Cenicriviroc, a dual CCR2 and CCR5 antagonist leads to a reduction in plasma fibrotic biomarkers in persons living with HIV on antiretroviral therapy.

Background: Chronic HIV is associated with increased inflammation and tissue fibrosis despite suppressive antiretroviral therapy (ART). Monocytes and macrophages have been implicated in the pathogenesis of fibrosis, facilitated by chemokine receptor interactions.Methods: We assessed systemic fibrotic biomarkers (transforming growth factor beta-1 [TGF-ß1], thrombospondin-1 [TSP-1], C-terminal pro-peptide of collagen type I [CICP], and IL-11) in banked plasma from a previously published 24-week open-label trial of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, among persons living with HIV (PLWH) on stable ART with undetectable plasma HIV RNA (<50 copies/mL). Fibrotic markers were assessed by ELISA and Luminex. Untreated HIV-seronegative individuals (n = 6) of similar age and demographics served as a comparator group.Results: Median age of PLWH was 55 years. At baseline, PLWH had higher median TGF-ß1 (2.11 vs 1.62 ng/mL, p = 0.01), TSP-1 (236.74 vs 83.29 ng/mL, p < 0.0001), and CICP (200.46 vs 111.28 ng/mL, p = 0.01), but lower IL-11 (36.00 vs 53.74 pg/mL, p = 0.01) compared to HIV-uninfected individuals. Over 24 weeks, median TGF-ß1 (-0.74 ng/mL, p = 0.006), TSP-1 (-52.12 ng/mL, p < 0.0001), and CICP (-28.12 ng/mL, p < 0.0001) decreased and IL-11 (28.98 pg/mL, p < 0.0001) increased in PLWH. At week 24, TGF-ß1, CICP, and IL-11 were similar between the two groups (p > 0.05), while TSP-1 remained elevated in PLWH (p = 0.009) compared to controls.Conclusions: PLWH had higher levels of the plasma fibrotic markers TGF-ß1, TSP-1, and CICP. After 24 weeks of CVC, fibrotic markers generally returned to levels comparable to HIV-uninfected controls. Dual CCR2 and CCR5 blockade may ameliorate the detrimental fibrotic events that persist in treated HIV.

Lower numbers of circulating Natural Killer T (NK T) cells in individuals with human T lymphotropic virus type 1 (HTLV-1) associated neurological disease.

Human T lymphotropic virus type 1 (HTLV-1) infects 10-20 million people worldwide. The majority of infected individuals are asymptomatic; however, approximately 3% develop the debilitating neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is also currently no cure, vaccine or effective therapy for HTLV-1 infection, and the mechanisms for progression to HAM/TSP remain unclear. NK T cells are an immunoregulatory T cell subset whose frequencies and effector functions are associated critically with immunity against infectious diseases. We hypothesized that NK T cells are associated with HAM/TSP progression. We measured NK T cell frequencies and absolute numbers in individuals with HAM/TSP infection from two cohorts on two continents: São Paulo, Brazil and San Francisco, CA, USA, and found significantly lower levels when compared with healthy subjects and/or asymptomatic carriers. Also, the circulating NK T cell compartment in HAM/TSP subjects is comprised of significantly more CD4(+) and fewer CD8(+) cells than healthy controls. These findings suggest that lower numbers of circulating NK T cells and enrichment of the CD4(+) NK T subset are associated with HTLV-1 disease progression.

Supporting orphans and vulnerable children affected by AIDS: using community-generated definitions to explore patterns of children's vulnerability in Zambia.

