Regulatory T Cell Suppression of Gag-Specific CD8+ T Cell Polyfunctional Response After Therapeutic Vaccination of HIV-1-Infected Patients on ART

We tested the hypothesis that therapeutic vaccination against HIV-1 can increase the frequency and suppressive function of regulatory, CD4+ T cells (Treg), thereby masking enhancement of HIV-1-specific CD8+ T cell response. HIV-1-infected subjects on antiretroviral therapy (N = 17) enrolled in a phase I therapeutic vaccine trial received 2 doses of autologous dendritic cells (DC) loaded with HIV-1 peptides. The frequency of CD4+CD25hiFOXP3+ Treg in blood was determined prior to and after vaccination in subjects and normal controls. Polyfunctional CD8+ T cell responses were determined pre- and post-vaccine (N = 7) for 5 immune mediators after in vitro stimulation with Gag peptide, staphylococcal enterotoxin B (SEB), or medium alone. Total vaccine response (post-vaccine–pre-vaccine) was compared in the Treg(+) and Treg-depleted (Treg-) sets. After vaccination, 12/17 subjects showed a trend of increased Treg frequency (P = 0.06) from 0.74% to 1.2%. The increased frequency did not correlate with CD8+ T cell vaccine response by enzyme linked immunosorbent assay for interferon γ production. Although there was no significant change in CD8+ T cell polyfunctional response after vaccination, Treg depletion increased the polyfunctionality of the total vaccine response (P = 0.029), with a >2-fold increase in the percentage of CD8+ T cells producing multiple immune mediators. In contrast, depletion of Treg did not enhance polyfunctional T cell response to SEB, implying specificity of suppression to HIV-1 Gag. Therapeutic immunization with a DC-based vaccine against HIV-1 caused a modest increase in Treg frequency and a significant increase in HIV-1-specific, Treg suppressive function. The Treg suppressive effect masked an increase in the vaccine-induced anti-HIV-1-specific polyfunctional response. The role of Treg should be considered in immunotherapeutic trials of HIV-1 infection

Fear of Birth Defects Is a Major Barrier to Soil-Transmitted Helminth Treatment (STH) for Pregnant Women in the Philippines

The World Health Organization recommends anthelminthic treatment for pregnant women after the first trimester in soil-transmitted helminth (STH) endemic regions to prevent adverse maternal-fetal consequences. Although studies have shown the high prevalence of infection in the Philippines, no research has evaluated deworming practices. We hypothesized that pregnant women are not receiving deworming treatment and we aimed to identify barriers to World Health Organization guideline implementation. We conducted key informant interviews with local Department of Health (DOH) administrators, focus group discussions with nurses, midwives, and health care workers, and knowledge, attitudes, and practices surveys with women of reproductive age to elicit perspectives about deworming during pregnancy. Key informant interviews revealed that healthcare workers were not deworming pregnant women due to inadequate drug supply, infrastructure and personnel as well as fear of teratogenicity. Focus group discussions showed that healthcare workers similarly had not implemented guidelines due to infrastructure challenges and concerns for fetal malformations. The majority of local women believed that STH treatment causes side effects (74.8%) as well as maternal harm (67.3%) and fetal harm (77.9%). Women who were willing to take anthelminthics while pregnant had significantly greater knowledge as demonstrated by higher Treatment Scores (mean rank 146.92 versus 103.1, z = −4.40, p<0.001) and higher Birth Defect Scores (mean rank 128.09 versus 108.65, z = −2.43, p = 0.015). This study concludes that World Health Organization guidelines are not being implemented in the Philippines. Infrastructure, specific protocols, and education for providers and patients regarding anthelminthic treatment are necessary for the successful prevention of STH morbidity and mortality among pregnant women

Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy – ACTG A5286

Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART)

Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART

Fear of Birth Defects Is a Major Barrier to Soil- Transmitted Helminth Treatment (STH) for Pregnant Women in the Philippines

