A Single HIV-1 Cluster and a Skewed Immune Homeostasis Drive the Early Spread of HIV among Resting CD4+ Cell Subsets within One Month Post-Infection

Charline Bacchus (1) , Antoine Cheret (2, 3) , Véronique Avettand-Fenoël (3) , Georges Nembot (4) , Adeline Mélard (3) , Catherine Blanc (5) , Caroline Lascoux-Combe (6) , Laurence Slama (7) , Thierry Allegre (8) , Clotilde Allavena (9) , Yazdan Yazdanpanah (2) , Claudine Duvivier (10) , Christine Katlama (11) , Cécile Goujard (12) , Bao Chau Phung Seksik (13) , Anne Leplatois (14) , Jean-Michel Molina (6) , Laurence Meyer (4) , Brigitte Autran (1) , Christine Rouzioux (3)

1 Immunité et Infection
2 Centre Hospitalier Gustave Dron
3 Laboratoire de Virologie [CHU Necker]
4 CESP - Centre de recherche en épidémiologie et santé des populations
5 LUMIC-CYPS - Plateforme Cytométrie Pitié-Salpêtrière
6 Service de maladies infectieuses et tropicales [Saint-Louis]
7 CHU Tenon [AP-HP]
8 Centre Hospitalier du Pays d'Aix
9 Service de maladies infectieuses et tropicales [Nantes]
10 Centre d'infectiologie Necker-Pasteur [CHU Necker]
11 CHU Pitié-Salpêtrière [AP-HP]
12 Service de Médecine interne - Immunologie clinique [Kremlin-Bicêtre]
13 Services de Maladies Infectieuses et Tropicales [CHU Bichat]
14 Hôpital l'Archet

Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-foldless (p = 0.0005) than inequally infected TCM (4.5), TTM (4.7) and TEM(4.6) cells. CD32CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that subset activation and skewed immune homeostasis determine the conditions of viral dissemination and early establishment of the HIV reservoir.

Domaines: Maladies infectieuses; Virologie; Immunité adaptative

Charline Bacchus, Antoine Cheret, Véronique Avettand-Fenoël, Georges Nembot, Adeline Mélard, et al.. A Single HIV-1 Cluster and a Skewed Immune Homeostasis Drive the Early Spread of HIV among Resting CD4+ Cell Subsets within One Month Post-Infection. PLoS ONE, 2013, 8 (5), pp.e64219. ⟨10.1371/journal.pone.0064219⟩. ⟨hal-01535801⟩