Two new papers offer differing perspectives on the
reservoirs of HIV that persist despite effective antiretroviral therapy. Nicolas Chomont
and colleagues demonstrate that when memory CD4 T cells containing integrated HIV proliferate (as most memory
CD4 T cells do occasionally in a process known as homeostatic self-renewal), they copy the HIV provirus along with their own genomes. When CD4 T cell numbers decline, homeostatic proliferation occurs more
frequently and Chomont’s paper shows that this is associated with an increase
in the number of latently infected memory CD4 T cells. The researchers describe
the cells that undergo more frequent proliferation in this setting as
“transitional memory” T cells. At earlier stages of infection when the CD4 T
cell pool is relatively intact, the reservoir of infected memory CD4 T cells is
found to be far smaller and integrated virus is primarily located in “central memory”
cells that divide less frequently.
Based on these findings, the study authors suggest that anticancer
drugs that interfere with memory T cell proliferation should be studied for
their potential to deplete the HIV reservoir. However, given the potential
toxicities associated with inhibiting T cell proliferation, the risk/benefit of
such trials would need to be carefully evaluated. A more ideal therapy would be
one that only targeted dividing CD4 T cells containing HIV DNA, but it is
currently unclear whether such an approach is within the realm of possibility.
The second paper – by Timothy Brennan and colleagues from
Bob Siliciano’s laboratory – uses genetic analyses of HIV sequences to show
that there is a reservoir of virus that seems to be coming from a cell type
other than memory CD4 T cells. The study finds that in most cases, the residual
virus detectable in individuals on suppressive ART is genetically distinct from
the virus found in memory CD4 T cells. The authors note in their conclusion:
“Numerous laboratories are actively pursuing various eradication strategies,
most of which involve some aspect of targeting and purging the latent reservoir
in resting memory CD4+ T cells. If
much of the residual viremia of patients undergoing HAART comes from another
reservoir or compartment as suggested here, then eradication strategies will
have to include ways to target and purge this additional reservoir to be
successful.”
Nature Medicine
Published online: 21 June 2009 | doi:10.1038/nm.1972
HIV reservoir size and persistence are driven by T cell
survival and homeostatic proliferation
Nicolas Chomont1,2,3, Mohamed El-Far1,2,3, Petronela
Ancuta3, Lydie Trautmann1,2,3, Francesco A Procopio1,2,3, Bader
Yassine-Diab1,2,3, Geneviève Boucher1, Mohamed-Rachid Boulassel4, Georges
Ghattas5, Jason M Brenchley6, Timothy W Schacker7, Brenna J Hill8, Daniel C
Douek8, Jean-Pierre Routy4,9, Elias K Haddad1,2,3,9 & Rafick-Pierre
Sékaly1,2,3,9,10,11
1. Laboratoire d'Immunologie, Centre de Recherche du Centre Hospitalier
de l'Université de Montréal (CR-CHUM) Saint-Luc, Montréal, Québec, Canada. 2.
Laboratoire d'Immunologie, Département de Microbiologie et d'Immunologie,
Université de Montréal, Québec, Canada. 3. Institute National de la Santé et de
la Recherche Médicale U743, CR-CHUM, Université de Montréal, Montréal, Québec,
Canada. 4. Immunodeficiency Service and Division of Hematology, Royal Victoria
Hospital, McGill University Health Centre (MUHC), McGill University, Montréal,
Québec, Canada. 5. Department of Gastroenterology, MUHC, Montréal, Québec,
Canada. 6. Laboratory of Molecular Microbiology, National Institute of Allergy
and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland,
USA. 7. Department of Medicine, University of Minnesota, Minneapolis,
Minnesota, USA. 8. Human Immunology Section, Vaccine Research Center, National
Institute of Allergy and Infectious Diseases, US National Institutes of Health,
Bethesda, Maryland, USA. 9. Department of Microbiology and Immunology, McGill
University, Montréal, Québec, Canada. 10. Department of Microbiology and
Immunology, Oregon Health and Science University, Portland, Oregon, USA. 11.
Vaccine and Gene Therapy Institute, Port-Ste Lucy, Florida, USA.
Abstract
HIV persists in a reservoir of latently infected CD4+ T
cells in individuals treated with highly active antiretroviral therapy (HAART).
Here we identify central memory (TCM) and transitional memory (TTM) CD4+ T
cells as the major cellular reservoirs for HIV and find that viral persistence
is ensured by two different mechanisms. HIV primarily persists in TCM cells in
subjects showing reconstitution of the CD4+ compartment upon HAART. This
reservoir is maintained through T cell survival and low-level antigen-driven
proliferation and is slowly depleted with time. In contrast, proviral DNA is
preferentially detected in TTM cells from aviremic individuals with low CD4+
counts and higher amounts of interleukin-7–mediated homeostatic proliferation,
a mechanism that ensures the persistence of these cells. Our results suggest
that viral eradication might be achieved through the combined use of strategic
interventions targeting viral replication and, as in cancer, drugs that
interfere with the self renewal and persistence of proliferating memory T
cells.
JVI Accepts, published online ahead of print on 17 June 2009
J. Virol. doi:10.1128/JVI.02568-08
Timothy P. Brennan, John O. Woods, Ahmad R. Sedaghat, Janet
D. Siliciano, Robert F. Siliciano, and Claus O. Wilke*
Department of Molecular Biology and Genetics, The Johns
Hopkins University School of Medicine, Baltimore, MD 21205; Institute for Cell
and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
Department of Medicine, The Johns Hopkins University School of Medicine,
Baltimore, MD 21205; Howard Hughes Medical Institute, Baltimore, MD 21205;
Center for Computational Biology and Bioinformatics and Section of Integrative
Biology, The University of Texas at Austin, Austin, TX 78712
Abstract
Highly active antiretroviral therapy (HAART) can reduce
HIV-1 viremia to clinically undetectable levels. Despite this dramatic
reduction, some virus is present in the blood. Additionally, a long-lived
latent reservoir for HIV-1 exists in resting memory CD4+ T cells. This
reservoir is believed to be a source of the residual viremia and is the focus
of eradication efforts. Here, we employ two measures of population structure,
analysis of molecular variance and the Slatkin-Maddison test, to demonstrate
that the residual viremia is genetically distinct from proviruses in resting
CD4+ T cells, but that proviruses in resting and activated CD4+ T cells belong to
a single population. Residual viremia is genetically distinct from proviruses
in activated CD4+ T cells, monocytes, and unfractionated peripheral blood
mononuclear cells. The finding that some of the residual viremia in patients on
HAART stems from an unidentified cellular source other than CD4+ T cells has
implications for eradication efforts.
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