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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1253. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Vanham, G. Search for Related Content PubMed Articles by Vanham, G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Jansen et al, page 1427 Are HIV-specific CD4+ T cells useless? Guido Vanham UNIVERSITY OF ANTWERP In this issue, Jansen and colleagues challenge the hypothesis that early HIV-specific CD4+ T cell responses might protect against disease progression. Their data suggest that neither HIV Gag-induced IL-2 nor IFN- production by CD4+ T cells is predictive of the clinical evolution. The authors first showed that HIV-specific IL-2 and/or IFN- responses at 1 year after seroconversion were similar in 7 rapid progressors and 6 long-term asymptomatics (LTAs); hence, this parameter was not predictive of the different clinical evolution. More importantly, in a large cohort study of 96 patients, Gag-specific responses at 1 year also failed to predict evolution toward AIDS. In the smaller longitudinal study, CD4+ T-cell responses were analyzed again at a later time, when the progressors had already evolved to AIDS, while the LTAs were still disease-free. Gag-specific cytokine responses were preserved in LTAs but were largely lost in progressors, whose viral load was much higher from the outset. From this impressive set of data, the authors conclude ".. .viral load [determines] the nature and magnitude of HIV-specific CD4+ T-cell responses, rather than HIV-specific CD4+ T-cell responses controlling HIV plasma viral load." Do the data by Jansen et al imply that the adaptive immune system is useless in preventing HIV progression? Is it even futile to try and induce protective immunity by immunization? Maybe it is too early for such desperate conclusions. Earlier studies have suggested that a preserved CD4+ T-cell function, probably by "helping" effector CD8 T cells, could protect against rising viral load and disease progression.1 Although many previous studies were rather small and/or cross-sectional, some were also prospective.2 Although well done, the present study suffers from some conceptual and technical limitations. First, CD4+ T-cell responses were evaluated 1 year after seroconversion, a time when the viral load has reached a set point that already reflects the equilibrium between "fitness" of the virus and all the patient's defense systems. One can argue that immune mechanisms around the time of seroconversion, including CD4+ and CD8+ T-cell responses, might determine the viral set point at 12 months. Moreover, a pool of "consensus" subtype B peptides together with anti-CD28 and anti-CD49 were used as the stimulus. This acceptable and convenient set-up has a few disadvantages. The consensus most probably differs from the patient's virus and therefore obscures possible isolate-specific responses.3 In addition, a response of a similar magnitude may represent a vigorous response to a narrow set of epitopes, resulting in immune escape and increasing viral load, or an equilibrated response to a broad range of epitopes, effectively controlling the virus. Moreover, it was recently suggested that not just IL-2 and IFN-, but more complex cytokine patterns need to be considered as correlates of protection.4 Finally, potential differences in antigen-presenting cell (APC) function may go unnoticed, since the set-up chosen largely circumvents the APC function. In their final sentence, the authors cast some doubt on vaccination, based on their observations in infected, treatment-naive patients. However, even if we accept that HIV at relatively low copy numbers can undermine the protective potential of CD4+ T-cell responses in these patients, it is still quite possible that prophylactic or therapeutic vaccination will induce protective CD4+ T-cell responses in subjects that are either uninfected or in whom the virus is completely suppressed by highly active antiretroviral therapy (HAART). In conclusion, these provocative data will undoubtedly stimulate the scientific discussion and inspire new studies to investigate which immune responses are protective and ultimately important to design efficient HIV vaccines and immunotherapies. References Lichterfeld M, Pantaleo G, Altfeld M. Loss of HIV-specific T cell proliferation in chronic HIV-1 infection: cause or consequence of viral replication? AIDS. 2005;19: 1225-1227.[Medline] [Order article via Infotrieve] Ratto-Kim S, Garner RP, Kim JH, et al. Prospective analyses of HIV1-specific proliferative responses, recall antigen proliferative responses and clinical outcomes in an HIV1-seropositive cohort. J Infect Dis. 2004;189: 1988-1995.[Medline] [Order article via Infotrieve] Altfeld M, Addo MM, Shankarappa R, et al. Enhanced detection of human immunodeficiency virus type 1-specific T-cell responses to highly variable regions by using peptides based on autologous virus sequences. J Virol. 2003;77: 7330-7340.[Abstract/Free Full Text] De Rosa SC, Lu FX, Yu J, et al. Vaccination in humans generates broad T cell cytokine responses. J Immunol. 2004;173: 5372-5380.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Prognostic value of HIV-1 Gag-specific CD4+ T-cell responses for progression to AIDS analyzed in a prospective cohort study Christine A. Jansen, Iris M. De Cuyper, Berend Hooibrink, Akke K. van der Bij, Debbie van Baarle, and Frank Miedema Blood 2006 107: 1427-1433. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Vanham, G. Search for Related Content PubMed Articles by Vanham, G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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