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AIDS:
doi: 10.1097/QAD.0b013e328344892e
Research Letters

Long-term nonprogressors and elite controllers in the ANRS CO5 HIV-2 cohort

Thiébaut, Rodolphea; Matheron, Sophieb; Taieb, Audreya; Brun-Vezinet, Francoiseb; Chêne, Genevièvea; Autran, Brigittec; for the immunology group of the ANRS CO5 HIV-2 cohort

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aINSERM U897, Bordeaux Segalen University, ISPED, Bordeaux, France

bBichat Claude Bernard Hospital, AP-HP, Denis Diderot Univ Paris 07, France

cUPMC Univ Paris 06, INSERM, UMR_ 945, AP-HP, Pitié-Salpêtrière Hospital, Cellular Immunology Laboratory, Paris, France.

Received 1 October, 2010

Revised 22 December, 2010

Accepted 11 January, 2011

Correspondence to Rodolphe Thiébaut, INSERM U897, ISPED, Université Bordeaux Segalen, 146 Rue Léo Saignat, 33076 Bordeaux, France. Tel: +33 5 57 57 45 21; fax: +33 5 56 24 00 81; e-mail: rodolphe.thiebaut@isped.u-bordeaux2.fr

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Abstract

Among 342 HIV-2-infected patients of the ANRS CO5 HIV-2 cohort, the prevalence of long-term nonprogressors (LTNPs) (i.e. asymptomatic for at least 8 years while maintaining CD4 cell count at least 500 cells/μl) and of HIV controllers (i.e. controlling HIV replication in the absence of antiretroviral treatment for at least 10 years) was 6.1% (95% confidence interval 3.9–9.1) and 9.1% (6.3–12.7), respectively. Most LTNPs (81%) were HIV controllers, whereas only 55% of HIV controllers were LTNPs.

Studies of nonpathogenic simian immunodeficiency virus (SIV)/HIV infections are important to understand the mechanisms of protection against the disease. Models of highly informative subgroups include natural hosts infections [1], long-term nonprogressors (LTNPs) who remain asymptomatic for many years and maintain high CD4 cell counts, or HIV controllers who spontaneously control HIV replication, in the absence of antiretroviral treatment. Comparisons of viruses and hosts characteristics between these subgroups, those who progressed and uninfected individuals, help in finding correlates of protection against infection and/or progression [2]. Recently, Grabar et al. [3] showed that both conditions are very rare in the very large ANRS CO4 French HIV Database of HIV-1-infected patients: LTNPs being twice as frequent as HIV controllers (0.43 vs. 0.22% among 46880 patients). Furthermore, there was a partial overlap between the two subgroups. On the one hand, only 42% of HIV controllers were LTNPs; in this situation, one of the main hypothetical mechanisms is that immune activation deteriorates the immune system, even though viral replication is controlled. On the other hand, 79% of LTNPs were not HIV controllers, a situation comparable to that of African green monkeys and sooty mangabeys that are natural host of SIV and in which the consequences of ongoing viral replication are controlled by the regulation of immune activation [4].

HIV-2 infection is another example of a reduced pathogenic infection with a lower risk of disease progression and transmissibility than HIV-1, which has already been related to differences in virus and host factors [5]. So far, the variability of disease progression in HIV-2-infected individuals has been poorly characterized [6]. This can be achieved through the estimation of the frequency of LTNPs and HIV controllers. The ANRS CO5 cohort is a cohort of HIV-2 patients that has included a total of 749 patients as of 2009 [7]. Briefly, it is an ongoing national prospective study initiated in 1994 in 111 clinical centers in France. Inclusion criteria to the cohort are HIV-2 infection only, age 18 years or greater, residence in France planned for at least 1 year and informed consent available. According to the same criteria used in HIV-1-infected patients and the same selection process [3], the frequency of LTNPs (asymptomatic HIV infection ≥8 years, nadir CD4 cell count ≥500 cells/μl without antiretroviral therapy) and HIV controllers (asymptomatic HIV infection ≥10 years, 90% of plasma HIV-2 RNA ≤500 copies/ml) were 6.1% [n = 21/342, 95% confidence interval (CI) = 3.9–9.1] and 9.1% (n = 31/342, 95% CI 6.3–12.7), respectively (Figure in Supplemental Digital Content, http://links.lww.com/QAD/A118). Frequency of elite LTNPs (nadir CD4 cell count >600/μl, and nondeclining CD4 cell count slope) and elite HIV-2 controllers (last plasma HIV-2 RNA below the detection limit of 100 copies/ml) were 1.5% (n = 5, 95% CI 0.54–3.2) and 8.8% (n = 30, 95% CI 6.1–12.1), respectively. Hence, all but one HIV controllers were elite controllers (30/31). Looking at the overlap between these two groups, 55% (n = 17/31, 95% CI 37.3–71.5) of HIV controllers were LTNPs and 19% (n = 4/21, 95% CI 6.4–39.8) of LTNPs were not HIV controllers. In comparison with data reported on HIV-1 infection, it is noteworthy that LTNPs and HIV controllers were 10–40-fold more frequent among HIV-2-infected patients (all P < 0.0001), HIV controllers being more frequent than LTNPs. Furthermore, the proportion of HIV controllers among LTNPs is four-fold more important than for HIV-1 (Fig. 1).