This study explores how communities in Zambia characterize vulnerable children in the context of HIV; demonstrates how estimates of vulnerability vary depending on definitions; and discusses the implications of these estimates for program delivery. Baseline research conducted in 2005 included cross-sectional community-based household surveys at six locations using multi-stage random sampling (totalling 1,503 households, reporting on 5,009 children) and participatory qualitative research (focus group and in-depth interviews) with adults and youth at four locations. Between 14 and 27% of children in the sample had experienced a parental death (2-5% maternal orphans, 7-13% paternal orphans, 4-10% double orphans). In addition, other characteristics that communities associated with children's vulnerability were prevalent: 26-34% had been taken into another household, 15-27% were living in female-headed households, and 11-28% were living in a household with someone who is chronically ill. Overall, 58-73% of children had one or more community-defined characteristics of vulnerability. This study highlights the need to carefully consider the meaning of "vulnerability" when targeting programmes to support children affected by HIV and AIDS. Local community input is vital to inform context-specific criteria for distributing programme resources. If used, eligibility criteria should be context-specific yet flexible to evolving community realities. In settings such as rural Zambia where levels of HIV-related vulnerability are high, it may be more efficient to target at the level of communities rather than assess individual households.

Critical involvement of OX40 ligand signals in the T cell priming events during experimental autoimmune encephalomyelitis.

OX40 ligand (OX40L) expressed on APCs, and its receptor, OX40 present on activated T cells, are members of the TNF/TNFR family, respectively, and have been located at the sites of inflammatory conditions. We have observed in OX40L-deficient mice (OX40L(-/-)) an impaired APC capacity and in our recently constructed transgenic mice expressing OX40L (OX40L-Tg), a markedly enhanced T cell response to protein Ags. Using these mice, we demonstrate here the critical involvement of the OX40L-OX40 interaction during the T cell priming events in the occurrence of experimental autoimmune encephalomyelitis (EAE). In OX40L(-/-) mice, abortive T cell priming greatly reduced the clinical manifestations of actively induced EAE, coupled with a reduction in IFN-gamma, IL-2, and IL-6 production in vitro. Adoptive transfer experiments however revealed an efficient transfer of disease to OX40L(-/-) mice using wild-type donor T cells, indicating an intact capacity of OX40L(-/-) mice to initiate effector responses. On the other hand, OX40L(-/-) donor T cells failed to transfer disease to wild-type recipient mice. Furthermore, OX40L-Tg mice developed a greater severity of EAE despite a delayed onset, while both OX40L-Tg/CD28(-/-) and OX40L-Tg/CD40(-/-) mice failed to develop EAE demonstrating a requisite for these molecules. These findings indicate a pivotal role played by OX40L in the pathogenesis of EAE.

Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand.

OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L, is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L monoclonal antibody, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-immunoglobulin (Ig)M stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice engendered apparent suppression of the recall reaction of T cells primed with both protein antigens and alloantigens and a significant reduction in keyhole limpet hemocyanin-specific IgG production. The impaired T cell priming was also accompanied by a concomitant reduction of both T helper type 1 (Th1) and Th2 cytokines. Furthermore, antigen-presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo.

A comparison of the 1995 and 1989 Kenya Situation Analysis Study findings.

PIP: This study examined quality of care in delivery of services among Ministry of Health Service Delivery Points (SDPs) in Kenya in 1989 and 1995. The situation analysis focused on method availability, IEC, supervision, training, number of clients served by method, choice of methods, information provided, and integration of services. More information was collected and a diversity of sites were included in 1995. The logistics system for contraceptive availability was viewed as low to moderate in 1989, with under 50% of the SDPs offering foam, condoms, and IUDs. Depo-Provera and Norplant were more available in 1995. Foam tablets were less available in 1995. Sterilization data was not available in 1989. In 1995, 25% of SDPs offered tubal ligation and 11% offered vasectomy. Method availability increased over time. IEC was rated as low in 1989. The display of family planning posters and the availability of pamphlets improved by 1995, but the lack of health talks on the day of the visit remained the same. Supervision was rated low in both 1989 and 1995, based on the number and quality of supervisory visits. Personnel and training were rated as moderate in 1989. In-service training for nurses delivering family planning increased from 1989 to 1995, from 32% to about 60%. During 1989-95, the proportion of clinics that served no clients for each method declined sharply, and the proportion of SDPs serving 1-19 clients/month increased sharply. There were large shifts in the proportion serving over 100 clients/month. The proportion of clinics serving oral pills to over 100 clients/month declined from 28% to 13%, and the proportion offering Depo-Provera increased from 4% to 25% during 1989-95. More clients had heard about permanent methods and fewer about spermicides. More clients had heard about side effects and their management in 1995. The Situation Analysis documented important changes and showed quality of care improvements.^ieng

Measuring reproductive health care after Cairo: findings from four situation analysis studies in Africa.

