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Objective: The factors associated with the development of immune reconstitution inflammatory syndrome in HIV patients commencing antiretroviral therapy have not been fully elucidated. Using a longitudinal study design, this study addressed whether alteration in the levels of T regulatory cells contributed to the development of IRIS in a West African cohort of HIV-1 and HIV-2 patients. Seventy-one HIV infected patients were prospectively recruited to the study and followed up for six months. The patients were categorized as IRIS or non-IRIS cases following published clinical guidelines. The levels of T regulatory cells were measured using flow cytometry at baseline and all follow-up visits. Baseline cytokine levels of IL-2, IL- 6, IFN-γ, TNF-α, MIP-1β, IL-1, IL-12, IL-13, and IL-10 were measured in all patients. Results: Twenty eight percent of patients (20/71) developed IRIS and were predominantly infected with HIV-1. Patients developing IRIS had lower nadir CD4 T cells at baseline (p = 0.03) and greater CD4 T cell reconstitution (p = 0.01) at six months post-ART. However, the development of IRIS was not influenced by the levels of T regulatory cells. Similarly, baseline cytokine levels did not predict the onset of IRIS. Conclusion: The development of IRIS was not associated with differences in levels of T regulatory cells or baseline proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

Background: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are persistent herpesviruses that have various immunomodulatory effects on their hosts. Both viruses are usually acquired in infancy in Sub-Saharan Africa, a region where childhood vaccines are less effective than in high income settings. To establish whether there is an association between these two observations, we tested the hypothesis that infection with one or both viruses modulate antibody responses to the T-cell independent meningococcal polysaccharide vaccine and the T-cell dependent measles vaccines. Methodology/Principal Findings: Infection with EBV and CMV was diagnosed by the presence of virus-specific IgM in the peripheral blood or by the presence of IgG at higher levels than that found in umbilical cord blood. Anti-meningococcus IgG and IgM were quantified by ELISA. Anti-measles antibody responses were quantified by haemagglutinin antibody inhibition assay. Infants infected with EBV had reduced IgG and IgM antibody responses to meningococcal polysaccharides and to measles vaccine. Infection with CMV alone predicted no changes in the response to meningococcal polysaccharide. While CMV alone had no discernable effect on the antibody response to measles, the response of infants infected with both CMV and EBV was similar to that of infants infected with neither, suggesting that the effects of CMV infection countered the effects of EBV on measles antibody responses. Conclusions: The results of this exploratory study indicate that infection with EBV is associated with reduced antibody responses to polysaccharides and to measles vaccine, but suggest that the response to T-cell dependent antigens such as measles haemagglutinin may be restored by infection with CMV. [ABSTRACT FROM AUTHOR]

Background: Detailed local HIV-1 sequence data are essential for monitoring the HIV epidemic, for maintaining sensitive sequence-based diagnostics, and to aid in designing vaccines. Results: Reported here are full envelope sequences derived from 38 randomly selected HIV-1 infections identified at a Gambian clinic between 1991 and 2009. Special care was taken to generate sequences from circulating viral RNA as uncloned products, either by limiting dilution or single genome amplification polymerase chain reaction (PCR). Within these 38 isolates, eight were subtyped as A and 18 as CRF02_AG. A small number of subtype B, C, D viruses were identified. Surprising, however, was the identification of six isolates with subtype J-like envelopes, a subtype found normally in Central Africa and the Democratic Republic of the Congo (DRC), with gag p24 regions that clustered with subtype A sequences. Near full-length sequence from three of these isolates confirmed that these represent a novel circulating recombinant form of HIV-1, now named CRF49_cpx. Conclusions: This study expands the HIV-1 sequence database from the Gambia and will provide important data for HIV diagnostics, patient care, and vaccine development. [ABSTRACT FROM AUTHOR]

Background: In a previously published study, we found that large differentiated subpopulations of CD8 T-cells emerged rapidly after CMV infection in young infants and persisted throughout the following year. Here we describe a follow-up study conducted on the same infants to establish whether the differentiated subpopulations continued through the second year post-infection. Methodology / Principal Findings: CMV-specific cells identified using tetramers remained more activated and differentiated than the overall CD8 population. The large subpopulation of differentiated cytotoxic (CD28-CD62L-Bcl-2lowCD95+perforin+) cells that emerged rapidly after infection remained stable after two years. No similar subpopulation was found in CMV-uninfected infants indicating that two years after infection, CMV remained a major factor in driving CD8 T-cell differentiation. Although markers of activation (CD45R0 and HLA-D) declined throughout the first year, HLA-D expression continued to decline during the second year and CD45R0 expression increased slightly. The age-related increase in IFNγ response observed during the first year continued but was non-significant during the second year, indicating that the rate of functional improvement had slowed substantially. Conclusions / Significance: The large differentiated subpopulations of CD8 T-cells that had emerged immediately after CMV infection persisted through the second year post-infection, while levels of activation and functional capacity remained fairly constant. [ABSTRACT FROM AUTHOR]

Background. Cytomegalovirus (CMV) is the most common congenital infection and can follow primary and recurrent maternal infection. We studied correlates of vertical transmission of CMV in The Gambia, where most children acquire CMV during the first year of life. Methods. A cohort of 281 mothers and infants was recruited at birth. Infants were prospectively followed up for CMV infection during the first year of life. Excretion of CMV and antiviral immune response were studied at birth in mothers of children infected in utero, early during infancy, or late during infancy or not infected at 1 year of age. Results. Congenital infection was diagnosed in 3.9% of newborns, and 85% of children were infected by 1 year. Excretion of CMV in colostrum or in the genital tract was more common in mothers of congenitally (100%) or early infected children (48%) than in mothers of late-infected (20%) or uninfected children (27%). Higher rates of viral excretion were associated with significantly higher levels of serum anti-CMV immunoglobulin G and higher frequencies of CMV-specific CD4+ T cells. Conclusion. In the context of recurrent maternal infection, transmission of CMV in utero and during early postnatal life is associated with excretion of the virus in colostrum and the genital tract. [ABSTRACT FROM AUTHOR]

Background:A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants. Trial Design:We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia. Methods:Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1. Results:From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive exvivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms. Conclusions:A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group. Trial Registration: ClinicalTrials.gov NCT00982579 The Pan African Clinical Trials Registry PACTR2008120000904116 [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection is endemic in Gambian infants, with 62% infected by 3 months and 85% by 12 months of age. We studied the CD8 T-cell responses of infants to CMV following primary infection. CMV-specific CD8 T cells, identified with tetramers, showed a fully differentiated phenotype (CD28- CD62L- CD95+ perforin+ granzyme A+ Bcl-2low). Strikingly, the overall CD8 T-cell population developed a similar phenotype following CMV infection, which persisted for at least 12 months. In contrast, primary infection was accompanied by up-regulation of markers of activation (CD45R0 and HLA-D) on both CMV-specific cells and the overall CD8 T-cell population and division (Ki-67) of specific cells, but neither pattern persisted. At 12 months of age, the CD8 T-cell population of CMV-infected infants was more differentiated than that of uninfected infants. Although the subpopulation of CMV-specific cells remained constant, the CMV peptide-specific gamma interferon response was lower in younger infants and increased with age. As the CD8 T-cell phenotype induced by CMV is indicative of immune dysfunction in the elderly, the existence of a similar phenotype in large numbers of Gambian infants raises the question of whether CMV induces a similarly deleterious effect. [ABSTRACT FROM AUTHOR]