A human immunodeficiency virus type 2 (HIV-2)-infected woman experienced asymptomatic superinfection with HIV-1 subtype AG. She did not have cross-neutralizing autologous HIV-1 antibodies before and shortly after HIV-1 superinfection. This evidence supports a mechanism other than cross-neutralizing antibodies for the mild course of HIV-1 infection in this woma

Böni, Jürg

Günthard, Huldrych F.

Huber, Milo

Kuster, Herbert

Schüpbach, Jörg

Shah, Cyril

Trkola, Alexandra

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BRIEF REPORT • CID 2009:48 (1 June) • e117B R I E F R E P O R THIV-1 Superinfection in an HIV-2–Infected Woman with SubsequentControl of HIV-1 Plasma ViremiaHuldrych F. Gu¨nthard,1 Milo Huber,1 Herbert Kuster,1 Cyril Shah,2Jo¨rg Schu¨pbach,2 Alexandra Trkola,1 and Ju¨rg Bo¨ni21Division of Infectious Diseases and Hospital Epidemiology and 2Swiss NationalCenter for Retroviruses, University of Zurich, Zurich, SwitzerlandA human immunodeficiency virus type 2 (HIV-2)–infectedwoman experienced asymptomatic superinfection with HIV-1 subtype AG. She did not have cross-neutralizing autologousHIV-1 antibodies before and shortly after HIV-1 superinfec-tion. This evidence supports a mechanism other than cross-neutralizing antibodies for the mild course of HIV-1 infec-tion in this woman.Interclade and intraclade superinfection with human immu-nodeficiency virus type 1 (HIV-1) strains has been well doc-umented during recent years. Incidence rates are estimated toreach 3%–8% per year (with higher levels during primary in-fection than during chronic infection), rendering superinfec-tion a major challenge for HIV drug and vaccine design [1–11]. In contrast, HIV-1 and HIV-2 coinfection is observed rel-atively infrequently in regions where both strains cocirculate athigh levels [11–13]. A prospective epidemiological study fromSenegal suggested that HIV-2–infected individuals may be pro-tected partially from HIV-1 infection [14, 15], although otherstudies in West Africa could not confirm these findings [16,17]. In addition, a variety of in vitro studies have proposedpotential protective mechanisms [14, 18–20]. A caveat of pre-vious studies remains: HIV-1 and HIV-2 dual infections couldrarely be attributed clearly to either coinfection or superinfec-tion, because sequential sampling to prove superinfection wasmissing in most cases. Here, we describe an HIV-2–infectedwoman who was unambiguously superinfected with HIV-1.Informed consent to conduct this study was obtained.Received 20 January 2009; accepted 19 February 2009; electronically published 21 April2009.Reprints and correspondence: Dr. Huldrych F. Gu¨nthard, Div. of Infectious Diseases andHospital Epidemiology, University Hospital Zurich, Ra¨mistrasse 100, 8091 Zurich, Switzerland(huldrych.guenthard@usz.ch).Clinical Infectious Diseases 2009; 48:e117–20 2009 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2009/4811-00E3$15.00DOI: 10.1086/598987Case report. In December 2001, a 39-year-old pregnantwoman from Benin presented to our hospital with pretermcontractions. The results of an HIV-1/2/O screening test werereactive. Western blot analysis revealed a positive result for HIV-2 but a negative result for HIV-1. Plasma HIV-1 RNA wasundetectable at that time (Roche Monitor HIV-1 assay, version1.5; detection limit, 50 copies/mL). HIV-2 infection had alreadybeen diagnosed in December 1999 (figure 1). The infant wasborn by cesarean delivery in the absence of antiretroviral treat-ment in December 2001 and remained free of HIV infection.To monitor for HIV-2 viremia, a product-enhanced reversetranscriptase assay [21] was performed in January 2002. Reversetranscriptase activity of 1266 nU/mL was detected (HIV RNAlevel, ∼24,000 copies/mL) [21] and was thought to be attrib-utable to HIV-2, because the plasma HIV-1 RNA test resultswere previously negative. The baseline CD4 cell count at thattime was 729 cells/mL (CD4 percentage, 48%). In May 2002,the CD4 cell count decreased suddenly to 340 cells/mL (CD4percentage, 26%). Subsequently, the CD4 cell count increasedto 578 cells/mL (CD4 percentage, 27%) and remained stable(440–600 cells/mL) for the next 5 years. In November 2005, aplasma HIV-1 RNA test was performed, the results of whichdemonstrated measurable viral RNA. The assay was repeated,and the results confirmed the reactivity. This result raised thequestions of whether this was a rare case of HIV-2 infectionthat was detectable by the Roche assay [22], whether the