Recent studies have estimated the kinetics of HIV-1 replication in infected individuals and defined the central role of HIV-1 replication in pathogenesis of HIV-1 infection (15
). The present study was undertaken to evaluate the potential for long-term suppression of viral replication following early therapy of vertical infection and to determine the immune consequences of such therapies.
Infants constitute an ideal population for studies investigating the virologic and immunologic consequences of early, potent combination therapies. Since the vertical transmission of HIV-1 from a woman to her infant is the predominant mode of pediatric HIV-1 infection, infants at risk can be readily identified and evaluated for HIV-1 infection. Available data suggest that the majority of infants acquire HIV-1 infection at delivery (14
). This, along with the ability to diagnose HIV-1 infection in the majority of infected infants within the first 4 weeks of life (20
), allows the identification and therapy of infants within days to weeks of acquiring infection.
In this cohort of infants who began antiretroviral therapy within 3 months of birth, early combination therapy was associated with a loss of plasma viremia and labile extrachromosomal replication intermediates. HIV-1 provirus has been persistently detected in the PBMC of all infants. However, limited availability of PBMC from these infants has precluded large-scale virus cocultivation to evaluate the replication competence of the detected provirus. Despite apparently normal immune systems, most infants did not develop persistent HIV-1-specific immune responses. Altogether, our data suggest that early, potent combination therapy may allow extremely stringent, if not complete, control of viral replication.
The lack of persistently detectable HIV-1 specific immune responses in these infants was surprising given the high levels of plasma virus (median, 105.3 RNA copies/ml) that were detected prior to therapy; in addition, plasma HIV-1 RNA was detected in most infants by ultrasensitive assay for up to 68 weeks. Plasma RNA presumably represented replicating virus and therefore should have served as an appropriate stimulus for both humoral and cell-mediated immune responses; however, even a nonreplicating source of antigen should have evoked antibody responses.
The lack of persistent HIV-1-specific immune responses in infants contrasts with the persistent HIV-1-specific immune responses reported in adults who receive combination antiviral therapy within 3 to 4 months of acquisition of infection (22
). Several investigators (22
) have reported persistently detectable HIV-1-specific CD4 T-lymphocyte responses in adults who received combination therapy during primary infection and have suggested that early, aggressive treatment of primary infection may facilitate the generation of these responses. While some groups have reported reduced antibody (25
) and CTL (23
) responses in adults treated during primary infection, the lack of persistently detectable responses is unusual (8
Clonal deletion of CD8+
T cell responses in the presence of very high levels of antigen has been previously reported in the context of acute murine lymphocytic choriomeningitis virus infection (26
). At least two lines of evidence argue against clonal deletion in our study population. First, the detection of HIV-1-specific antibody and lymphoproliferative responses in the peripheral blood of infant P-3742 following the breakthrough in viral replication argues against clonal deletion of HIV-1-reactive CD4 T lymphocytes. Additionally, the persistent detection of antibody and CD8 T-lymphocyte-mediated, HIV-1-specific CTL responses (4
) in infants with uncontrolled viral replication argues against this.
The paucity of persistently detectable HIV-1-specific immune responses despite prolonged plasma viremia suggests that there may be a period during which the generation of immune responses is inefficient in infants. These data are compatible with prior data from our laboratory (18
) and others (11
) suggesting a reduced ability to generate virus-specific immune responses in young infants. This might be due to a reduced efficiency of antigen presentation by infant dendritic cells (particularly to naïve T lymphocytes (33
) or to a diminished ability of infant lymphocytes to produce factors, such as cytokines (36
), important for the generation and maintenance of cell-mediated immunity. Suppression of viral replication during this period of relative immunological immaturity might critically limit the priming and expansion of virus-specific immune responses.
The development of normal antibody and cell-mediated immune responses to vaccine antigens (e.g., tetanus) or other viral (e.g., EBV) infections in these infants suggests that HIV-1-specific immune responses are particularly impaired. Factors that could contribute to this include the acquisition of infection in the presence of high titers of passively acquired, maternal HIV-1-specific antibodies and/or the selective depletion of HIV-1-specific CD4 T cells through the cytopathic effects of the virus or other mechanisms. Studies to better understand the factors that influence the generation of HIV-1-specific immune responses in these infants are under way. These studies include assays that detect intracellular cytokines in CD4 T lymphocytes by flow cytometry following in vitro stimulation, which appear to be more sensitive than lymphoproliferative assays for the detection of HIV-1-specific CD4 T-lymphocyte responses (29
; A. C. McNeil, W. L. Shupert, J. A. Mican, and M. Connors, presented at the 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, Calif., 30 January–2 February 2000).
In summary, early, potent combination antiretroviral therapy of HIV-1-infected infants allowed the long-term suppression of viral replication and preservation of immune function. In contrast to what is typically seen in adults treated early, persistent HIV-1-specific immune responses were not detected in most infants. The absence of detectable, persistent HIV-1-specific immune responses suggests that vaccine-induced, HIV-specific immune responses may be helpful in further controlling the virus early in life.