Inequities in the incidence of HIV infection and AIDS with continued persistence of HIV-associated neurocognitive disorders (HAND) exist in populations in Hawaii (HI) and Puerto Rico (PR). We previously reported that peripheral monocyte HIV DNA levels are high in patients in Hawaii with HAND and we now hypothesize that similar findings would be observed in the cerebrospinal fluid (CSF) cellular subsets. Cerebrospinal fluid cells were obtained from patients from PR and HI undergoing neurocognitive testing and sorted into monocytes (CD14+) and lymphocytes (CD14-) and HIV DNA was measured. From six PR subjects (three HAND, three normal cognition, NC) and six HI subjects (three HAND, three NC), HIV DNA burden in CD14+ cells was higher in HAND than NC patients; NC patients had higher HIV DNA burden in CD14-cells versus HAND. Differences in HIV DNA burden in particular CSF cellular subsets suggest that HIV DNA burden may play a role in HAND neuropathogenesis.

Objectives: Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14(+) enriched monocytes predicted cognitive impairment and brain injury., Methods: We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14(+) enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF)., Results: The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14(+) HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14(+) HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions., Interpretation: Reservoir burden of HIV DNA in monocyte-enriched (CD14(+)) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS.

Objective: We evaluated regional brain volumes and cerebral metabolite levels as correlates of HIV DNA in peripheral blood mononuclear cells (PBMCs)., Methods: In this cross-sectional study, 35 HIV+ subjects aged ≥40 years (25 with detectable PBMC HIV DNA; 10 with HIV DNA <10 copies/10(6) cells, the threshold of detection) and 12 seronegative controls underwent structural brain MRI and magnetic resonance spectroscopy at 3 T. HIV+ subjects were on combination antiretroviral therapy ≥1 year; all but 1 had plasma HIV RNA <50 copies/mL. We used logistic regression to evaluate relationships of likely predictor variables to the outcome of PBMC HIV DNA detectability in the HIV+ subjects. Effects of serostatus and HIV DNA on regional brain volumes (normalized to intracranial volume) and on metabolite ratios over creatine were evaluated by analyses of covariance, controlling for age., Results: Relative to the HIV+ group with undetectable HIV DNA, subjects with detectable HIV DNA demonstrated decreased volumes of cerebellar (-14%, p = 0.020) and total subcortical (-10%, p = 0.024) gray matter. Compared to healthy controls, only the detectable HIV DNA group showed significant (p < 0.05) enlargement of lateral ventricles and volumetric reductions of caudate, putamen, thalamus, hippocampus, nucleus accumbens, brainstem, total cortical gray matter, and cerebral white matter. Detectable HIV DNA was not associated with significantly altered cerebral metabolite levels., Conclusion: Inability to clear peripheral blood of HIV DNA is associated with regional brain atrophy in well-controlled HIV infection, supporting the involvement of peripheral viral reservoirs in the neuropathogenesis of persistent HIV-related neurocognitive disorders.

Human immunodeficiency virus type 1 (HIV)-infected individuals are at risk for anal cancer, which is caused by human papillomavirus (HPV). The relationship between HIV and HPV that leads to anal cancer remains unclear. Recent data, however, suggest that the continued persistence of HIV DNA in patients treated with combined antiretroviral therapy leads to progression of HIV disease and other HIV-associated complications. Therefore, we investigated the relationship among anal low- and high-grade squamous intraepithelial lesions (LGSIL/HGSIL), high-risk HPV genotypes, and high HIV DNA copy numbers. Anal cytology specimens were assayed for HPV genotype and HIV DNA copy number. High-risk HPV genotypes (odds ratio OR: 3.73; 95% confidence interval CI: 1.08-12.91; p=0.04) and high HIV DNA copy numbers (OR(per 100 HIV DNA copies): 1.13; 95% CI: 1.01-1.27, p=0.04) were both associated with LGSIL/HGSIL. When considering both high-risk HPV genotypes and HIV DNA copy numbers in predicting LGSIL/HGSIL, HIV DNA copy number was significant (OR(per 100 HIV DNA copies): 1.09; 95% CI: 0.96-1.23, p=0.04) but not high-risk HPV genotypes (OR: 2.30, p=0.28), which did not change when adjusted for nadir CD4 cell count and HIV RNA levels. The findings warrant further investigation of HIV DNA and its relationship with HPV in LGSIL/HGSIL pathogenesis.

