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.”
Published online: 21 June 2009 | doi:10.1038/nm.1972
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.
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
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.