HIV-1 seroreversion following antiretroviral therapy in an HIV-infected child initially presenting with acquired immunodeficiency syndrome

HIV-1 seroreversion following antiretroviral therapy in an HIV-infected child initially presenting with acquired immunodeficiency syndrome

Neubert, Jennifer^a; Laws, Hans-Juergen^a; Adams, Ortwin^b; Münk, Carsten^c; Krämer, Melanie^c; Niehues, Tim^d; Korn, Klaus^e; Fleckenstein, Bernhard^e; Petri, Edmund^f; Borkhardt, Arndt^a

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^aPediatric Oncology, Immunology and Rheumatology, Germany

^bInstitute for Virology, Germany

^cAIDS Research Group, Clinic for Gastroenterology, Hepatology and Infectiology, Germany

University Hospital Düsseldorf, Moorenstr.5 40225 Düsseldorf, Germany

^dDepartment of Pediatrics, Helios Clinic Krefeld, Lutherplatz 40 47805 Krefeld, Germany

^eInstitute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen-Nuremberg, Germany

^fDepartment of Pediatrics, Clemens Hospital, Düsbergweg 124, 48153 Münster, Germany.

Received 21 October, 2009

Accepted 30 October, 2009

Correspondence to Jennifer Neubert, Pediatric Oncology, Immunology and Rheumatology, University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Tel: +49 211 811 8297; fax: +49 211 811 6539; e-mail: Jennifer.neubert@uni-duesseldorf.de

In adults, HIV-1 seroreversion following antiretroviral therapy is rare and has been reported only in patients who were treated shortly after primary HIV-1 infection ^[1–3]. In HIV-1 infected infants, seroreversion after suppression of viral replication appears to be more frequent than in adults ^[4,5]. However, these infants were asymptomatic or mildly symptomatic and were treated in the first 3 months of life. After this time period, especially when the clinical picture of AIDS has been developed, seroreversion following antiretroviral therapy has not been reported yet. Here, we report the unusual case of seroreversion following antiretroviral therapy in a child vertically infected with HIV initially presenting with AIDS defining conditions.

A child of African origin was diagnosed with vertically acquired HIV infection at the age of 4 months. The boy had been admitted with wasting syndrome. Shortly after admission, he developed pneumocystis jirovecii pneumonia and was tested HIV-1 RNA positive. At diagnosis, HIV-RNA was 139 670 copies/ml, and the CD4 cell count was 1093/μl (14%). The normal CD4 cell count range at this age is 1294–4012/μl or 37.6–46.4% ^[6].

Initial HIV-1 serology was positive using ELISA (HIV-1/2 gO and HIV Ag/Ab Combo, Abbott, Wiesbaden, Germany) and western blotting (Inno-LIA HIV I/II Score, Innogenetics, Hannover, Germany). The western blot showed reactivity with almost all HIV-1 bands (sgp 120 1+, gp41 2+, p31 1+, p24 2+, p17−). Antiretroviral therapy with lamivudine, zidovudine, nevirapin and nelfinavir was initiated.

Seven weeks after initiation of therapy, plasma HIV-1 RNA load was below the detection limit (<50 copies/ml), CD4 cell count was 1316/μl (17%) and his clinical condition had improved. At the age of 2 years, the boy changed his HIV care provider. The HIV care provider contacted us to ask whether this child was indeed HIV-1 infected. Serological HIV tests had been performed at the age of 4 years and revealed seronegativity in both ELISA and western blot. Western blot analysis revealed negative bands for sgp120, gp41, p31, p17 and a slightly reactive p24 band. Reactivity for p24 alone is interpreted as a negative western blot result in standard diagnostic testing ^[7]. In addition to HIV-1 seronegativity, the patient had undetectable HIV-1 RNA, excellent immune reconstitution with normal for age CD4 cell count 1180/μl (40%), and he was asymptomatic. Retrospective analysis of serum samples revealed partial seroreversion at the age of 15, 18 and 25 months (p24 2+, p17 1+, sgp120−, gp41−, p31−). To rule out viral eradication, testing for pro-viral HIV-1 DNA was performed and was positive, confirming persistent HIV-1 infection. Sequencing revealed the HIV-1 subtype CRF02-AG. A 32-bp deletion in the CCR5 gene was excluded.

This case demonstrates that antiretroviral treatment, even in a severely symptomatic and immunosuppressed child, can result in such suppression of viral replication that specific HIV-1 antibodies are not detectable any more. In this child, the seropositivity at diagnosis with a positive ELISA test and intense bands in the western blot at diagnosis was most likely due to passively acquired maternal antibodies; the partial seropositivity at the age of 25 months with a positive band for p24 and p17 implies that the patient was able to mount some kind of antibody response to HIV as maternal antibodies are usually cleared by this time. Presumably, the presence of high titres of maternal antibodies when viral replication began may have initially suppressed the primary immune response and, later, the loss of antigenic stimuli due to minimal HIV-1 replication following antiretroviral therapy could have led to inappropriate antibody response. Our patient had normal for age B-cells and B-cell subsets, normal immunoglobulin levels, and showed an adequate antibody response following immunization indicating that he has no B-cell defect.

HIV-1 infected patients with undetectable plasma viral load and seronegativity are a diagnostic challenge. In standard HIV clinical testing algorithms, patients with negative ELISA antibody tests are considered to be uninfected ^[8]. An HIV-1-infected patient with undetectable viral load and negative antibody test is currently misidentified as being HIV negative, and this has implications regarding the safety of blood products and organ donation. In our case, uncertainty regarding the HIV-1 status of the patient arose after changing the HIV-care provider, as there was no evidence that the boy was HIV-1 infected (undetectable viral load, a negative HIV-1 antibody test, normal lymphocyte subsets and no clinical sign of HIV-1 infection). In such a case, detection of pro-viral DNA appears to be helpful to reconfirm HIV-1 infection. It is important to understand that despite HIV-1 seroreversion, there remains persistent infection and that stopping antiretroviral therapy in such cases can lead to viral rebound and HIV-1 antibody production ^[2,5].

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