Intrinsic resistance to HIV-1 of macrophages and CD4+ T cells from HIV controllers
Background:
How HIV
controllers (HIC) maintain undetectable viremia without therapy is unknown. The strong CD8+ T cell HIV
suppressive capacity found in many, but not all, HIC may contribute to long
lasting viral control. However, other earlier defence mechanisms may be involved. Here we
examined intrinsic HIC cell resistance to HIV-1 infection.
Methods:
50 HIC from the ANRS CO18 cohort, 43 healthy
donors (HD), 9 chronic viremic patients (VIR) and 12 HAART treated patients
(ART) were included. The susceptibility to HIV-1 infection of monocyte-derived macrophages
(MDM) and anti-CD3-activated CD4+ T cells was assessed by p24ELISA in
supernatants, single-round luciferase-reporter HIV-1 particles or
qPCR assay of integrated forms. Ultrasensitive cell
associated HIV-1 DNA assays was done by real-time PCR. Expression of cellular
factors was evaluated by PCR and western blot. siRNA transfection was
performed by Nucleofection. Mann-Whitney test was used.
Results:
After in vitro challenge, monocyte-derived macrophages
(p=0.003) and anti-CD3-activated CD4+ T cells (p< 0.0001)
from HIC showed low HIV-1 susceptibility. CD4 T cell resistance was
independent of HIV-1 coreceptors and affected also SIVmac infection (P=0.006). CD4+ T cells (but not
macrophages) from HIC expressed ex vivo higher levels of p21Waf1/Cip1,
which has been involved in the control of HIV-1 replication, than cells from
control subjects. However, HIV restriction in anti-CD3-activated CD4+ T cells
and macrophages was not associated to p21 expression. Restriction
affected preintegrative
steps of HIV-1 replication and could
be overcome by conditions enhancing infection (such as spinoculation and high
cell density), suggesting the action of a saturable mechanism. Importantly, cell-associated HIV-1
DNA load was extremely low in HIC (1.45 log copies/106
PBMC) and correlated with
CD4+ T cell permissiveness to infection (Spearman
0.45, p=0.041; n=21).
Conclusion:
Our results point to a contribution of
intrinsic cell resistance to the control of infection and the containment of viral reservoir in HIC.
A. Saez-Cirion1, C. Hamimi1, A. Bergamaschi1, A. David1, P. Versmisse1, A. Mélard2, F. Boufassa3, F. Barré-Sinoussi1, O. Lambotte4,5, C. Rouzioux2,6, G. Pancino1, ANRS CO18 cohort
1Institut Pasteur, Unite de Regulation des Infections Retrovirales, Paris, France, 2AP-HP, CHU Necker-Enfants Malades, Laboratoire de Virologie, Paris, France, 3Inserm U1018, Hôpital Bicêtre, Le Kremlin-Bicêtre, France, 4Inserm U1012, Le Kremlin-Bicêtre, France, 5AP-HP, Hôpital Bicêtre, Service de Médecine Interne et Maladies Infectieuses, Le Kremlin-Bicêtre, France, 6Université Paris-Descartes, Faculté de Médecine, Paris, France