initialserological diagnosis of HIV-2 infection had been incorrect, orwhether the patient had HIV-1 and HIV-2 coinfection.Sequencing of the amplicon and phylogenetic analysis re-vealed an HIV-1 sequence related to clade A. Thus, a retro-spective analysis of stored samples was started. Western blotanalysis from May 2002 revealed that, in addition to the pre-vious HIV-2 infection, HIV-1 infection had been newly ac-quired (figure 1); in addition, plasma HIV-1 RNA was detect-able at the low level of 540 copies/mL. A plasma sample fromJanuary 2002, a time point at which the HIV-1 Western blotresult was still negative, was also tested for HIV-1 RNA, and aviral load of 722 copies/mL was detected. Thus, asymptomaticprimary HIV-1 infection occurred in January 2002. Subse-quently, the HIV-1 RNA level increased to 1760 copies/mL inOctober 2002, spontaneously decreased to 63 copies/mL in Jan-uary 2005, and then oscillated between 60 and 660 copies/mLduring the entire follow-up period (until the end of July 2008).No HIV-associated disease developed during the entire obser-vation period of 6 years, and it was not necessary to startantiretroviral treatment. HIV-1 proviral DNA amplifications fore118 • CID 2009:48 (1 June) • BRIEF REPORTFigure 2. Line immunoassay with specimens obtained before and afterhuman immunodeficiency virus type 1 (HIV-1) seroconversion. All speci-mens were tested retrospectively in parallel with strips of the same lot.Positions of HIV-1– or HIV-2–specific envelope antibodies are shown inbold. The specimen obtained on day 0 (in January 2002) showed sero-positivity only for HIV-2. Seroconversion to HIV-1 is evident by the in-duction of HIV-1–specific envelope antibodies and by an increase of thereactivity to matrix protein p17 and endonuclease p31 in the specimenfrom day 127. NEG, seronegative reaction control.Figure 1. Synopsis of the time of events. Day 0 is defined as the day when diagnosis of human immunodeficiency virus type 1 (HIV-1) superinfectionwas made (in January 2002). The logarithmic scale delineates the longitudinal plasma HIV-1 load (squares) and neutralizing antibody titers of 70%(NT70%) and 90% (NT90%). The horizontal dotted line represents the cutoff value (!40 copies/mL) for nondetectability of any neutralizing activityagainst the autologous virus isolate. CD4 cell counts are represented by triangles. In addition, sequential Western blot (WB) results for HIV-2 andHIV-1, by the time of HIV-1 virus isolation from plasma samples, are shown to mark their overall temporal relationship.gag and pol genes were positive. Phylogenetic analysis of theentire gag p24 sequence revealed recombinant virus CRF02_AG.The results of several plasma HIV-2 RNA tests remained neg-ative, whereas HIV-2 proviral DNA was undetectable by stan-dard polymerase chain reaction (PCR) but was detected un-ambiguously by a high DNA input nested DNA PCR [23].Phylogenetic analysis of the sequenced amplicon revealed HIV-2 subtype B.A replication-competent isolate of the superinfecting strainwas isolated after 1580 days of follow-up. Of note, no HIV-1–neutralizing activity was detectable in the patient’s plasma sam-ples before HIV-1 superinfection (figure 1). Thus, HIV-2 lackedthe ability to induce a protective, cross-neutralizing activityagainst HIV-1. A significant anti–HIV-1–neutralizing activityevolved after several months of HIV-1 infection, consistent withprevious reports [24, 25].Assays used. For HIV-1 and HIV-2 antibodies, the follow-ing assays were used: HIV-1/2/O enzyme-linked immunosor-bent assay (for screening), Western blot analysis (Genelabs Di-agnostics), and line immunoassay (INNO-LIA HIV I/II Score;Innogenetics). For HIV-1 RNA, the Cobas Amplicor HIV-1Monitor assay, version 1.5, was used. Retrospective analyses ofHIV-1 RNA in plasma samples or proviral DNA in peripheralblood mononuclear cells (PBMCs) used in-house real-timePCR with primers in gag and pol. For HIV-2 RNA or DNAPCR, PCR with primers in the gag leader sequence was used[26]. To measure reverse transcriptase activity, an ultrasensitiveparticle-enhanced reverse transcriptase assay was used [21].The superinfecting autologous HIV-1 isolate was isolatedfrom CD4 cells obtained after 1580 days of follow-up, and theautologous plasma neutralization activity was measured in aPBMC-based neutralization assay as described elsewhere [27].Discussion. We report an unambiguous case of superin-fection with HIV-1 CRF02_AG in an HIV-2–infected woman.Although the initial HIV-1 load