Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis

Human immunodeficiency virus (HIV) rapidly penetrates into the brain and establishes a persistent infection of macrophages/microglia. Activation of these cells by HIV results in the secretion of soluble factors that destabilize neuronal calcium homeostasis, encourage oxidative stress and result in neural damage. This damage is thought to underlie the cognitive-motor dysfunction that develops in many HIV-infected patients. Studies have suggested that neurotrophins may protect neurons from the toxic effects of HIV-associated proteins. To better understand the pathogenic mechanisms and the neuroprotective potential of neurotrophin ligands, we evaluated neuronal damage, calcium homeostasis and mitochondrial functions after exposure of cultured rat neurons directly to HIV gp120 or to conditioned medium from human monocyte-derived macrophages treated with gp120. We then assessed the ability of a new non-peptide p75 neurotrophin receptor ligand, LM11A-31, to stabilize calcium homeostasis and prevent the development of pathology. Each toxic challenge resulted in a delayed accumulation of intracellular calcium coupled to a decrease in the rate of calcium clearance from the cell. The delayed calcium accumulation correlated with the development of focal dendritic swellings (beading), cytoskeletal damage and impaired movement of mitochondria. Addition of LM11A-31 to the cultures at nanomolar concentrations eliminated cell death, significantly reduced the pathology, suppressed the delayed accumulation of calcium and restored mitochondrial movements. The potent neuroprotection and the stabilization of calcium homeostasis indicate that LM11A-31 may have excellent potential for the treatment of HIV-associated neurodegeneration

Transmigration of macrophages across the choroid plexus epithelium in response to the feline immunodeficiency virus

Although lentiviruses such as human, feline and simian immunodeficiency viruses (HIV, FIV, SIV) rapidly gain access to cerebrospinal fluid (CSF), the mechanisms that control this entry are not well understood. One possibility is that the virus may be carried into the brain by immune cells that traffic across the blood–CSF barrier in the choroid plexus. Since few studies have directly examined macrophage trafficking across the blood–CSF barrier, we established transwell and explant cultures of feline choroid plexus epithelium and measured trafficking in the presence or absence of FIV. Macrophages in co-culture with the epithelium showed significant proliferation and robust trafficking that was dependent on the presence of epithelium. Macrophage migration to the apical surface of the epithelium was particularly robust in the choroid plexus explants where 3-fold increases were seen over the first 24 h. Addition of FIV to the cultures greatly increased the number of surface macrophages without influencing replication. The epithelium in the transwell cultures was also permissive to PBMC trafficking, which increased from 17 to 26% of total cells after exposure to FIV. Thus, the choroid plexus epithelium supports trafficking of both macrophages and PBMCs. FIV significantly enhanced translocation of macrophages and T cells indicating that the choroid plexus epithelium is likely to be an active site of immune cell trafficking in response to infection

Initial Feasibility of a Woman-Focused Intervention for Pregnant African-American Women

African-American women who use crack are vulnerable to HIV because of the complex social circumstances in which they live. Drug-abuse treatment for these women during pregnancy may provide time for changing risk behaviors. This paper examines the initial 6-month feasibility of a women-focused HIV intervention, the Women's CoOp, adapted for pregnant women, relative to treatment-as-usual among 59 pregnant African-American women enrolled in drug-abuse treatment. At treatment entry, the women were largely homeless, unemployed, practicing unsafe sex, and involved in violence. Results indicated marked reductions in homelessness, use of cocaine and illegal drugs, involvement in physical violence, and an increase in knowledge of HIV from baseline to 6-month followup for both conditions. Findings suggest that the Women's CoOp intervention could be successfully adapted to treat this hard-to-reach population. Future studies should examine the efficacy of the pregnancy-adapted Women's CoOp for women not enrolled in drug-abuse treatment

Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection

To begin to unravel the complexity of HIV-associated changes in the brain, broader, multifaceted analyses of cerebrospinal fluid (CSF) are needed that examine a wide range of proteins reflecting different functions. CSF from HIV-infected patients with a range of cognitive deficits was compared to CSF from uninfected, cognitively normal patients to begin to identify protein changes associated with HIV infection and neurological disease progression. Uninfected patients showed relatively consistent patterns of protein expression. Highly expressed proteins in CSF included monocyte chemotactic protein-1, tissue inhibitors of metalloproteases, granulocyte colony-stimulating factor, adiponectin, soluble tumor necrosis factor receptor-1, urokinase-type plasminogen activator receptor, and insulin-like growth factor binding protein-2. Inflammatory and anti-inflammatory cytokines were expressed at low levels. HIV-infected patients showed increases in inflammatory proteins (interferon-gamma, tumor necrosis factor-alpha), anti-inflammatory proteins (IL-13), and chemokines but these correlated poorly with neurological status. The strongest correlation with increasing severity of neurological disease was a decline in growth factors, particularly, brain-derived neurotrophic factor and NT-3. These studies illustrate that HIV infection is associated with parallel changes in both inflammatory and neuroprotective proteins in the CSF. The inverse relationship between growth factors and neurological disease severity suggests that a loss of growth factor neuroprotection may contribute to the development of neural damage and may provide useful markers of disease progression

Suppression of Immunodeficiency Virus-Associated Neural Damage by the p75 Neurotrophin Receptor Ligand, LM11A-31, in an In Vitro Feline Model