The effect that HIV type 1 (HIV) has on neurocognition is a dynamic process whereby peripheral events are likely involved in setting the stage for clinical findings. In spite of antiretroviral therapy (ART), patients continue to be at risk for HIV-associated neurocognitive disorders (HAND), which might be related to persistence of inflammation. In a yearly assessment of HIV DNA levels in activated monocytes, increased HIV DNA copies were found in patients with persistent HAND. Furthermore, activated monocytes from patients with high HIV DNA copies secreted more inflammatory cytokines. Since these activated monocytes traffic to the CNS and enter the brain, they may contribute to an inflammatory environment in the CNS that leads to HAND.

High levels of human immunodeficiency virus (HIV) DNA in peripheral blood mononuclear cells (PBMCs), and specifically within CD14+ blood monocytes, have been found in HIV-infected individuals with neurocognitive impairment and dementia. The failure of highly active antiretroviral therapy (HAART) to eliminate cognitive dysfunction in HIV may be secondary to persistence of HIV-infected PBMCs which cross the blood-brain barrier, leading to perivascular inflammation and neuronal injury. This study assessed brain cortical thickness relative to HIV DNA levels and identified, we believe for the first time, a neuroimaging correlate of detectable PBMC HIV DNA in subjects with undetectable HIV RNA. Cortical thickness was compared between age- and education-matched groups of older (>40 years) HIV-seropositive subjects on HAART who had detectable (N = 9) and undetectable (N = 10) PBMC HIV DNA. Statistical testing revealed highly significant (P < 0.001) cortical thinning associated with detectable HIV DNA. The largest regions affected were in bilateral insula, orbitofrontal and temporal cortices, right superior frontal cortex, and right caudal anterior cingulate. Cortical thinning correlated significantly with a measure of psychomotor speed. The areas of reduced cortical thickness are key nodes in cognitive and emotional processing networks and may be etiologically important in HIV-related neurological deficits.

Purpose: To assess the proportion as well as predictors of anal dysplasia in HIV-infected Asian/Pacific Islanders., Methods: This was a retrospective chart review evaluating the proportion of anal dysplasia among a multiethnic population from an ambulatory university-based HIV clinic in Hawaii. Demographic, clinical, and virologic parameters were examined with respect to abnormal anal Pap smear. Variables included: Pap smear results (outcome variable), cytology results, age, self-reported ethnicity, CD4/ nadir CD4 counts, HIV viral load, antiretroviral therapy use, Hepatitis B and C co-infections, history of sexually transmitted diseases, personal history of cancer, tobacco use, alcohol use, intravenous drug abuse, family history of cancer, and history of genital/anal warts., Results: There were no significant differences in rates of abnormal Pap smear among the ethnic groups. Abnormal Pap smears were associated with history of genital warts (7% normal vs. 18% abnormal, p=.01) and alcohol consumption (16% vs. 27%, p=.05). Hepatitis B infection and current anti-retroviral therapy (ART) were associated with normal Pap cytology (9.7% vs. 0%, p=.03) and (96.8% vs. 86.5%, p=.05) respectively., Conclusions: No differences in the proportion of abnormal Pap smears were seen among ethnic groups followed within an ambulatory HIV clinic.

We determined the incidence of and risk factors for distal sensory polyneuropathy (DSP) in individuals on HAART. Sixty-one HIV-positive subjects on HAART for at least 6 months and neuropathy free were retrospectively selected. The study included subjects who had previously tolerated d-drugs without developing DSP. Neuropathy incidence over 4 years was calculated. Cox proportional hazards models were used to determine risk factors associated with incident DSP. Nineteen subjects developed DSP over a mean follow-up of 2.4 years. Subjects never treated with a d-drug developed DSP at a rate of 21 cases per 100 person-years (95% CI, 8.9-33.7). Subjects with a history of d-drug treatment but not on a d-drug at enrollment developed DSP at a rate of 17 cases per 100 person-years (95% CI, 2.1-31.8). Those on d-drug treatment developed DSP at a rate of 25 cases per 100 person-years (95% CI, 8.7-41.6). Multivariable analysis identified age [hazard ratio (HR) = 1.09; p < 0.01] and low CD4(+) nadir [hazard ratio (HR) = 0.79; p = 0.03] as significant risk factors. Current or prior history of treatment with d-drug was not a significant risk factor for incident DSP in subjects who had previously tolerated d-drug treatment without developing a toxic DSP. Age and low CD4(+) are risk factors for incident DSP. However, current or prior history of d-drug treatment is not a significant risk factor for incident DSP in subjects who had previously tolerated d-drug treatment without developing a toxic DSP.