Abstract The World Health Organization recommends anthelminthic treatment for pregnant women after the first trimester in soiltransmitted helminth (STH) endemic regions to prevent adverse maternal-fetal consequences. Although studies have shown the high prevalence of infection in the Philippines, no research has evaluated deworming practices. We hypothesized that pregnant women are not receiving deworming treatment and we aimed to identify barriers to World Health Organization guideline implementation. We conducted key informant interviews with local Department of Health (DOH) administrators, focus group discussions with nurses, midwives, and health care workers, and knowledge, attitudes, and practices surveys with women of reproductive age to elicit perspectives about deworming during pregnancy. Key informant interviews revealed that healthcare workers were not deworming pregnant women due to inadequate drug supply, infrastructure and personnel as well as fear of teratogenicity. Focus group discussions showed that healthcare workers similarly had not implemented guidelines due to infrastructure challenges and concerns for fetal malformations. The majority of local women believed that STH treatment causes side effects (74.8%) as well as maternal harm (67.3%) and fetal harm (77.9%). Women who were willing to take anthelminthics while pregnant had significantly greater knowledge as demonstrated by higher Treatment Scores (mean rank 146.92 versus 103.1, z = 24.40, p,0.001) and higher Birth Defect Scores (mean rank 128.09 versus 108.65, z = 22.43, p = 0.015). This study concludes that World Health Organization guidelines are not being implemented in the Philippines. Infrastructure, specific protocols, and education for providers and patients regarding anthelminthic treatment are necessary for the successful prevention of STH morbidity and mortality among pregnant women

Comparison of Immunologic Assays for Detecting Immune Responses in HIV Immunotherapeutic Studies: AIDS Clinical Trials Group Trial A5181▿

This study was designed to evaluate which of several T-cell-specific, immune response assays are the most relevant in measuring the key characteristics of an effective immune response to HIV-1. Using 5 HIV-1 antigens as stimulants, we assessed lymphocyte proliferation, supernatant gamma interferon (IFN-γ) cytokine production (CP), single-cell IFN-γ production by enzyme-linked immunospot (ELISPOT) assay, with and without Epstein-Barr virus-transformed B-lymphoblastoid cell lines (B-LCLs), and intracellular cytokine production (ICC) for IFN-γ and interleukin 2 (IL-2) by flow cytometry. We used these to compare specimens from HIV-1-infected subjects who were virally suppressed with a stable antiretroviral therapy (ART) regimen (group A) with specimens from subjects not on ART but with HIV-1 viremia of <3,000 copies/ml (group B). The lymphocyte proliferation assay (LPA) did not significantly differentiate between the two groups. Using fresh peripheral blood mononuclear cells (PBMCs), the CP and ELISPOT assays for IFN-γ detected the greatest differences between the two groups, specific for three of the five HIV-1 antigens, whereas significant differences were seen only in response to one antigen when cryopreserved cells were used. The strongest correlations were seen between the CP and ELISPOT assays. The ELISPOT B-LCL assay showed a cell concentration-dependent increase in IFN-γ production compared to that shown by the standard ELISPOT assay but did not differentiate between the groups. In the ICC assay, greater numbers of IFN-γ-producing T cells were seen in group B, and little or no detectable IL-2 production was seen in both groups. These studies highlight complexities of immunologic monitoring of T-cell responses in multisite clinical trials in HIV infection and outline considerations for optimizing these efforts

STH Treatment for Pregnant Women: Perspectives of Health Care Providers.

<p>The National STH Coordinator, Regional STH Coordinator, and municipal health officers (MHOs) provided their perspectives during key informant interviews (KIIs). Nurses, midwives, and barangay health workers provided data during focus group discussions (FGDs).</p

Comparison of CD45RO, FOXP3, GITR, and CTLA4 expression.

<p>The mean percentage expression in CD4⁺CD25^HI T cells was compared among normal control (NC; N = 10) and the HIV-1-infected subjects pre- and post-vaccine (N = 17). CD4⁺CD25^HI expression of GITR and CTLA4 in HIV-1-infected subjects (pre- and post-vaccine) was higher than in NC. (P<0.01)</p

Gating of Treg in representative subjects.

<p>Shown above is the gating used to determined the Treg frequency in a representative normal control (A) and an HIV-1-infected subject, pre-vaccine (B). The Treg population was defined as CD3⁺CD4⁺CD25^HIFOXP3⁺.</p