Publications

RP105, phylogenetically related to Toll-like receptor (TLR)-4, is reported to facilitate B cell activation by the TLR4-agonist lipopolysaccharide (LPS)--but to limit LPS-induced cytokine production by antigen-presenting cells. Here, we show that the role of RP105 extends beyond LPS recognition and that RP105 positively regulates macrophage responses to Mycobacterium tuberculosis (Mtb) lipoproteins. Mtb-infected RP105(-/-) mice exhibited impaired proinflammatory cytokine responses associated with enhanced bacterial burden and increased lung pathology. The Mtb 19 kDa lipoprotein induced release of tumor necrosis factor in a manner dependent on both TLR2 and RP105, and macrophage activation by Mtb lacking mature lipoproteins was not RP105 dependent. Thus, mycobacterial lipoproteins are RP105 agonists. RP105 physically interacted with TLR2, and both RP105 and TLR2 were required for optimal macrophage activation by Mtb. Our data identify RP105 as an accessory molecule for TLR2, forming part of the receptor complex for innate immune recognition of mycobacterial lipoproteins.

Defining the antiviral efficacy of CD8 T cells is important for immunogen design, and yet most current assays do not measure the ability of responses to neutralize infectious virus. Here we show that human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) clones and cell lines derived from infected persons and targeting diverse epitopes differ by over 1,000-fold in their ability to retard infectious virus replication in autologous CD4 T cells during a 7-day period in vitro, despite comparable activity as assessed by gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay. Cell lines derived from peripheral blood mononuclear cells stimulated in vitro with peptides representing targeted Gag epitopes consistently neutralized HIV better than Env-specific lines from the same person, although ineffective inhibition of virus replication is not a universal characteristic of Env-specific responses at the clonal level. Gag-specific cell lines were of higher avidity than Env-specific lines, although avidity did not correlate with the ability of Gag- or Env-specific lines to contain HIV replication. The greatest inhibition was observed with cell lines restricted by the protective HLA alleles B*27 and B*57, but stimulation with targeted Gag epitopes resulted in greater inhibition than did stimulation with targeted Env epitopes even in non-B*27/B*57 subjects. These results assessing functional virus neutralization by HIV-specific CD8 T cells indicate that there are marked epitope- and allele-specific differences in virus neutralization by in vitro-expanded CD8 T cells, a finding not revealed by standard IFN-gamma ELISPOT assay currently in use in vaccine trials, which may be of critical importance in immunogen design and testing of candidate AIDS vaccines.

BACKGROUND

Worldwide, mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV) represents the most common means by which children acquire HIV infection. Efficacious and effective interventions to prevent in utero and intrapartum transmission of HIV infection have been developed and implemented. However, a large proportion of MTCT of HIV occurs postnatally, through breast milk transmission.

OBJECTIVES

The objectives of this systematic review were to collate and assess the evidence regarding interventions to decrease late postnatal MTCT of HIV, and to determine the efficacy of such interventions in decreasing late postnatal MTCT of HIV, increasing overall survival, and increasing HIV-free survival.

SEARCH STRATEGY

Electronic searches were undertaken using PubMed, EMBASE and other databases for 1980-2008. Hand searches of reference lists of pertinent reviews and studies, as well as abstracts from relevant conferences, were also conducted. Experts in the field were contacted to locate any other studies. The search strategy was iterative.

SELECTION CRITERIA

Randomized clinical trials assessing the efficacy of interventions to prevent MTCT of HIV through breast milk were included in the analysis. Other trials and intervention cohort studies with relevant data also were included, but only when randomization was not feasible due to the nature of the intervention (i.e., infant feeding modality).

DATA COLLECTION AND ANALYSIS

Data regarding HIV infection status and vital status of infants born to HIV-infected women, according to intervention, were extracted from the reports of the studies.

MAIN RESULTS

Six randomized clinical trials and one intervention cohort study were included in this review. Two trials addressed the issue of shortening the duration of (or eliminating) exposure to breast milk. In a trial of breastfeeding versus formula feeding, formula feeding was efficacious in preventing MTCT of HIV (the cumulative probability of HIV infection at 24 months was 36.7% in the breastfeeding arm and 20.5% in the formula arm [p = 0.001]), but the mortality and malnutrition rates during the first two years of life were similar in the two groups. In a trial of early cessation of breastfeeding, HIV-free survival was similar between those children who ceased breastfeeding around four months of age and those who continued breastfeeding. Another trial addressing vitamin supplementation found more cases of HIV infection among children of mothers in the vitamin A arm. Efficacy for other vitamin supplements was not shown. An intervention cohort study evaluated the risk of MTCT according to infant feeding modality, and found increased risks of MTCT among breastfed children who also received solids (hazard ratio = 10.87, p = 0.018) as well as higher 3-month mortality rates (hazard ratio = 2.06) among infants given non- breast milk feedings (instead of exclusive breastfeeding). Three trials evaluated antiretroviral prophylaxis to breastfeeding infants. One trial found that breastfeeding with zidovudine prophylaxis (transmission rate = 9.0%) was not as effective as formula feeding (transmission rate 5.6%) in preventing late postnatal HIV transmission (p = 0.04). Breastfeeding with zidovudine prophylaxis and formula feeding had comparable HIV-free survival rates at 18 months (p = 0.60). Two trials of extended nevirapine prophylaxis demonstrated efficacy. In the first (data combined from trials conducted in three different countries), a six-week course of nevirapine resulted in a lower risk of HIV transmission by six weeks of age (p=0.009), but not at six months of age (p = 0.016). In the second, nevirapine administration until 14 weeks of age (5.2%) or nevirapine with zidovudine until 14 weeks of age (6.4%) resulted in significantly lower risks of MTCT of HIV by 9 months of age than a control regimen of peripartum prophylaxis (10.6%) (p < 0.001). HIV-free survival was significantly better through the age of 9 months in both extended prophylaxis groups, and through the age of 15 months in the extended nevirapine group.

AUTHORS' CONCLUSIONS

Complete avoidance of breastfeeding is efficacious in preventing MTCT of HIV, but this intervention has significant associated morbidity (e.g., diarrheal morbidity if formula is prepared without clean water). If breastfeeding is initiated, two interventions 1). exclusive breastfeeding during the first few months of life; and 2) chronic antiretroviral prophylaxis to the infant (nevirapine alone, or nevirapine with zidovudine) are efficacious in preventing transmission.