Objective: To assess the short-term effects of extended-release niacin (ERN) on endothelial function in HIV-infected patients with low high-density lipoprotein-cholesterol (HDL-c) levels., Methods: Randomized controlled study to determine the short-term effects of ERN on endothelial function, measured by flow-mediated vasodilation (FMD) of the brachial artery, in HIV-infected adults with low HDL-c. Participants on stable HAART with fasting HDL-c less than 40 mg/dl and low-density lipoprotein-cholesterol less than 130 mg/dl were randomized to ERN or control arms. ERN treatment started at 500 mg/night and titrated to 1500 mg/night for 12 weeks. Controls received the same follow-up but were not given ERN (no placebo). Participants were excluded if they had a history of cardiac disease, uncontrolled hypertension, diabetes mellitus, or were on lipid-lowering medications such as statins and fibrates. Change in FMD was compared between arms with respect to baseline HDL-c., Results: Nineteen participants were enrolled: 89% men, median age 50 years, 53% white/non-Hispanic, median CD4 cell count 493 cells/microl, and 95% of them had HIV RNA below 50 copies/ml. Participants receiving ERN had a median HDL-c (interquartile range) increase of 3.0 mg/dl (0.75 to 5.0) compared with -1.0 mg/dl in controls (-6.0 to 2.5), a P value is equal to 0.04. The median change in FMD was 0.91% (-2.95 to 2.21) for ERN and -0.48% (-2.65 to 0.98) for controls (P = 0.67). However, end of study FMD for ERN was significantly different from controls after adjusting for baseline differences in FMD and HDL-c, 6.36% (95% confidence interval 4.85-7.87) and 2.73% (95% confidence interval 0.95-4.51) respectively, a P value is equal to 0.048., Conclusion: This pilot study demonstrated that short-term niacin therapy could improve endothelial function in HIV-infected patients with low HDL-c.

Human immunodeficiency virus (HIV) DNA in peripheral blood mononuclear cells was previously associated with neuropsychological function. By including individuals encompassing the full range of HIV-1-associated neurocognitive disorders, this study reports results from subjects with normal cognition, minor cognitive motor disorder, and HIV-1-associated dementia. Individuals with normal cognition had relatively low HIV DNA levels compared to those with minor cognitive motor disorder and HIV-1-associated dementia. Neuropsychological deficits were significantly associated with entry HIV DNA in all domains. These findings demonstrate for the first time that the severity of HIV-1-associated neurocognitive disorders is proportional to the amount of circulating HIV DNA.

The authors previously found a strong association between elevated HIV proviral DNA (HIV DNA) and a diagnosis of HIV-1-associated dementia (HAD) vs. normal cognition. It is unclear whether HIV DNA globally affects the diagnosis of HAD or whether the effect is limited to individual neuropsychological deficits. This exploratory study examined baseline HIV DNA and its association with individual neuropsychological deficits. HIV DNA was significantly associated with baseline neuropsychological deficits independent of age, ethnicity, IQ, and plasma HIV-1 RNA levels. However, HIV DNA did not predict future changes in neuropsychological deficits. The data suggest that HIV DNA and neuropsychological deficits may co-vary over time.

Low CD4 lymphocyte count was a marker for neurological disease in human immunodeficiency virus type 1 (HIV-1); but is now less common among patients with access to highly active antiretroviral therapy. In this study, the authors determine the reliability of self-reported CD4 nadir and its predictive value for neurological status. The authors identify a high degree of reliability (r = .90). After adjusting for age, current CD4 count, and duration of HIV-1, CD4 nadir relates to a current diagnosis of HIV-associated dimentia (HAD) (odds ratio [OR]: 1.395 (1.106-1.761), P = .005) and distal symmetric polyneuropathy (DSPN) (OR: 1.479 (1.221-1.769, P < .001).

