A study led by Hiroyu Hatano from Steve Deeks’s group at UCSF reports that adding the integrase inhibitor raltegravir (Isentress) to a standard antiretroviral (ART) regimen failed to reduce residual HIV replication, or the HIV reservoir, in a group of individuals with suboptimal CD4 count increases despite prolonged HIV suppression. The intensification approach also did not significantly increase CD4 T cell counts or reduce levels of immune activation, which the authors note adds to the evidence that low-level HIV replication is unlikely to be a major cause of suboptimal CD4 T cell gains in people on ART.
Interestingly, a secondary analysis--conducted in collaboration with Barbara Shacklett’s laboratory at UC Davis--revealed a novel association between the magnitude of HIV Gag-specific CD8 T cell responses in gut-associated lymphoid tissue (GALT) and the size of the HIV reservoir (as measured by proviral DNA in peripheral blood mononuclear cells). Hatano and colleagues caution that the findings are preliminary and require confirmation by larger studies, but also write: “approaches aimed at expanding HIV-specific CD4+ and CD8+ T cell responses in the gut mucosa may accelerate clearance of the viral reservoir. The next logical step would be to pursue therapeutic vaccine studies using HIV vaccines that elicit strong mucosal T cell responses in HAART-treated patients.”
Coincidentally, a paper that appeared online today in the journal Blood describes an approach to augmenting HIV-specific CD8 T cell immunity in GALT. The researchers sampled HIV-specific CD8 T cells from individuals on ART, expanded them in the laboratory, and then re-infused them. Persistence up to 84 days was documented, as well as trafficking to GALT. Many of the cells displayed a “central memory” phenotype, which is believed to be important due to the ability of these cells to self-renew and proliferate robustly upon encountering antigen. Although the infusion approach has practical limitations, the study authors suggest that their results imply that vaccination strategies aiming to boost systemic and GALT HIV-specific CD8 T cell responses are worth pursuing.
J Infect Dis. (2011) 203 (7): 894-897. doi: 10.1093/infdis/jiq150
Hide and Seek… Can We Eradicate HIV by Treatment Intensification?
Julian Schulze zur Wiesch1,2 and Jan van Lunzen1,2 1University Medical Center, Hamburg-Eppendorf, Infectious Diseases Unit 2Heinrich-Pette-Institute Leibniz Institute for Experimental Virology, Hamburg, Germany
(See the article by Hatano et al., on pages 960–68.)
J Infect Dis. (2011) 203 (7): 960-968. doi: 10.1093/infdis/jiq138
Hiroyu Hatano1, Timothy L. Hayes2, Viktor Dahl3, Elizabeth Sinclair1, Tzong-Hae Lee4, Rebecca Hoh1, Harry Lampiris1,5, Peter W. Hunt1, Sarah Palmer3, Joseph M. McCune1, Jeffrey N. Martin1, Michael P. Busch1,4, Barbara L. Shacklett2 and Steven G. Deeks1
1University of California, San Francisco 2University of California, Davis 3Karolinska Institutet and Swedish Institute for Infectious Disease Control, Solna, Sweden 4Blood Systems Research Institute, San Francisco 5San Francisco VA Medical Center, California Reprints or correspondence: Hiroyu Hatano, MD, San Francisco General Hospital, Bldg 80, Ward 84, 995 Potrero Ave, San Francisco, CA 94110.
Abstract
Background. Some human immunodeficiency virus (HIV)–infected individuals are not able to achieve a normal CD4+ T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size.
Methods. Thirty treated subjects with CD4+ T cell counts of <350 cells/mm3 despite viral suppression for ≥1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38+HLA-DR+CD8+ T cells in peripheral blood mononuclear cells (PBMCs).
Results. The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue.
Conclusions. Low-level viremia is not likely to be a significant cause of suboptimal CD4+ T cell gains during HIV treatment.
Blood First Edition Paper, prepublished online March 21, 2011; DOI 10.1182/blood-2010-11-320226.
Aude G. Chapuis1, Corey Casper2, Steve Kuntz2, Jia Zhu2, Annelie Tjernlund3, Kurt Diem2, Cameron J. Turtle1, Melinda L. Cigal1, Roxanne Velez1, Stanley Riddell1, Lawrence Corey2 and Philip D. Greenberg1
1 Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; 2 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; 3 Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Abstract
Most HIV+ individuals require lifelong highly active anti-retroviral therapy (HAART) to suppress HIV replication, but fail to eliminate the virus in part because of residual replication in gut-associated lymphoid tissues (GALT). Naturally-elicited HIV-specific CD8+T-cells generated in the acute and chronic infectious phases exhibit anti-viral activity, but decrease in number following HAART. Therapeutic vaccines represent a potential strategy to expand cellular responses, although previous efforts have been largely unsuccessful, conceivably due to a lack of responding HIV-specific central-memory CD8+T-cells (Tcm). To determine if patients receiving HAART possess CD8+T-cells with Tcm qualities that are amenable to augmentation, HIV-specific CD8+T-cell clones were derived from HIV-reactive CD28+CD8+T-cell lines isolated from 7 HIV+ HAART-treated patients, expanded ex vivo, and re-infused into their autologous host. Tracking of the cells in vivo revealed that clones could persist for 84 days, maintain expression and/or re-express CD28, up-regulate CD62L, secrete IL-2, proliferate upon cognate antigen encounter and localize to the rectal mucosa. These results suggest some infused cells exhibited phenotypic and functional characteristics shared with Tcm in vivo, and imply that more effective therapeutic vaccination strategies targeting CD8+Tcm in patients on HAART might provide hosts with expanded, long-lasting immune responses not only systemically but also in GALT.
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