Feline immunodeficiency virus (FIV) infection like human immunodeficiency virus (HIV), produces systemic and central nervous system disease in its natural host, the domestic cat, that parallels the pathogenesis seen in HIV-infected humans. The ability to culture feline nervous system tissue affords the unique opportunity to directly examine interactions of infectious virus with CNS cells for the development of models and treatments that can then be translated to a natural infectious model. To explore the therapeutic potential of a new p75 neurotrophin receptor ligand, LM11A-31, we evaluated neuronal survival, neuronal damage and calcium homeostasis in cultured feline neurons following inoculation with FIV. FIV resulted in the gradual appearance of dendritic beading, pruning of processes and shrinkage of neuronal perikarya in the neurons. Astrocytes developed a more activated appearance and there was an enhanced accumulation of microglia, particularly at longer times post-inoculation. Addition of 10 nM LM11A-31, to the cultures greatly reduced or eliminated the neuronal pathology as well as the FIV effects on astrocytes and microglia. LM11A-31 also, prevented the development of delayed calcium deregulation in feline neurons exposed to conditioned medium from FIV treated macrophages. The suppression of calcium accumulation prevented the development of foci of calcium accumulation and beading in the dendrites. FIV replication was unaffected by LM11A-31. The strong neuroprotection afforded by LM11A-31 in an infectious in vitro model indicates that LM11A-31 may have excellent potential for the treatment of HIV-associated neurodegeneration

Pregnant and Nonpregnant Women in Cape Town, South Africa: Drug Use, Sexual Behavior, and the Need for Comprehensive Services

The multiple risks associated with methamphetamine use are of serious concern for women. These risks and consequences are magnified during pregnancy. This secondary analysis of a parent study compared 26 pregnant to 356 nonpregnant women in Cape Town, South Africa, on selected demographic, psychosocial, and HIV-risk domains to identify their treatment service needs. Proportionally, more pregnant than nonpregnant women are using methamphetamine, P = .01, although a very high rate of women used methamphetamine. Women reported similar monthly rates of sexual intercourse, but pregnant women were significantly less likely to report condom use, P < .0001, maintaining their risky behavior. Both groups reported elevated Center for Epidemiological Studies Depression Scale CES-D means, suggesting a need for depression treatment. Results demonstrate a pervasive need for women's comprehensive treatment, regardless of pregnancy status. Moreover, findings support the urgent need for women-focused and pregnancy-specific treatment services for methamphetamine use. Finally, a job-skills training/employment component focus is suggested

Pregnant and Nonpregnant Women in Cape Town, South Africa: Drug Use, Sexual Behavior, and the Need for Comprehensive Services

The multiple risks associated with methamphetamine use are of serious concern for women. These risks and consequences are magnified during pregnancy. This secondary analysis of a parent study compared 26 pregnant to 356 nonpregnant women in Cape Town, South Africa, on selected demographic, psychosocial, and HIV-risk domains to identify their treatment service needs. Proportionally, more pregnant than nonpregnant women are using methamphetamine, P = .01, although a very high rate of women used methamphetamine. Women reported similar monthly rates of sexual intercourse, but pregnant women were significantly less likely to report condom use, P < .0001, maintaining their risky behavior. Both groups reported elevated Center for Epidemiological Studies Depression Scale CES-D means, suggesting a need for depression treatment. Results demonstrate a pervasive need for women's comprehensive treatment, regardless of pregnancy status. Moreover, findings support the urgent need for women-focused and pregnancy-specific treatment services for methamphetamine use. Finally, a job-skills training/employment component focus is suggested

Results of a Pilot Test of a Brief Computer-Assisted Tailored HIV Prevention Intervention for Use with a Range of Demographic and Risk Groups

There is a need for brief HIV prevention interventions that can be disseminated and implemented widely. This article reports the results of a small randomized field experiment that compared the relative effects of a brief 2-session counselor-delivered computer-tailored intervention and a control condition. The intervention is designed for use with African American, non-Hispanic white and Hispanic males and females who may be at risk of HIV through unprotected sex, selling sex, male to male sex, injecting drug use or use of stimulants. Participants (n=120) were recruited using a quota sampling approach and randomized using block randomization, which resulted in 10 male and 10 female participants of each racial/ethnic group (i.e. African-American, non-Hispanic white and Hispanic) being assigned to either the intervention or a control arm. In logistic regression analyses using a generalized estimating equations approach, at 3-month followup, participants in the intervention arm were more likely than participants in the control arm to report condom use at last sex (Odds ratio [OR] = 4.75; 95% Confidence interval [C.I.] = 1.70, 13.26; p = 0.003). The findings suggest that a brief tailored intervention may increase condom use. Larger studies with longer followups are needed to determine if these results can be replicated

Pregnant and Nonpregnant Women in Cape Town, South Africa: Drug Use, Sexual Behavior, and the Need for Comprehensive Services

The multiple risks associated with methamphetamine use are of serious concern for women. These risks and consequences are magnified during pregnancy. This secondary analysis of a parent study compared 26 pregnant to 356 nonpregnant women in Cape Town, South Africa, on selected demographic, psychosocial, and HIV-risk domains to identify their treatment service needs. Proportionally, more pregnant than nonpregnant women are using methamphetamine, P = .01, although a very high rate of women used methamphetamine. Women reported similar monthly rates of sexual intercourse, but pregnant women were significantly less likely to report condom use, P &lt; .0001, maintaining their risky behavior. Both groups reported elevated Center for Epidemiological Studies Depression Scale CES-D means, suggesting a need for depression treatment. Results demonstrate a pervasive need for women&apos;s comprehensive treatment, regardless of pregnancy status. Moreover, findings support the urgent need for women-focused and pregnancy-specific treatment services for methamphetamine use. Finally, a job-skills training/employment component focus is suggested