less
susceptible to ENF, whereas low R5 co-receptor expression favours response
to ENF. We previously found in patients on ENF a significant CD4 T cell
recovery despite virological failure and selection of resistant viruses (AIDS
2002; 16:1959–1961). Herein, we report the evolution of gp41-genotypes
along 80 weeks of ENF therapy in these patients and determine the mechanisms
underlying their CD4 T cell gain.
METHODS:
Four heavily antiretroviral-experienced patients with
genotypic/phenotypic resistance to both protease/perverse transcriptase
inhibitors enrolled in the Phase III clinical trial of ENF (TORO 2) were
studied. Pol and gp41 sequences from each patient were analysed at baseline
and every 2 months thereafter. Plasma viraemia, CD4 T cell counts, .32-ccr5,
sincytium- induced (SI) virus phenotype, proportion of clones harbouring ENF
resistance mutations, activation markers and apoptosis in naive and memory T
cells, T cell turnover, HIV-specific CD8 responses and TRECs were examined.
Cellular origin of plasma HIV particles was investigated. Patients with
similar characteristics not exposed to ENF were used as controls.
RESULTS:
All patients experienced a significant viral load drop after beginning
ENF therapy (>1 log) but rebounded shortly thereafter; high levels of plasma
viraemia have persisted since then. HR1 mutations were selected at failure
in all cases (N43D in three subjects
and G36V/D in another) and persisted in most of the clones examined along 80
weeks. No other changes associated with resistance appeared within HR1
during follow-up. Multiple polymorphisms in HR2 were observed in viruses
from all these subjects. All patients were wild-type homozygous for ccr5.
A net gain in the CD4 count of 69, 71, 221 and 510 CD4 cells/µl was
seen in all of them despite virological failure. A significant lower immune
response (low level of activation, CTL reactivity and T cell turnover) was
found in ENFtreated patients compared to controls. Moreover, a higher
percentage of naive T cells was found in subjectson ENF. A patient showed a
shift from X4 to R5 viruses, being on ENF, and experienced the greatest CD4
T cell rise. At the end of follow-up, all ENF-treated patients harboured R5
NSI viruses.
CONCLUSIONS:
A single mutation within HR1 (aa 36–45) results in virological failure
to ENF. Individuals on ENF may experience CD4 T cell rises despite
virological failure due to a redistribution of CD4 T cells, hypothetically
driven by low levels of T cell activation. Furthermore, selection of R5
viruses by ENF may result in a lower HIV deleterious effect on thymic
function.
