The mechanisms by which HIV causes chronic lung disease (CLD), the most common complication in HIV- infected children, are poorly understood. Virus reservoirs persist in the lung despite long-term suppression of plasma viremia by traditional antiretroviral therapy (ART). Thus, it is important to specifically identify the cells hat harbor HIV during ART that promote inflammation and CLD. Our long-term goal is to inhibit or reverse development of CLD that arises despite ART in HIV-infected children. As a first step, the purpose of this proposal is to verify that macrophages, in addition to CD4+ T cells, serve as virus reservoir cells in the lung of SIV- infected newborns following ART. Our central hypothesis is that tissue macrophages are a major virus (SIV) reservoir very early after infection as well as during the transition from short-lived to longer-lived macrophages in tissues of SIV-infected newborn macaques that develop more rapid disease than adults. The rationale for our hypothesis is that (i) SIV infections in newborn macaques parallel the rapid disease progression observed in HIV-infected children, and (ii) in the primate model, the reservoir sites of SIV can be examined in finer detail and under more controlled experimental conditions than in HIV-infected humans. To fully understand the role of macrophages in the lung it becomes essential to study lung tissue rather than rely on BAL specimens that only contain AM. These studies will identify virus host cell reservoirs in ART-treated SIV-infected macaques that will guide future development of novel therapeutic strategies in HIV-infected children.
The aims are:
Aim 1. To define the magnitude of lung tissue damage of SIV-infected newborn macaques following ART initiated at different times post infection. Our working hypothesis is that virus infection in the ung of infected newborn macaques will be higher in monocyte/macrophage lineage cells early after SIV infection and will correlate with the magnitude of tissue damage. This is based on preliminary data showing earlier and higher virus infection rate in tissue macrophages of SIV-infected neonates. We also hypothesize that earlier initiation of ART after infection in neonates will decrease the pool of SIV-infected macrophage reservoirs more than later initiation of ART and that the size of the virus reservoir will dictate the severity of lung inflammation.
Aim 2. To determine if depletion of lung monocyte/macrophages or CD4+ T cells in SIV-infected new- born macaques undergoing effective ART reduces chronic inflammation in the lung. Our working hypothesis is that in vivo depletion of CD4+ cells (anti-CD4) in SIV-infected newborn macaques undergoing effective ART will directly demonstrate the contribution of CD4+ T cells (vs macrophages) in the pathogenesis of the lung tissue damage. Conversely, the in vivo depletion of alveolar macrophages (liposome-alendronate) of the lung of the SIV-infected newborn macaques undergoing effective ART will define the contribution of macrophages (vs. CD4+ T cells) to the lung pathogenesis.
Highly-active antiretroviral therapy (HAART) has dramatically reduced mother to child transmission and disease progression of HIV in developed countries, but the number of pediatric HIV-1 infections continues to increase worldwide, especially in developing countries. Chronic lung disease especially remains among the most commonly-observed conditions in HIV-infected children undergoing HAART. The goals of this study are of public health importance and will apply a nonhuman primate model of pediatric AIDS disease to determine specifically the cell(s) that act as lung viral reservoir that may be critical for the chronic inflammation of the lung of HIV infected children with HAART.
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