Human immunodeficiency virus (HIV) infection in peripheral blood mononuclear cells (PBMCs) might be influencing the development of wasting in the era of potent antiretroviral therapy. In a retrospective study of 57 subjects, HIV proviral DNA levels in PBMCs were higher in subjects whose body weight decreased by >5% one year after initiation of highly active antiretroviral therapy, compared with subjects whose body weight was stable or increased (median HIV proviral DNA load, 8.9 vs. 0.9 copies/10(6) PBMCs; P = .006).

There are discrepant findings regarding the risk of HIV-associated dementia (HAD) relating to apolipoprotein E4, suggesting other factors may modulate risk. Furthermore, evidence suggests a changing phenotype of HAD in the era of highly active antiretroviral therapy (HAART), prompting a need to determine if new disease markers have emerged. In this analysis, APOE genotype was determined for 182 participants enrolled in the Hawaii Aging with HIV Cohort. After controlling for age and diabetes status, an independent risk of HAD relating to E4 was seen in older participants [OR=2.898 (1.031-8.244)] but not in younger participants [OR=0.373 (0.054-1.581)]. Several proposed mechanisms may underlie this association. Consideration of non-traditional risk factors for HAD in older HIV patients may yield new markers of disease in the era of HAART.

Background: Antiretroviral therapy has improved survival for HIV-1-infected individuals. The neuroepidemiologic implications of HIV-1 in an aging population are not well known, particularly the prevalence of HIV-associated dementia (HAD)., Methods: The authors report a baseline cross-sectional analysis of 202 HIV-1-seropositive individuals enrolled into one of two groups of the Hawaii Aging with HIV Cohort: older (50 or more years old, n = 106) and younger (20 to 39 years old, n = 96). Neuropsychological, neurologic, medical, and laboratory data were obtained at enrollment. Participant cognitive status was classified (research case definitions) using American Academy of Neurology (1991) criteria in a consensus conference of physicians and neuropsychologists., Results: HAD was more frequent in older (25.2%) compared to younger (13.7%) individuals (p = 0.041) corresponding to an OR of 2.13 (95% CI: 1.02 to 4.44) for the older compared to the younger group. After adjusting for education, race, substance dependence, antiretroviral medication status, viral load, CD4 lymphocyte count, and Beck Depression Inventory score, the odds of having HAD among individuals in the older group was 3.26 (1.32 to 8.07) times that of the younger group., Conclusions: Older age is associated with increased HAD in this HIV-1 cohort. Underlying mechanisms are unclear but do not appear related to duration of HIV-1 infection.

In the current era of highly active antiretroviral therapy (HAART), the prevalence of HIV-associated non-Hodgkin lymphoma (H-NHL) is not as high as in the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, but still remains above that of non-HIV-infected individuals. Therefore, the epidemiology suggests that the pathogenesis of H-NHL may be multifactoral, involving the interaction of the immune system with HIV or other pathogens. Although HIV is a retrovirus, it is not characterized with the typical oncogenic potential associated with insertional mutagenesis. HIV integration occurs as a necessary step in the life cycle allowing for replication and transcription of the viral genome to take place. While HIV is thought to integrate randomly, more recent studies have suggested that integration occasionally occurs in a less random fashion. While the majority of H-NHL may be secondary to immune dysfunction, this non-random integration may be a factor leading to pathogenesis of a small subset of H-NHL since the pathways involved in malignancies usually require an accumulation of abnormalities leading to proliferation and transformation. A common element among lymphomas in this setting of immune dysfunction is the inability to control a pathogen that acts as an ongoing immune activator. Thus, an increased risk of H-NHL emerges from the combination of immunodeficiency, increased immune activation and possible HIV insertional mutagenesis. The focus of this review will be on the role viral pathogenesis plays in oncogenic transformation., (Copyright 2004 Bentham Science Publishers Ltd.)

