The reduction with antiretroviral therapy (ART) of HIV RNA in blood, and HIV RNA in infected
cells and in viruses associated with the follicular dendritic cell (FDC) network in lymphatic
tissues, typically follows a two-phase pattern of decline. The half-life of the first-phase
is about 1 day and that of the second phase is about 14 days, with comparable estimates for
first-phase decay in SIV-infected rhesus macaques.
While substantial evidence supports the current view that first-phase decay reflects the
death of activated CD4+ T cells infected before ART was begun, the sources of viral RNA in
the second phase have not as yet been conclusively established. Possible sources of viral RNA
that have been invoked in mathematical models, or for which there is experimental evidence,
include longer-lived infected cells such as macrophages and resting CD4+ T cells,
dissociation of virus from the FDC network, and productively infected CD4+ T cells that are
not subject to clearance by host immune responses because of waning levels of HIV antigen.
Raltegravir (MK-0518) belongs to a new class of integrase inhibitors that potently suppress
HIV and SIV replication, and reportedly markedly alters the second phase HIV decline in a way
that challenges the current view that longer-lived infected cells are the source of virus in
this phase. While mathematical modeling of decay of HIV RNA in blood was most consistent with
1) cells newly infected by long-lived cells, or 2) from activation of latently infected cells
with full-length unintegrated HIV DNA as a source of second phase virus, we think the data
are also quite consistent with the greater efficacy of integrase inhibitors in a particular
cell type and/or anatomic site such as the gut.
In this protocol we will test the hypothesis that the rapid decrease in HIV replication
associated with raltegravir is due to a more complete suppression of viral replication in
lymphatic compartments such as lymph nodes and gastrointestinal lymphatic tissue. We will
also investigate compartment-specific intracellular levels of raltegravir to potentially
explain differences in changes in these compartments.
Phase:
N/A
Details
Lead Sponsor:
University of Minnesota University of Minnesota - Clinical and Translational Science Institute