Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: a proof-of-concept study.
BACKGROUND
The latency of HIV-1 in resting CD4+ T-lymphocytes constitutes a major obstacle for the eradication of virus in patients on antiretroviral therapy (ART). As yet, no approach to reduce this viral reservoir has proven effective.


METHODS
Nine subjects on effective ART were included in the study and treated with high dosage intravenous immunoglobulin (IVIG) for five consecutive days. Seven of those had detectable levels of replication-competent virus in the latent reservoir and were thus possible to evaluate. Highly purified resting memory CD4+ T-cells were activated and cells containing replication-competent HIV-1 were quantified. HIV-1 from plasma and activated memory CD4+ T-cells were compared with single genome sequencing (SGS) of the gag region. T-lymphocyte activation markers and serum interleukins were measured.


RESULTS
The latent HIV-1 pool decreased with in median 68% after IVIG was added to effective ART. The reservoir decreased in five, whereas no decrease was found in two subjects with detectable virus. Plasma HIV-1 RNA >or= 2 copies/mL was detected in five of seven subjects at baseline, but in only one at follow-up after 8-12 weeks. The decrease of the latent HIV-1 pool and the residual plasma viremia was preceded by a transitory low-level increase in plasma HIV-1 RNA and serum interleukin 7 (IL-7) levels, and followed by an expansion of T regulatory cells. The magnitude of the viral increase in plasma correlated to the size of the latent HIV-1 pool and SGS of the gag region showed that viral clones from plasma clustered together with virus from activated memory T-cells, pointing to the latent reservoir as the source of HIV-1 RNA in plasma.


CONCLUSIONS
The findings from this uncontrolled proof-of-concept study suggest that the reservoir became accessible by IVIG treatment through activation of HIV-1 gene expression in latently-infected resting CD4+ T-cells. We propose that IVIG should be further evaluated as an adjuvant to effective ART.
Lindkvist
Annica
A
Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institute, Stockholm, Sweden.
Edén
Arvid
A
Department of Infectious Diseases, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
Norström
Melissa M
MM
The Swedish Institute for Infectious Disease Control, Solna, Sweden.|Department of Microbiology, Tumour and Cell Biology MTC, Karolinska Institute, Stockholm, Sweden.
Gonzalez
Veronica D
VD
Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
Nilsson
Staffan
S
Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden.
Svennerholm
Bo
B
Department of Clinical Virology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
Karlsson
Annika C
AC
The Swedish Institute for Infectious Disease Control, Solna, Sweden.|Department of Microbiology, Tumour and Cell Biology MTC, Karolinska Institute, Stockholm, Sweden.
Sandberg
Johan K
JK
Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
Sönnerborg
Anders
A
Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institute, Stockholm, Sweden.|Department of Infectious Diseases, Karolinska Institute, Stockholm, Sweden.
Gisslén
Magnus
M
Department of Infectious Diseases, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.