Objective: To determine if aging changes the frequency, severity, or manifestations of symptomatic distal sensory polyneuropathy (SxDSPN) in patients with HIV-1., Methods: Prospective observations of 70 older (age < or = 50) and 56 younger (age 20 to 40) patients with HIV, and a control group of 48 older non-HIV patients, were conducted utilizing neurologic examination, neuropsychological testing, lumbar puncture, laboratory, and medical history., Results: The frequency of SxDSPN among older HIV patients was 50.4%, compared to 19.6% among younger HIV patients (p < 0.001). SxDSPN among control patients occurred in 4.2%, similar to the general population. Older compared to younger HIV patients demonstrated more severe symptoms (p = 0.02) and greater deficits for vibration (p < 0.01). Increasing numbers of neuropathic comorbidities among older compared to younger HIV patients were associated with increasing severity of deficits to pinprick (p = 0.003). Dementia and SxDSPN coexisted in 36% of the older HIV patients and in none of the younger HIV patients (p = 0.021). Older HIV patients with nadir CD4 < or =200 cells/mL were 4.23 times as likely to have SxDSPN than older patients with nadir CD4 >200 cells/mL (p = 0.007). Vibratory deficits excessive to pinprick deficits predicted SxDSPN among older (OR 2.83) but not younger seropositive patients (p = 0.036)., Conclusions: Age > or = 50 increases the frequency of SxDSPN, and is associated with both vibratory loss as the predominant sensory deficit and increased severity of pinprick loss among symptomatic patients with neuropathic comorbidities. SxDSPN is associated with both dementia and low nadir CD4 in HIV-positive patients aged 50 and greater.

HIV-infected individuals are at risk for developing certain types of cancers. While there are data to show that non-random HIV integration may occur, our goal was to identify preferential genomic sites where HIV integration might be targeted leading to oncogenesis. Initially, a linker-primer PCR strategy was used to identify HIV integration in isolated macrophages. Inverse-PCR was then used to analyze specimens from patients diagnosed with HIV-associated malignancies. From isolated macrophages, integration near a toll-like receptor on chromosome 4 was found. Necropsy tissues from 11 cases were analyzed with 1 tumor specimen found to have HIV integrated in chromosome 22q13.2 and within 300 kb of HSCBCIP1 (CAP-binding protein complex interacting homologue). Tumor-specific primers were then used to screen uninvolved tissue from the same patient, which did not amplify the site-specific region. This report demonstrates that in both an in vitro system and human malignant tissue, specific viral integration can be identified.

Performing a liver biopsy in patients infected with HIV and hepatitis C virus (HCV) is considered the standard of practice to assess hepatic involvement but carries risks to patients. This pilot study was designed to identify single photon emission computed tomography (SPECT) parameters that correlate with liver disease stage. HIV-coinfected and HCV-coinfected individuals undergoing a liver biopsy had a SPECT scan performed. The results showed that a number of SPECT parameters were associated with histologic changes in architecture, fibrosis, and cirrhosis, of which two SPECT parameters, the minimum pixel count for spleen region of interest and maximum pixel count for right hepatic lobe, correctly classified 39 of 46 SPECT/biopsy pairs. In conclusion, this pilot trial identified SPECT parameters that correlated with liver histology changes. A larger study is needed to demonstrate whether SPECT parameters alone or with other markers can provide information on fibrosis with the clinical significance obtained through liver biopsy.

Recent studies of pregnant women and animal models have raised concerns regarding potentially serious mitochondrial toxicity-related side effects in infants born to mothers who received nucleoside reverse transcriptase inhibitors (NRTIs) during their pregnancy to prevent HIV-1 perinatal transmission. The aim of this study was to assess mitochondrial DNA (mtDNA) content of cord blood and placenta in HIV-infected pregnant women receiving NRTI compared with HIV-negative women, hypothesizing that placenta and cord blood mtDNA copies per cell would be decreased in women on NRTI therapy. Immediately following delivery, placenta and cord blood were obtained from eight HIV-infected pregnant women on NRTIs and five HIV-negative women. Assessment of mtDNA copies per cell was accomplished by quantitative real-time PCR. The mean mtDNA copies per cell from the placenta of the HIV-infected women compared with HIV-negative women was 152 +/- 119 and 880 +/- 136 ( =.0016), respectively. Similarly, the mean mtDNA copies per cell from the cord blood of the HIV-positive women compared with HIV-negative women was 144 +/- 101 and 865 +/- 331 ( =.0026), respectively. There was a statistically significant decrease in mtDNA copies per cell in placenta and cord blood between the HIV-infected women on NRTIs compared with HIV-negative women. Further studies are needed to better understand the morbidity to infants and mothers treated with NRTI to prevent vertical transmission of HIV.

