Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton.
Eradication of HIV-1 with highly active antiretroviral therapy (HAART) is not possible due to the persistence of long-lived, latently infected resting memory CD4(+) T cells. We now show that HIV-1 latency can be established in resting CD4(+) T cells infected with HIV-1 after exposure to ligands for CCR7 (CCL19), CXCR3 (CXCL9 and CXCL10), and CCR6 (CCL20) but not in unactivated CD4(+) T cells. The mechanism did not involve cell activation or significant changes in gene expression, but was associated with rapid dephosphorylation of cofilin and changes in filamentous actin. Incubation with chemokine before infection led to efficient HIV-1 nuclear localization and integration and this was inhibited by the actin stabilizer jasplakinolide. We propose a unique pathway for establishment of latency by direct HIV-1 infection of resting CD4(+) T cells during normal chemokine-directed recirculation of CD4(+) T cells between blood and tissue.
Cameron
Paul U
PU
Infectious Diseases Unit, Alfred Hospital, Melbourne, Victoria 3004, Australia.
Saleh
Suha
S
Sallmann
Georgina
G
Solomon
Ajantha
A
Wightman
Fiona
F
Evans
Vanessa A
VA
Boucher
Genevieve
G
Haddad
Elias K
EK
Sekaly
Rafick-Pierre
RP
Harman
Andrew N
AN
Anderson
Jenny L
JL
Jones
Kate L
KL
Mak
Johnson
J
Cunningham
Anthony L
AL
Jaworowski
Anthony
A
Lewin
Sharon R
SR
D000199:Actins / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology*; D002467:Cell Nucleus / Q000276:immunology; D018925:Chemokines / Q000276:immunology* / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019707:Receptors, Chemokine / Q000276:immunology; D016662:Virus Integration / Q000187:drug effects / Q000276:immunology*; D053586:Virus Internalization; D017735:Virus Latency / Q000276:immunology*; D014779:Virus Replication
D000199:Actins; D018925:Chemokines; D019707:Receptors, Chemokine