Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence.
Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of treatment and to identify cells replenished by ongoing replication. Decay rates of subsets of latently HIV-infected cells paradoxically decreased with time since establishment, reflecting heterogeneous lymphocyte activation and clearance. Residual low-level replication can replenish cellular reservoirs; however, it does not account for prolonged clearance rates in patients without detectable viremia. In patients receiving potent antiretroviral therapy, the latent pool has a heterogeneous and dynamic composition that comprises a progressively increasing proportion of stable lymphocytes. Eradication will not be achieved with complete inhibition of viral replication alone.
Strain
M C
MC
Department of Medicine and Pathology, University of California at San Diego, La Jolla, CA 90293, USA.
Günthard
H F
HF
Havlir
D V
DV
Ignacio
C C
CC
Smith
D M
DM
Leigh-Brown
A J
AJ
Macaranas
T R
TR
Lam
R Y
RY
Daly
O A
OA
Fischer
M
M
Opravil
M
M
Levine
H
H
Bacheler
L
L
Spina
C A
CA
Richman
D D
DD
Wong
J K
JK
D023241:Antiretroviral Therapy, Highly Active; D002470:Cell Survival; D004279:DNA, Viral / Q000097:blood / Q000235:genetics; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000473:pathology* / Q000821:virology*; D017354:Point Mutation; D013997:Time Factors; D014766:Viremia / Q000097:blood / Q000821:virology; D014779:Virus Replication
D004279:DNA, Viral; D054303:HIV Reverse Transcriptase