In vivo effects of HIV-1 exposure in the presence and absence of single-dose nevirapine on cellular plasma activation markers of infants born to HIV-1-seropositive mothers

Abstract

Short-course antiretroviral drug regimens reduce the risk of mother-to-child transmission of HIV-1, but mechanisms affording protection of such interventions remain poorly defined. Because T-cell activation is an important factor in productive HIV-1 infection, we tested the hypothesis that single-dose nevirapine (NVP) reduces immune activation, which in turn reduces the likelihood of transmission. We compared concentrations of cord and maternal blood plasma immune activation markers, neopterin, beta2-microglobulin, and soluble l-selectin, in 2 groups of HIV-1-exposed newborns whose mothers either received NVP at the onset of labor or who only received NVP as postexposure prophylaxis within 72 hours of birth and among HIV-unexposed controls. In utero exposure of the infant to HIV-1, regardless of NVP exposure, led to demonstrable increases in immune activation markers, this being most notable in the presence of preexisting infection. Contrary to what was hypothesized, immune activation was increased by prebirth exposure to single-dose NVP, with this effect being enhanced in infants already infected at birth. Our data suggest that reductions in immune activation do not explain transmission prevention effects of single-dose NVP. Our data also suggest a biological explanation for why HIV-1-infected infants exposed perinatally to antiretroviral drugs might experience hastened disease progression, namely, in some HIV-1-infected individuals, NVP may synergize with HIV-1 to enhance an environment that favors increased HIV-1 replication.

FIGURE 1

Levels of soluble immune activation markers in plasma of infants born to HIV-seronegative and HIV-seropositive mothers. A, Levels of neopterin (ng/mL) (i and iv), β₂-m (μg/mL) (ii and v), and sl-selectin (ng/mL) (iii and vi) of infants born to HIV-1 seropositive mothers in the absence (PEP) and in the presence (DART) of a single-dose of NVP, respectively. Immune activation marker levels measured in uninfected (control) infants are included. B, This panel depicts the effects of single-dose NVP exposure (DART) versus absence of NVP exposure (PEP) on the levels of neopterin (ng/mL), β₂-m (μg/mL), and sl-selectin (ng/mL) of infants who remained uninfected (EU) (i, ii, and iii, respectively) or who become infected IP (iv, v, and vi, respectively) or in utero (IU) (vii, viii, and ix, respectively). Data are presented as medians (horizontal bar), 25th and 75th percentiles (boxes), and 10th and 90th percentiles (bars). Significant differences between groups and sample numbers per group are indicated.

FIGURE 2

Levels of soluble immune activation markers of HIV-1–infected mothers grouped according to infection status of the infant and NVP exposure. A, Levels of neopterin (ng/mL), β₂-m (μg/mL), and sl-selectin (ng/mL) in uninfected (control) mothers and HIV-1–seropositive mothers who did not receive NVP (PEP group) and those who did receive NVP at the start of labor (DART group), grouped according to infection outcome of the infant (EU, IP, and IU). B, Comparison of the effects on levels of neopterin (ng/mL), β₂-m (μg/mL), and sl-selectin (ng/mL) of single-dose NVP exposure (DART) versus absence of NVP exposure (PEP) in HIV-1–seropositive mothers grouped according to infection status of the infant (EU, IP, or IU). Data are presented as medians (horizontal bar), 25th and 75th percentiles (boxes), and 10th and 90th percentiles (bars). Significant differences between groups and sample numbers per group are indicated.