Proviruses with identical sequences comprise a large fraction of the replication-competent HIV reservoir.
The major obstacle to curing HIV infection is the persistence of cells with intact proviruses that can produce replication-competent virus. This HIV reservoir is believed to exist primarily in CD4+ T-cells and is stable despite years of suppressive antiretroviral therapy. A potential mechanism for HIV persistence is clonal expansion of infected cells, but how often such clones carry replication-competent proviruses has been controversial. Here, we used single-genome sequencing to probe for identical HIV sequence matches among viruses recovered in different viral outgrowth cultures and between the sequences of outgrowth viruses and proviral or intracellular HIV RNA sequences in uncultured blood mononuclear cells from eight donors on suppressive ART with diverse proviral populations. All eight donors had viral outgrowth virus that was fully susceptible to their current ART drug regimen. Six of eight donors studied had identical near full-length HIV RNA sequences recovered from different viral outgrowth cultures, and one of the two remaining donors had identical partial viral sequence matches between outgrowth virus and intracellular HIV RNA. These findings provide evidence that clonal expansion of HIV-infected cells is an important mechanism of reservoir persistence that should be targeted to cure HIV infection.
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.|Howard Hughes Medical Research Fellows Program, Howard Hughes Medical Institute, Bethesda, Maryland, United States of America.
John K
0000-0001-5905-2049
JK
Bui
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Michele D
MD
Sobolewski
AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research operated by Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.
Brandon F
BF
Keele
HIV Dynamics and Replication Program, National Cancer Institute, Frederick, Maryland, United States of America.
Jonathan
J
Spindler
HIV Dynamics and Replication Program, National Cancer Institute, Frederick, Maryland, United States of America.
Andrew
0000-0002-0470-9880
A
Musick
HIV Dynamics and Replication Program, National Cancer Institute, Frederick, Maryland, United States of America.
Ann
A
Wiegand
Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research operated by Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.
Brian T
0000-0002-2777-7376
BT
Luke
Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research operated by Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.
Wei
W
Shao
HIV Dynamics and Replication Program, National Cancer Institute, Frederick, Maryland, United States of America.
Stephen H
SH
Hughes
Department of Molecular Biology and Microbiology, Tufts University, Boston, Massachusetts, United States of America.
John M
JM
Coffin
HIV Dynamics and Replication Program, National Cancer Institute, Frederick, Maryland, United States of America.
Mary F
MF
Kearney
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
John W
JW
Mellors
D019380:Anti-HIV Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000235:genetics*; D019562:Viral Load / Q000235:genetics
D019380:Anti-HIV Agents