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