"The purpose of this paper is to begin a preliminary assessment of some reproductive health indicators within the context of family planning programs, using data from expanded Situation Analyses conducted in four recent African studies. The studies, conducted in 1994-1995, cover Senegal, Zanzibar (studied separately from Tanzania), Kenya, and Botswana...."

The Situation Analysis Study of the family planning program in Kenya.

A new, relatively "quick and clean" operations research approach called a "situation analysis" was developed for examining the strengths and weaknesses of the family planning program of Kenya. Field research teams visited a stratified random sample of 99 of the Ministry of Health's approximately 775 service delivery points. Observation techniques and interviewing were used to collect information on program components and on the quality of care provided to new family planning clients during the observation day. As late as 1986, the Kenya program was rated "weak" and "poor" in the international literature. The Kenya Situation Analysis Study found a functioning, integrated maternal and child health/family planning program serving large numbers of clients, with an emphasis on oral contraceptives and Depo-Provera (and an underemphasis on permanent methods). Although a number of program problems were revealed by the study, overall, in terms of performance, a rating of "moderate" is suggested as more appropriate for Kenya's national family planning program today. In terms of the quality of care, a "moderate to moderate-high" rating is suggested.

PIP: In 1989, researchers conducted a situation analysis of 100 service delivery points (SDPs) in Kenya. They wanted to evaluate the usefulness of collecting and analyzing data on factors that influence the impact of family planning (FP). FP workers took a gynecological history and blood pressure on 96% of new clients and did a pelvic exam on 73%. 80 SDPs had Depo-Provera and foam tablets on hand and 85 had condoms. Even though the Ministry of Health had 8 varieties of oral contraceptives (OCs), not all SDPs had all types. 97 SDPs had the OC Microgynon, yet 24 had 10 cycles. 53 SDPs had at least 1 FP poster on the wall. 38 had charts or other educational aids. None provided educational material for the clients to take home with them. 32 SDPs had health talks and only 16 addressed FP. 1 on 1 client counseling made up somewhat for this lack of information (31% of clients interviewed reported the clinic as their 1st source of FP information). Yet the SDP workers often did not tell clients about contraindications, complications, and how to manage complications. Supervision was minimal. 87 SDPs kept records on FP clients. 81 SDPs had referred some women for FP services. Only 54% of the nurses and midwives attended the core 7 week training course in FP designed to certify them to deliver FP services. A mean of 9443 clients attended these SDPs each month. 71% used OCs, 19% Depo-Provera, 5% condoms, and 5% IUDs and foam. 94% of clients learned of 2+ methods at the SDPs, especially OCs and Depo-Provera. FP workers provided little information about sterilization. The researchers observed the quality of care indicators on an 1 client/clinic basis which probably biased the results in a positive direction. Nevertheless, FP workers did know how to provide acceptable good care. These results showed that the quality of FP in Kenya should be upgraded from weak and poor to moderate to moderately high.

Characteristics of new contraceptive acceptors in Zimbabwe.

This report examines the characteristics of all new acceptors entering the Zimbabwe National Family Planning Council (ZNFPC) program from 4-8 March 1985. During the study period, ZNFPC clinics and community-based distributors provided 3,269 new clients with modern family planning methods. More than half of the women were under the age of 25 years and had fewer than three living children. When asked why they were initiating the use of modern contraception, 90 percent of the women indicated that their intention was to space or delay the next pregnancy ("spacers"), while 10 percent indicated that they wished to stop reproduction ("stoppers"). A comparison of the two groups suggests that the average "spacer" among new acceptors is 24 years old and has 2.6 living children, of whom the youngest is 12.0 months, while the average "stopper" is 34 years old and has 6.2 living children, of whom the youngest is 25.9 months.