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 May 14;8(5):e64219. doi: 10.1371/journal.pone.0064219. Print 2013.

Abstract

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-fold less (p = 0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3-CD4+ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / virology*
  • DNA, Viral / metabolism
  • Female
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / physiology*
  • Homeostasis / immunology*
  • Humans
  • Male
  • Middle Aged
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / virology*
  • Time Factors
  • Viral Load / immunology
  • Young Adult

Substances

  • DNA, Viral

Grants and funding

This research was funded by the National French Agency on AIDS Research (Agence Nationale de Recherche sur le Sida, http://www.anrs.fr/), and supported by Merck Sharp & Dohme, Jansen, ViiV Healthcare and Gilead. C. Bacchus received a predoctoral fellowship from Pierre and Marie Curie University. The funders and supporters had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.