was low (722 copies/mL) andpeaked at only 1760 copies/mL, the sudden decrease in theCD4 cell count in this patient is consistent with primary HIV-1 infection and suggests that the superinfection occurred fromDecember 2001 through January 2002, when results of the HIV-1 RNA assay were first positive but the results of INNO-LIAwere negative for HIV-1–specific envelope antibodies (figure2). HIV-1 and HIV-2 coinfection could clearly be ruled out byBRIEF REPORT • CID 2009:48 (1 June) • e119identification of an HIV-2–positive Western blot result for thispatient in December 1999. Of note, the patient did not ex-perience any symptoms or signs of an acute retroviral syn-drome. During the following 6 years, the HIV-1 load sponta-neously decreased and oscillated at low levels (60–660 copies/mL), and the CD4 cell count fluctuated between 440 and 600cells/mL (CD4 percentage, 23%–30%). It has to be consideredthat the infecting HIV-1 strain, as most isolates of CRF02_AG,contained a critical mismatch in 1 of the HIV-1 monitor primerbinding sites [28]; thus, the viral load may have been under-estimated. Despite repeated attempts, HIV-2 RNA remainedundetectable in plasma, but persistence of HIV-2 infectioncould be documented by measuring HIV-2 proviral DNA levelsin PBMCs with use of a supersensitive high-input procedure[23]. This case illustrates that, in an HIV-2–infected patientwho encounters a sudden decrease in CD4 cell count, potentialHIV-1 superinfection needs to be verified.Previous studies have suggested that HIV-2 infection maypartially protect patients from subsequent HIV-1 infection butnot vice versa [15, 29]. Whether this is indeed the case is stillunder debate. Several clinical and basic research studies chal-lenged these observations [16, 17], whereas other in vitro in-vestigations located potential mechanisms by which HIV-2 in-fection could restrict or protect patients from HIV-1 infection,including CCR5 downregulation by HIV-2 [14], cross-reactiveanti–HIV-1 antibody induced by HIV-2 [20], higher b-che-mokine levels in HIV-2–infected patients [19], and viral inter-ference at the transcriptional level [18]. To test the hypothesisthat, in our patient, potentially cross-reactive anti–HIV-1 an-tibodies might have been induced by the previous HIV-2 in-fection, we longitudinally assessed neutralizing activity of thepatient plasma against the autologous HIV-1 virus isolate. Ofnote, before and shortly after superinfection, no anti–HIV-1plasma–neutralizing activity was detectable (figure 1). However,optimal antibody response could not be tested, because a viralisolate from the time of primary HIV-1 infection was notavailable.In conclusion, our case is particular in several ways. First, itis a rare case of an unambiguously documented HIV-2 andHIV-1 superinfection. Second, the patient had asymptomaticacute HIV-1 infection with a low viral load, and subsequently,HIV-1 RNA levels remained low in the absence of any treatmentfor 6 years. HIV-1 superinfection only transiently led to a de-crease in CD4 cell count, and for the entire follow-up period,no disease progression occurred; altogether, the course of theinfection resembles chronic HIV-2 infection rather than HIV-1 infection. We could not detect cross-neutralizing antibodiesagainst HIV-1 induced by HIV-2. Thus, mechanisms other thanneutralizing antibody response were most likely responsible forthis benign course of disease.AcknowledgmentsWe thank the patient, for participating in this study, and Joseph Wong,for helpful discussions and for reading the manuscript.Financial support. Swiss National Science Foundation (320000–116035 to H.F.G.).Potential conflicts of interest. All authors: no conflicts.References1. Casado C, Pernas M, Alvaro T, et al. Coinfection and superinfectionin patients with long-term, nonprogressive HIV-1 disease. J Infect Dis2007; 196:895–9.2. Chohan B, Lavreys L, Rainwater SM, Overbaugh J. Evidence for fre-quent reinfection with human immunodeficiency virus type 1 of adifferent subtype. J Virol 2005; 79:10701–8.3. Jost S, Bernard MC, Kaiser L, et al. A patient with HIV-1 superinfection.N Engl J Med 2002; 347:731–6.4. Koelsch KK, Smith DM, Little SJ, et al. Clade B HIV-1 superinfectionwith wild-type virus after primary infection with drug-resistant cladeB virus. 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HIV-1 Superinfection in an HIV-2-Infected Woman with Subsequent Control of HIV-1 Plasma Viremia

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