Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation.
HIV establishes reservoirs of infected cells that persist despite effective antiretroviral therapy (ART). In most patients, the virus begins to replicate soon after treatment interruption. However, a low frequency of infected cells at the time of treatment interruption has been associated with delayed viral rebound. Likewise, individuals who control the infection spontaneously, so-called HIV-1 controllers (HICs), carry particularly low levels of infected cells. It is unclear, however, whether and how this small number of infected cells contributes to durable viral control. Here we compared 38 HICs with 12 patients on effective combined antiretroviral therapy (cART) and found that the low frequency of infected cells in the former subjects was associated both with less efficient viral reactivation in resting CD4(+) T cells and with less efficient virion production ex vivo We also found that a potent HIV-specific CD8(+) T cell response was present only in those HICs whose CD4(+) T cells produced virus ex vivo Long-term spontaneous control of HIV infection in HICs thus appears to be sustained on the basis of the inefficient reactivation of viruses from a limited number of infected cells and the capacity of HICs to activate a potent HIV-specific CD8(+) T cell response to counteract efficient viral reactivation events.



There is a strong scientific interest in developing strategies to eradicate the HIV-1 reservoir. Very rare HIV-1-infected patients are able to spontaneously control viremia for long periods of time (HIV-1 controllers [HICs]) and are put forward as a model of HIV-1 remission. Here, we show that the low viral reservoirs found in HICs are a critical part of the mechanisms underlying viral control and result in a lower probability of HIV-1 reactivation events, resulting in limited HIV-1 release and spread. We found that those HICs in whom viral reactivation and spread from CD4(+) T cells in vitro were the most difficult were those with diminished CD8(+) T cell responses. These results suggest that, in some settings, low HIV-1 reservoirs decisively contribute to at least the temporary control of infection without antiretroviral therapy. We believe that this work provides information of relevance in the context of the search for HIV-1 remission.
Université Paris Sud, UMR-1184, Paris, France.|CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Fontenay-aux-Rose, France.|INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, France.|APHP, Service de Médecine Interne-Immunologie Clinique, Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France.
Nicolas
N
Noel
AIDS Research Institute-IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Ruth
R
Peña
Institut Pasteur, Unité HIV Inflammation et Persistance, Paris, France.
Annie
A
David
APHP, Hôpital Necker, Service de Virologie, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, EA7327, Paris, France.
Veronique
V
Avettand-Fenoel
AIDS Research Institute-IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Itziar
I
Erkizia
AIDS Research Institute-IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Esther
E
Jimenez
Université Paris Sud, UMR-1184, Paris, France.|INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, France.
Camille
C
Lecuroux
APHP, Hôpital Necker, Service de Virologie, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, EA7327, Paris, France.
Christine
C
Rouzioux
INSERM, U1018, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France.
Faroudy
F
Boufassa
Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France.
Gianfranco
G
Pancino
Université Paris Sud, UMR-1184, Paris, France.
Alain
A
Venet
Service de Virologie Moléculaire, IBMM, Université Libre de Bruxelles (ULB), Gosselies, Belgium.
Carine
C
Van Lint
AIDS Research Institute-IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Universitat de Vic, Barcelona, Spain.|Institució Catalana de Recerca i EstudisAvançats (ICREA), Barcelona, Spain.
Javier
J
Martinez-Picado
Université Paris Sud, UMR-1184, Paris, France.|CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Fontenay-aux-Rose, France.|INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, France.|APHP, Service de Médecine Interne-Immunologie Clinique, Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France.
Olivier
O
Lambotte
Institut Pasteur, Unité HIV Inflammation et Persistance, Paris, France asier.saez-cirion@pasteur.fr jgarciaprado@irsicaixa.es.
Asier
A
Sáez-Cirión
AIDS Research Institute-IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain asier.saez-cirion@pasteur.fr jgarciaprado@irsicaixa.es.
Julia G
JG
Prado
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000254:growth & development / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
D019380:Anti-HIV Agents; D012367:RNA, Viral