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Old and new plasma biomarkers in HIV-1-infected African–American women

Poli, Guido

doi: 10.1097/QAD.0b013e32834a1e77
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AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.

Correspondence to Guido Poli, AIDS Immunopatogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, Via Olgettina n. 58, 20132 Milan, Italy. Tel: +39 02 2643 4909; fax: +39 02 2643 4905; e-mail: poli.guido@hsr.it

Received 4 June, 2011

Accepted 21 June, 2011

The search of correlates of HIV disease progression (or of its lack) that may shed light on its immunopathogenesis has been pursued for decades, starting with ‘old markers’ such as neopterin [1] and acid-labile interferon-α (IFNα) [2]. Both biomarkers showed a tight correlation with the secretion of IFNγ by immune cells [in particular by, CD4+ T helper-1 (Th1) cells, CD8+ T lymphocytes and natural killer cells] activated, directly or indirectly, by the HIV replication.

In the present issue of AIDS, Keating et al. have evaluated a panel of 32 candidate markers in the plasma/serum of HIV-1-positive US women, mostly of African–American ethnicity [3]. The infected population was subdivided into those receiving HAART and successfully controlling their viremia (i.e. showing HIV-1 RNA <80 copies/ml) vs. women who did not receive HAART and failed to spontaneous control virus replication (plasma HIV-1 RNA > 10 000 copies/ml); a group of age-matched HIV-seronegative, healthy women served as further control. A central finding of the study was that most ‘pro-inflammatory’ biomarkers tested did not differ among the three groups of women, whereas a few did in a clear-cut fashion. Tumor necrosis factor-α (TNFα), a pro-inflammatory cytokine that fuels HIV transcription by activating the host transcription factor nuclear factor-κB [4], correlated with higher viremia levels, as other studies have reported [5]. A chemokine, CXCL10, previously known as IFNγ-inducible protein (IP-10) [6], and shown to stimulate HIV-1 replication in vitro[7], was also positively correlated with the levels of viremia and to lower CD4+ T-cell counts. Conversely, chemokines previously credited with anti-HIV effects, namely CCL4/macrophage inflammatory protein-1β [8] and CCL22/macrophage-derived chemokine [9,10], showed an inverse correlation with viremia. Of note, this inverse correlation was also demonstrated in the case of CX3CL1/fractalkine and interleukin-17 (IL-17). CX3CL1/fractalkine has been hypothesized to represent a driver of HIV replication and pathogenesis [11], particularly in the central nervous system [12], also due to the potential use of its receptor as HIV-1 entry coreceptor [13]. In addition, a polymorphism of its receptor observed in whites (CX3CR1-I249 M280) and leading to decreased binding of the chemokine was strongly associated with an accelerated disease progression [14]. IL-17 is a pro-inflammatory cytokine elaborated by the Th17 subset of T lymphocytes and other cells and it is known to play a role in allergy, inflammation and autoimmune diseases [15]. Although the potential role of IL-17 in HIV replication remains unexplored, Th17 and Th1/Th17 cells have been reported to be exquisitely sensitive to HIV infection both in vivo and in vitro[16,17].

However, the most intriguing finding of the study was that three growth factors, namely epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor2 (FGF2), that is, ‘cytokine-like’ molecules usually connected to the regulation of growth and differentiation of epithelial or endothelial cells or fibroblasts, were also positively correlated with the number of circulating CD4+ T cells in infected women assuming HAART. Concerning the role of these (and potentially other) growth factors in HIV infection, a few indications of their involvement in HIV disease already exist. Expression of HIV-1 Gag was shown to decrease the downregulation of EGF receptor [18], whereas the regulatory protein Tat could induce the transcription and the release of basic FGF in glomerular epithelial cells known as podocytes [19]. Concerning VEGF, infected individuals discordant for their response to HAART (i.e. not recovering significantly in terms of CD4+ T-cell counts) showed significantly higher levels of plasma VEGF and EGF in respect to concordant patients [20], whereas elevated levels of VEGF were observed in an immunodeficient mouse model of HIV-induced encephalitis [21].

Although these results are clearly interesting and novel, at least in part, the study bears important limitations, first of all the relative small number of participants included. Second, African–American women, the dominant ethnical group in the study, are known to show higher basal levels of pro-inflammatory markers even in the absence of overt disease [22,23]. Third, the role of hepatitis C virus co-infection (as analyzed and discussed by the authors) needs to be evaluated with an appropriately tailored study, particularly concerning the role of CX3CL1/fractalkine in liver fibrogenesis [24]. Fourth, as mentioned by the authors, a prospective study evaluating the ‘performance’ of the biomarkers here identified in HIV-1-positive women (and eventually men as well) initiating HAART is needed in order to confirm these findings. Finally, the observation that some markers, such as CXCL10/IP-10, were not found elevated in previous reports using conventional ELISA assays and not multiplex tests (as adopted by the authors) underscores the importance of independent validation studies in the field of biomarkers [25].

From a pathogenetic viewpoint, a striking observation is that several biomarkers associated with primary HIV infection [26] were not found significantly perturbed in the present study. This apparent discrepancy underscores the completely different biology of a still intact immune system undergoing rapid activation in the attempt to counteract the ex-novo viral attack from that of a chronically infected individual in whom the ‘scars’ of the antiviral fight are mixed with the progressive state of immunological deficiency (yet curtailed by HAART).

In conclusion, this study reminds us that the interaction of HIV with the human immune system and its broader consequences for tissue homeostasis have not been yet completely understood, leaving the door open for identifying novel markers of disease progression and stimulating the search for better strategies of immunological reconstitution.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

CD4+ T cells; chemokines; cytokines; HAART; HIV

© 2011 Lippincott Williams & Wilkins, Inc.