Fig. 1
Fig. 1
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The estimates of the frequency of LTNPs and HIV controllers were provided for the purpose of comparison with the results in HIV-1-infected patients and the calculation followed the same rules, but they should be interpreted with caution in the context of HIV-2 infection for two reasons. First, the requirement of duration of the follow-up available greater than 8 years may have led to a potential underestimation of LTNPs and HIV controllers. However, we believe that, in the context of universal access to care, this was also the case for HIV-1 estimates and this should not modify the overlap between the groups. Second, both studies are based on clinical cohorts that cannot include patients who are not yet diagnosed, especially because they remain asymptomatic, in a context of universal access to care [8]. We, therefore, believe our study yielded an underestimation of the frequency of LTNPs and HIV controllers.

This simple description of extreme groups in the HIV-2 cohort illustrates the differences in HIV replication and disease progression between these two retroviral infections and provides some insight into potential mechanisms of progression and nonprogression in this population of infected patients. Low HIV-2 replication appears to be the main characteristic of LTNPs, although some of the HIV-2 controllers experienced disease progression as in HIV-1 infection. Lymphocyte activation and/or other hypothetical causes of immune deterioration may also play an important role in HIV-2 disease that remain to be explored more deeply in relation to this low replicative capacity of HIV-2.

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Acknowledgements

The ANRS CO5 HIV-2 cohort is supported by a grant of the Agence Nationale de Recherches sur le Sida et les hépatites virales.

B.A., R.T. and S.M. (study conception and design); B.A., F.B.-V., and S.M. (acquisition of data); R.T. and A.T. (data analysis); R.T. and S.M. (drafting the manuscript); R.T., B.A., F.B.-V., G.C. and S.M. (critical revision of the manuscript); R.T., B.A., A.T., F.B.-V., G.C. and S.M. (final manuscript approval) contributed to the article.

None of the authors of this article has any financial or personal relationships with people or organizations that could inappropriately influence this work.

The composition of the immunology group is as follows: Victor Appay, Brigitte Autran, Francoise Brun-Vezinet, Rémi Cheynier, Anne Hosmalin, Sophie Matheron, Gianfranco Pancino, Rodolphe Thiébaut, and Vincent Vieillard.

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References

1. Sodora DL, Allan JS, Apetrei C, Brenchley JM, Douek DC, Else JG, et al. Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts. Nat Med 2009; 15:861–865.

2. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 2007; 27:406–416.

3. Grabar S, Selinger-Leneman H, Abgrall S, Pialoux G, Weiss L, Costagliola D. Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV. AIDS 2009; 23:1163–1169.

4. Jacquelin B, Mayau V, Targat B, Liovat AS, Kunkel D, Petitjean G, et al. Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest 2009; 119:3544–3555.

5. Rowland Jones SL, Whittle HC. Out of Africa: what can we learn from HIV-2 about protective immunity to HIV-1? Nat Immunol 2007; 8:329–331.

6. Drylewicz J, Matheron S, Lazaro E, Damond F, Bonnet F, Simon F, et al. Comparison of viro-immunological marker changes between HIV-1 and HIV-2-infected patients in France. AIDS 2008; 22:457–468.

7. Matheron S, Pueyo S, Damond F, Simon F, Lepretre A, Campa P, et al. Factors associated with clinical progression in HIV-2 infected-patients: the French ANRS cohort. AIDS 2003; 17:2593–2601.

8. van der Loeff MF, Larke N, Kaye S, Berry N, Ariyoshi K, Alabi A, et al. Undetectable plasma viral load predicts normal survival in HIV-2-infected people in a West African village. Retrovirology 2010; 7:46.

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© 2011 Lippincott Williams & Wilkins, Inc.

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