Objective: To determine whether the peripheral fat wasting (lipodystrophy), which is seen in association with highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI), is associated with a decrease in subcutaneous adipose tissue mitochondrial DNA (mtDNA) content or with large mtDNA deletions or insertions., Design: A four cohort cross-sectional study., Methods: The mtDNA content of subcutaneous fat tissue from the neck, abdomen and thigh was determined by polymerase chain reaction utilizing the amplification of three different mtDNA fragments. The results from HIV-infected patients with peripheral fat wasting following more than 6 months of NRTI-containing HAART were compared with the results from three different control cohorts: HIV-infected patients with a similar treatment history without lipodystrophy; HIV-infected patients naive to antiretroviral therapy and HIV sero-negative participants., Results: A decrease in mtDNA content was found in HAART-treated HIV-infected patients with peripheral fat wasting in comparison with subjects in the control cohorts. No large mitochondrial deletions or insertions were found., Conclusions: Lipodystrophy with peripheral fat wasting following treatment with NRTI-containing HAART is associated with a decrease in subcutaneous adipose tissue mtDNA content.

An essential component of the HIV-1 life cycle involves insertion in the genome of an infected cell. The site of HIV-1 integration has the potential to disrupt a gene and perturb a normal cellular function. To begin to address whether disease pathogenesis may correlate with the site of insertion, flanking cellular sequences at these HIV integrated regions were directly amplified from peripheral blood mononuclear cells DNA from a broad range of infected individuals using an inverse polymerase chain reaction strategy. Amplified flanking regions were sequenced and examined for similarity to the nucleic acid database. In this group of analyzed samples, the HIV-1 provirus was inserted within non-coding regions throughout the genome of the infected host, in which 7/14 sites were positioned in close proximity to different Alu repetitive elements while 2/14 sites were located within intron sequences. Insertions were also detected at sites without a specific gene designation but not within short tandem repetitive sequences, telomeres or centromeric repeat regions. Altogether, it is expected that this approach will yield new information on sites of integration by HIV-1 that may be associated with the pathogenic manifestations of disease progression.

We recently reported clonal human immunodeficiency virus (HIV involvement in four acquired immune deficiency syndrome (AIDS)-associated non-B-cell lymphoproliferations. In three of these cases HIV expression was localized to tumor-associated macrophages. Because one of the cases had a major component involved in angioproliferation, we speculated that some form of Kaposi's sarcoma (KS), which also has a major component of angioproliferation, might be involved clonally with HIV. The current study is an evaluation of four cases of KS and control tissues taken from four patients who died with complications of HIV disease. With use of the inverse polymerase chain reaction technique to identify clonal forms of HIV, a clonal form of HIV was found in one of four KS cases. The HIV-positive tumor was an early KS lesion of the bowel, and uninvolved bowel from the same patient showed no clonal HIV. Immunohistochemical analysis demonstrated the presence of prominent HIV-expressing macrophages that also coexpressed high levels of HIV tat, basic fibroblast growth factor, and interleukin-6. These data provide evidence for a pathogenic process termed "sequential neoplasia," wherein a clonal macrophage provides a growth factor milieu stimulating the proliferation of a responder cell population that ultimately becomes autonomous. In the current case, the macrophages expressing HIV were located adjacent to the KS tumor tissue and were found to be producing known KS growth factors. The absence of finding clonal HIV in three more advanced KS lesions suggests that the clonal macrophage may be required only for early pathogenesis and that sequential neoplastic changes occurring in the endothelial cells gave rise to autonomous KS.(ABSTRACT TRUNCATED AT 250 WORDS)

HIV-associated neurocognitive disorders (HAND) persist despite plasma HIV RNA suppression with antiretrovirals (ARV). Sequestered reservoirs in the central nervous system and circulating monocytes are theorized to contribute to persistent brain injury. We previously demonstrated that elevated intracellular HIV DNA from circulating cells was associated with HAND in ARV-treated and ARV-naive subjects. We now report that failure to suppress intra-monocyte HIV DNA 3.5 years after initiating ARV is linked to persistent HAND and subjects with dementia are least likely to suppress intra-monocyte HIV DNA at 3.5 years. These findings suggest that antiviral strategies may need to target intra-monocyte HIV DNA. [ABSTRACT FROM AUTHOR]