We found that HIV-1 specific antigen responses were stronger and broader in HESN neonates/infants at the time nearest to birth, and decayed both in magnitude and breadth as time from birth progressed. This observation reinforces previous studies showing that neonates can mount a vigorous virus-specific response at the time of birth or shortly thereafter. Although we contend that the decay in the magnitude and breadth of HIV-1 antigen specific immune response in these HESN infants is due to the absence of viral antigens, we cannot rule out an effect from post-partum ZDV exposure, or the emergence of a regulatory immune cell population, which might suppress HIV-1 specific immune responses.
Previous studies have measured decay rates for HIV-1 and CMV specific epitopes in eight treatment naïve HIV-1 infected adults initiating HAART (Casazza et al., 2001
). In that study, a rapid decline was observed in HIV-1 specific CD8+ T cell responses at HAART initiation, with a subsequent rebound in HIV-1 specific CD8+ T cell responses during treatment interruptions. The authors concluded that the decrease in HIV-1 CD8+ T cell responses represented a normal memory response to the withdrawal of HIV-1 antigen by HAART and calculated a median half-life rate of decay of 38
weeks (Casazza et al., 2001
). This was much longer than the median decay rate of 45
days previously measured in a cohort of treated HIV-1 infected adults (Ogg et al., 1999
), a value that may specifically reflect an early, rapid phase of decay of T cell responses after HAART initiation. This might be followed by a much slower decay rate, which would markedly influence the calculation of the aggregate or overall decay rate. The kinetics of decay observed in HESN infants is not similar to that in adults, which may be accounted for by the presence of replicating virus in adult cohorts, where virus replication cannot be demonstrated in these uninfected children. Previous studies with breast-feeding permitted in prenatal care guidelines, have documented robust HIV-1 specific CD4+ T helper responses in HIV-1 exposed uninfected newborns. Such T helper responses could extend the activity of IFN-γ secreting HIV-1 specific CTLs, which in turn may protect against post-partum infection.
The ability of HESN infants to mount a memory mucosal immune response was not addressed in our study due to the prohibiting of breast-feeding. Future studies of breast-fed HESN infants could address the persistence of memory CTL responses in the absence of viral replication or antigen presentation. Such data could further address differences in the immune responses between adults and children. It is interesting to observe measurable HIV-1 specific T cell responses in infants whom are likely to have had minimal exposure to HIV-1 antigen (the majority of mothers were on ARV treatment), but it also points to the possibility of a low dose virus stimulus for a higher HIV-1 specific T cell response. We have used the standardized nomenclature of HESN, but we do not know the true viral burden that these infants were exposed to. It would have been desirable to study the decay of responses to other antigens, and to study an unexposed infant cohort, but due to limited cell numbers, and ethical difficulties in obtaining serial samples from healthy infants, these studies were not performed. We also cannot definitely establish whether the T cells have redistributed out of the blood, or have the capacity to be reactivated. Another reason for the apparent decline could be simply a change in functionality from interferon-γ production to a resting population with more proliferative capacity and less immediate effector function.
In summary, our results support previous reports of HIV-1 specific T cell responses in HESN infants and the dynamic nature of T cell immunity in the context of a developing immune system. If HIV-1 specific T cell responses are contributing to protection against infection in neonates, our data supports a therapeutic vaccine approach to boost responses over the time an infant would be breast-fed. Our calculated rate of decay in these HESN infants was not comparable to that measured in adults starting antiretroviral therapy, suggesting that the natural rate of decay of antigen specific T cell sub-populations may be a significant contributor to the overall kinetics of antigen responses in addition to continued antigenic exposure.