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HIV at ICAAC "HIV Cure" 2013
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(Sept 10-13, Denver, CO)
(Sept 10-13, Denver, CO)
Report written for NATAP by David H. Shepp, MD Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine North Shore University Hospital - Manhasset, NY
The Cure. While contemporary antiretroviral therapy (ART) can continuously suppress HIV to very low levels, it does not eliminate the latent reservoir which can rekindle HIV infection if ART is discontinued. Finding alternatives to life-long ART is an active area of HIV research. Treatments that aim to maximally suppress HIV replication, then purge the latent reservoir are pursuing a "sterilizing cure" in which all replication competent HIV is eliminated. This approach will likely be most successful when HIV replication is fully suppressed and the size of the latent reservoir is as small as possible. To help identify patients meeting these criteria, Parisi et al performed a longitudinal study quantitating peripheral blood mononuclear cell (PBMC) HIV DNA and plasma HIV RNA using an ultrasensitive assay in patients initiating ART [1]. One hundred eighty one patients who reached and maintained HIV RNA <50 copies/mL were tested at baseline 24, 36 and 48 months. Lower HIV DNA values correlated strongly with the likelihood of achieving plasma HIV RNA <2.5 copies/mL. Patients treated during primary HIV infection also were more likely to have a lower HIV DNA and reach plasma HIV RNA <2.5 copies. This study adds further evidence that early initiation of ART and maximal suppression of plasma HIV help identify patients with low HIV DNA reservoirs in peripheral blood. Such patients may be the most suitable candidates for interventions to purge the HIV reservoir.
In a alternate approach, a 'functional cure" would be achieved if HIV replication was limited by a stimulated host immune response or by genetic engineering of CD4 cells to induce resistance to infection, even if low level HIV replication and the latent reservoir remained. To that end, scientists at Sangamo BioScience and collaborators reported on the effects of adoptive transfer of CCR5-modified autologous T-cells [2]. Based on a previous observation of greater success in creating bialleleic deletion of the CCR5 gene, the current study was carried out in 10 HIV-infected subjects heterozygous for the CCR5Δ32 deletion. All were taking fully suppressive ART. Eight weeks after receiving an infusion of genetically modified T-cells, ART was interrupted.
Three subjects were excluded from the analysis after being found to harbor X4 virus. The seven remaining participants, all had viral rebound during treatment interruption. One patient resuppressed HIV RNA to undetectable levels and has remained undetectable for 8 weeks in an ongoing ART interruption. Another patient transiently resuppressed virus to undetectable levels and has continued off ART with viremia hovering in the 1,000 copy range for nearly 11 months. The other patients all had high level viral rebound, although one had not yet finished the planned 16 week treatment interruption. As seen with other patients treated with this technology, following infusion of the genetically modified cell pool, CD4 lymphocyte counts rose dramatically, increasing by >1000/mm3 at one month, declining slowly thereafter but remaining elevated over baseline at one year.
Many questions remain about this therapeutic approach. Since very few patients have been treated and there is no control group, it is hard to tell if the few patients who controlled viremia did so as a result of the intervention or if these might be either spontaneous or post-treatment controllers. To be an alternate to ART, treatment would need to induce viral suppression of comparable magnitude and durability in a high percentage of recipients, which has not yet been demonstrated. The rise in CD4 cells is impressive but only a small fraction these cells contain the genetic modification. The mechanism driving expansion of unmodified T-cells and their functional characteristics need to be determined. Also, the long-term safety of genetically modified T-cell infusions needs to be established.
1. Parisi SG, Samantha A, Scaggiante R, et al. Strong Correlation Between The Reduction of Cellular HIV-DNA Load and Achievement Of HIV Plasma Viremia <2.5 Copies/ml In An Observation Period Of 4 Years of Effective Antiretroviral Therapy in Naive Patients. 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-673.
2. Ando A, Lalezari J, Blick G, et al. Functional Control of Viremia in CCR5-Δ32 Heterozygous (Δ32HZ) HIV+ Subjects Following Adoptive Transfer of Zinc Finger Nuclease CCR5 Modified Autologous CD4 T-cells (SB-728-T). 53rd ICAAC, Denver CO, Sept 10-13, 2013, Abstract H-1464c.
ICAAC: Strong Correlation Between The Reduction Of Cellular HIV-DNA Load And Achievement Of HIV Plasma Viremia<2.5 Copies/ml In An Observation Period Of 4 Years Of Effective Antiretroviral Therapy In Naïve Patients - (09/16/13)
ICAAC: Host Immune Environment Significantly Impact the Level of CD4 Reconstitution and the Effects on Latent Reservoir in HIV Subjects Receiving ZFN CCR5 Modified CD4 T-cells (SB-728-T) - (09/16/13)
ICAAC: Sangamo BioSciences announces presentation of clinical Data Demonstrating Functional Control of Viremia in HIV-Infected Subjects treated with SB-728-T - (09/16/13)
ICAAC: Functional Control of Viremiain CCR5-Δ32 Heterozygous (Δ32HZ) HIV+ Subjects Following Adoptive Transfer of Zinc Finger Nuclease CCR5 Modified AutologousCD4 T-cells (SB-728-T) - (09/16/13)
53rd ICAAC Interscience Conference on Antimicrobial Agents and Chemotherapy
September 10-13
2013, Denver CO
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