Publication Abstract Display | Type: Published Abstract | Title: Divergent evolution of phenotypic antiretroviral susceptibility of HIV isolated from cerebrospinal fluid and plasma. | Authors: Letendre SL, Paxinos E, Wong J, Petropoulos C, Whitcomb J, Galovich J, Hellmann N, McCutchan JA, Ellis RJ | Year: 2002 | Publication: Antiviral Therapy | Volume: 7 Issue: Suppl 1 Pages: 66 | Abstract:BACKGROUND: HIV strains isolated from immuneprivileged
sites, such as the central nervous system
(CNS), can differ in env, gag, and pol compared with
those from other tissues. Differences in pol may have
important clinical consequences since many antiretrovirals
(ARVs) poorly penetrate the blood-brain barrier.
For example, subtherapeutic ARV concentrations in
the CNS might accelerate development of resistant
strains in the CNS. Conversely, HIV evolution in the
CNS may be restricted in the relative absence of ARV
and immune pressures, maintaining wild-type strains
that are more susceptible, rather than more resistant,
than those in plasma. This alternative would explain
observations that therapy can suppress HIV replication
in cerebrospinal fluid (CSF) even when it fails to do so
in plasma.
METHODS: To define inter-compartmental HIV
differences, we serially sample plasma and CSF in
individuals initiating or interrupting ARV therapy. After
a change in therapy, matched blood and CSF samples
are obtained within an hour interval up to nine times
over 12 weeks. Each subject’s primary medical provider
selects their ARV regimen. This report describes the
course of an illustrative participant following interruption
(TI) and re-initiation of zidovudine-lamivudine-nelfinavir.
HIV RNA was measured by the RT-PCR (Roche
Amplicor). Susceptibility to ARVs was measured with
phenotype resistance testing (PRT, ViroLogic
PhenoSense). Population genotyping was performed
using GeneSeq HIV. Phylogenetic relationships were
analysed using maximum parsimony and maximum
likelihood methods.
RESULTS: The subject interrupted therapy with HIV
RNA levels of 6973 in plasma and <50 in CSF. Six
matched pairs obtained over 82 days demonstrated that HIV replication peaked at 72 457 in plasma after
16 days and at 41 081 in CSF after 47 days. Baseline
PRT indicated reduced susceptibility to abacavir,
lamivudine and nelfinavir in plasma. Strains isolated
from plasma and CSF had concordant phenotypes
16 days after TI. Susceptibility patterns diverged
47 days post-TI: the original pattern persisted in plasma
but a new pattern was observed in CSF, demonstrating
susceptibility to all drugs. Phylogenetic analysis indicated
that the strains from CSF were monophyletic. Reinitiation
of therapy resulted in suppression of replication
in CSF, but not in plasma.
CONCLUSIONS: Antiretroviral therapy susceptibility
of HIV strains isolated from plasma and CSF can
diverge during TI and may predict subsequent therapeutic
response. In CSF, HIV replication returned more
slowly but, paradoxically, reversion to strains with wildtype
susceptibility occurred more quickly. Emergence of
a monophyletic, fully susceptible strain in CSF, but not
in plasma, suggests derivation from an archived CNS
source. CNS-specific selection pressures may favour
replication of such wild-type strains, which may explain
why HIV replication is more readily suppressed there.
By suppressing HIV replication in the CNS even when it
fails in plasma, ARV therapy may have neuroprotective
benefits in patients with few treatment options. |
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