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Viral Replication Capacity as a Correlate of HLA B57/B5801-Associated Nonprogressive HIV-1 Infection¹

Marjon Navis^*, Ingrid Schellens, Debbie van Baarle, José Borghans, Peter van Swieten^*, Frank Miedema, Neeltje Kootstra^* and Hanneke Schuitemaker^2,*

^* Sanquin Research, Landsteiner Laboratory, and Center for Infectious Diseases and Immunity Amsterdam (CINIMA) at the Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands; and University Medical Center Utrecht, Utrecht, The Netherlands

HLA B57 and the closely related HLA B5801 are over-represented among HIV-1 infected long-term nonprogressors (LTNPs). It has been suggested that this association between HLA B57/5801 and asymptomatic survival is a consequence of strong CTL responses against epitopes in the viral Gag protein. Moreover, CTL escape mutations in Gag would coincide with viral attenuation, resulting in low viral load despite evasion from immune control. In this study we compared HLA B57/5801 HIV-1 infected progressors and LTNPs for sequence variation in four dominant epitopes in Gag and their ability to generate CTL responses against these epitopes and the autologous escape variants. Prevalence and appearance of escape mutations in Gag epitopes and potential compensatory mutations were similar in HLA B57/5801 LTNPs and progressors. Both groups were also indistinguishable in the magnitude of CD8⁺ IFN- responses directed against the wild-type or autologous escape mutant Gag epitopes in IFN- ELISPOT analysis. Interestingly, HIV-1 variants from HLA B57/5801 LTNPs had much lower replication capacity than the viruses from HLA B57/5801 progressors, which did not correlate with specific mutations in Gag. In conclusion, the different clinical course of HLA B57/5801 LTNPs and progressors was not associated with differences in CTL escape mutations or CTL activity against epitopes in Gag but rather with differences in HIV-1 replication capacity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was financially supported by the Landsteiner Foundation for Blood Transfusion Research Grant 0317 and the Netherlands Organization for Scientific Research Veni Grants 916.36.024 (to N.K.) and 916.36.003 (to J.B.). The Amsterdam Cohort Studies receive financial support from the Netherlands National Institute for Public Health and the Environment.

² Address correspondence and reprint requests to Dr. Hanneke Schuitemaker, Plesmanlaan 125, Amsterdam, The Netherlands. E-mail address: h.schuitemaker{at}sanquin.nl

³ Abbreviations used in this paper: LTNP, long-term nonprogressor; ACH, Amsterdam cohort; L (with number), LTNP participant; P (with number), progressor participant; SC, seroconversion.

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