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Failure of bone marrow transplantation to eradicate
HIV reservoir despite efficient HAART
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[Correspondence]
AIDS:Volume 21(6)30 March 2007p 776-777
Avettand-Fenoel, Veroniquea,d; Mahlaoui, Nizarb; Chaix, Marie-Laurea,d;
Milliancourt, Catherinea; Burgard, Mariannea,d; Cavazzana-Calvo,
Marinac; Rouzioux, Christinea,d; Blanche, Stephaneb,d
aServices de Virologie, France
bImmuno-hematologie, France
cBiotherapie, Assistance Publique - Hopitaux de Paris, CHU Necker - Enfants Malades, Paris, France
dUniversite Paris-Descartes, Faculte de Medecine, EA3620, Paris, France.
Received 10 October, 2006
Accepted 21 November, 2006
This work is dedicated to the nice young patient who courageously participated in this therapeutic proposal.
Sponsorship: This work was supported by grants from Assistance Publique - Hopitaux de Paris and Universite Paris 5 EA3620.
One of the challenges in HIV infection is viral eradication, as underlined by recent studies [1]. Allogeneic bone marrow transplantation (BMT) has been suggested to be able to reconstitute patients' haematopoietic systems after the clearance of HIV-infected cells with intensive chemotherapy and radiation [2,3]. In 1999, Huzicka [3] reviewed 32 allogeneic bone marrow transplants in HIV-infected patients between 1982 and 1996; in two cases, HIV seemed to be eradicated as judged by negative HIV-DNA and HIV-RNA levels using classic polymerase chain reaction [4,5].
We report here the first case of BMT in an HIV-1-infected patient treated by HAART. To explore HIV reservoirs, we used a sensitive method to quantify HIV-DNA levels in peripheral blood mononuclear cells (PBMC) and biopsies.
A Romanian 17-year-old man had a transfusion-related HIV-1 infection diagnosed at 8 years of age. He was asymptomatic with a CD4 cell count greater than 350 cells/νl until he developed Burkitt's lymphoma in June 2003 and then received effective HAART. He developed monocytic acute myeloid leukemia in April 2005. After transiently effective chemotherapy (ELAM02), a relapse occurred in September and a second line of chemotherapy followed by a human leukocyte antigen phenoidentical BMT was proposed in October. Marrow cytoablation consisted of a conditioning regimen including idarubicine, fludarabine and aracytine. Horse antilymphocytic serum and cyclosporine were used. Haematological restoration was observed at day 19 posttransplant, and chimerism study showed a 100% donor phenotype at days 30 and 119 posttransplant. Cytogenetic remission was confirmed on bone marrow at day 124. The patient suffered early and prolonged cutaneous and digestive graft-versus-host disease (grade III) partly controlled with a combination of immunosuppressive therapy. He presented with several infectious complications and died in multivisceral failure at day 191 posttransplant. During all the procedures, HAART was maintained except for a short interruption for suspected toxicity between days 114 and 134 posttransplant.
HIV DNA was quantified in PBMC, bone marrow cells and biopsies, using a real-time polymerase chain reaction assay amplifying the LTR region according to a previously described technique [6]. The lowest threshold possible was obtained and was adapted to each sample even in cases with few cells during the aplastic and immunosuppressive phases, because the maximum tests per sample were performed to explore all available cells. Before transplantation, HIV DNA was at 2.76 log10 copies/106 PBMC. The medullar sample was at 1.77 log10 copies/106 bone marrow cells before BMT; it contained 60% monoclonal blasts, suggesting that blasts were not infected otherwise the HIV-DNA load would have been dramatically higher. The plasma HIV-RNA load (Cobas Monitor; Roche, France) was undetectable for 18 months before BMT. After BMT, HIV RNA in the plasma remained at less than 1.7 log10 copies/ml. HIV-DNA levels in PBMC became undetectable during over 4 months (< 2 log10 copies/106 PBMC), although more than one million PBMC was explored (Fig. 1). Sixteen days after HAART cessation, however, rebounds of HIV RNA (4.61 log10 copies/ml) and HIV DNA (2.50 log10 copies/106 PBMC) were detected (Fig. 1). Resumption of HAART at day 134 returned viral loads to undetectable levels at day 152 (Fig. 1). HIV DNA was still detectable (< 1.5-2.5 log10 copies/106 PBMC; Fig. 1) but was undetectable in oesophageal, antral, duodenal and rectal biopsies performed 12 days after HAART resumption (< 2.3-3.3 log10 copies/106 cells).
We performed a phylogenetic analysis based on the gp120 C2-V3 sequences on four plasma viral strains (two in 2003 and two in 2006 after BMT). They clustered together but two separate lineages were identified (one for the strains of 2003 and one of 2006) with a high bootstrap value (> 95), suggesting that different quasispecies circulated before and after BMT. It confirmed that the viral reservoir previously constituted was not eradicated.
Negative results on HIV DNA after BMT gave hope of a significant reduction of the reservoir, indeed HIV remission. The organism was repopulated by donor-derived cells that could mount a successful antiviral response through cytotoxic T lymphocytes [3]. Moreover, graft-versus-host disease could have destroyed residual haematopoietic cells potentially harbouring virus [5], including infected macrophages [3]. We did not, however, observe HIV-1 eradication. Unfortunately, the HIV-1 replication recovery a few days after HAART interruption unambiguously showed the persistence of an infectious viral residual reservoir, may be in profound tissues. Despite the use of intensive pretransplant cytoablative conditioning with chemotherapy combined with 18 months of potent effective HAART before BMT (contrary to zidovudine alone used in cases described before 1996), the goal of HIV eradication was not achieved for this patient with a relatively high HIV-DNA level in PBMC [6]. We hypothesized that recipient antigen-presenting cells as well as totipotent haematopoietic progenitors can survive and play a critical role as a virus reservoir [7-9]. Finally, this case emphasizes that the establishment of an 'eradication concept' needs to be evaluated after HAART cessation.
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