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Limitations of current antiretroviral therapy in HIV-1 infection: the search for new
strategies
Sankatsing, S.U.C.
Publication date
2004
Link to publication
Citation for published version (APA):
Sankatsing, S. U. C. (2004). Limitations of current antiretroviral therapy in HIV-1 infection: the
search for new strategies.
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CHAPTERR 8
HIV-11 seroreversion in an HIV-1 seropositive
patientt treated during acute infection with HAART
andd mycophenolate mofetil
S.. Jurriaans, S.U.C. Sankatsing, J.M. Prins, H. Schuitemaker, J.M.A.. Lange, A.C. van der Kuyl, M. Cornelissen
HIV-1HIV-1 seroreversion
Seroreversionn for anti-HIV-1 antibodies has been documented in babies from infectedd mothers due to loss of maternal antibodies 1~3, and in late-stage AIDS patientss 4, probably due to loss of immune cells. Other supposed cases of seroreversionn could be attributed to sample mix-up and other errors in testing 5
.. Temporary seronegative was reported in a Dutch patient 6, but it was unclearr whether the patient presented with an early HIV-1 infection or with end-stagee AIDS. Consistent seronegativity has been described in a few HIV-1 infectedd patients7*10.
Heree we describe a case of seroreversion after start of HAART during acute HIV-infection,, with seronegativity being sustained for almost one year, after whichh the patient discontinued drug therapy leading to an immediate increase inn both viral load and antibody titre.
AA Dutch homosexual male developed fever, a sore throat and a skin rash in Octoberr 2000. HIV-1 RNA tested positive on November 7, anti-HIV-1 antibodiess were undetectable. Three weeks later, a Western-blot showed reactivityy with all categories of HIV-1 antigens, and serology was positive for HIV-11 Ab, HAV IgM and total Ab, HBs and HBc Ab, CMV IgG, EBV VCA-IgG andd anti-EBNA. In December 2000, HAART with five drugs (ddl/3TC/ABC/NVP/IDV+RTV)) and 2g/day mycophenolate mofetil (MMF) was startedd as part of a trial studying the efficacy of addition of MMF to HAART in treatmentt naive patients 11. The plasma HIV-1 RNA load had then already declinedd to 680 copies/ml, with a CD4 count of 1.63 x 109 cells/L Sequencing off the pro/pol region revealed a normal subtype B virus. Deletions in the nef genee or in the LTR, which could have contributed to a low-replicating viral phenotypee 12, were not detected. The patient did also not have a 32-bp deletionn in the CCR5 gene (data not shown) 13, suggesting that his low viral loadd could be attributed to strong anti-HIV-1 T-cell responses 14.
Too monitor therapy efficacy, plasma HIV-1 RNA was measured with the NucliSenss assay (bioMérieux, Boxtel, The Netherlands), until the detection levell of the assay, 400 copies/ml, was reached, after which quantification was donee with an ultrasensitive adaptation of the NucliSens assay with a detection
ChapterChapter 8
limitt of 5 copies/ml . The anti-HIV-1 antibody titre in serum was measured simultaneouslyy with the IMx System (IMx System HIV-1/HIV-2
ABBOTTT Laboratories, Abbott Park, II, USA).
Plus, ,
Figuree 1 Changes in plasma HIV-1 RNA and serum antibody levels over time in a
HIV-11 seroreverter (subject MAN004)
startt HAART
100000
MAN004 4 -HIV-11 RNA
-HIV-11 Ab II 1000 < < z z 100 0 == 10
Openn symbols are below the detection limit of the assay (5 cps/ml for HIV-1 RNA), or negativee in the IMx System antibody assay (ratio < 1). Arrows indicate start and end of therapyy with HAART and MMF (2g/day, after 12 weeks 1g/day). MMF and HAART were stoppedd after 48 and 56 weeks of therapy, respectively. CD4 cell counts remained high: 1.63x109/ll at therapy start, and 1.50x109/l before ending HAART. During HAART, CD4 counts rangedd between 1.34 - 2.36 x109/l.
Twoo weeks after start of HAART, plasma HIV-RNA was found to be below the detectionn limit of 5 copies/ml (Fig. 1). Surprisingly, serum anti-HIV-1 antibody titress were decreasing in parallel. Within two months, the patient became seronegativee (Fig. 1). Follow-up showed that seronegativity persisted for almostt 1 year, with a concomitant undetectable plasma HIV-RNA. At that time thee patient decided to stop therapy, which resulted in an immediate rise in bothh plasma HIV-RNA and serum anti-HIV-1 antibodies. Viral RNA could be detectedd as early as 6 days after ending HAART, whereas HIV-specific antibodiess became detectable again within one month (Fig. 1). To test if this 146 6
HIV-1HIV-1 seroreversion
regainedd seropositivity was due to superinfection with a second virus, we sequencedd a pol gene fragment one year after infection. The fragment clusteredd strongly with the sequence obtained at presentation (bootstrap value =100;; data not shown), indicating viral reactivation.
Too our knowledge, this is the first report of a true and stable seroreversion in ann HIV-1 infected patient without AIDS. Eight other patients with acute HIV-1 infectionn in the same trial, of whom three also received MMF, did not serorevert.. Although their plasma HIV-RNA reduction was comparable to the patientt described here, their anti-HIV-1 antibody titre was either stable or slowlyy increasing. MMF has been shown to decrease B-cell counts in transplantt patients 16. It does not affect anti-CMV response 17, but can reduce antibodyy formation when antigen and MMF are given simultaneously 18,19, whichh is not the case in our patient. Still, MMF treatment could have contributedd to the seroreversion observed here, although this is probably not a generall mechanism, as the other HIV-1 infected patients receiving MMF did nott show a decrease in HIV-1 antibody titres.
Thee patient was fully able to mount an antibody response to HIV-1, given the positivee serology results before and after HAART and the completely reactive Westernn blot. Furthermore, he showed antibody responses to a variety of viruses,, indicating that he has no B-cell defect, instable antibodies or fast antibodyy clearance. Probably, strong HIV-specific T-cell responses, the early potentt anti-viral therapy, and the MMF treatment together resulted in decreasedd viral antigen exposure and abrogation of antibody formation.
ChapterChapter 8
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