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A rationale for new therapeutic approaches in HIV-1 eradication

Posted by mauro_magnani on 03 Jul 2010 at 09:47 GMT

Berger & Pastan [1] have underlined the urgent need of developing therapeutic strategies aimed at eradicating HIV-1 infections. The rationale is clearly explained and widely accepted by the international scientific community, namely: HAART from blocking specific steps of the HIV replication cycle prevents new rounds of infection but fail to kill cells that are already infected. Thus, the solution can not be found in HAART “intensification”. Furthermore, attempts to activate latently infected cells have not provided evident clinical benefits [2]. Berger & Pastan suggest that the solution could be found in complementing HAART treatments with immunotoxins, particularly those that are directed against HIV-1 gp120 and contains the C-terminal domain of Pseudomonas exotoxin A. Indeed this approach was already tested several years ago, without success [3], but the Authors now argue that the specificity of the immunotoxin has been greatly improved and that the use of the same, in conjunction with HAART, makes a significant difference over the previous strategy.
Independently of the immunotoxin domain responsible for the target specificity, there are abundant preclinical and clinical evidences to suggest caution in the use of this class of compounds (for a review see [4]). Most of the experience comes from cancer treatments were these immunotoxins have some clinical benefit in treating haematological malignancies but fail in reaching solid tumours. In addition to previous safety concerns, already documented in the cited clinical trials [4], I would like to ad one specific for the use of these new drugs in HIV-1 patients. It has recently been recognized that HIV-1 infection is associated with significantly high plasma lipopolysaccharide concentrations (LPS) and that this correlate with progression to disease [5, 6]. It has been independently documented [7] that multiple organ injury caused by Pseudomonas exotoxin A, are exacerbate by the presence of bacterial lipopolysaccharides. Thus, safety of exotoxin A in HIV-1 infected patients needs to be evaluated considering the possible presence of circulating LPS. Immunogenicity is another critical point to be considered. In nearly all clinical studies a high percentage of patients developed anti-immunotoxin antibodies [4].
Although the use of immunotoxins need to be carefully evaluated in terms of safety and efficacy, certainly the main question raised by Berger & Pastan [1] about the development of unconventional strategies to clear the HIV-1 reservoirs by approaches that does not simply interfere with viral production but also kill infected cells, especially macrophages, need to be addressed. I would like to bring to the attention of PLoS readership that HIV-1 infection of cell reservoirs is associated with the expression of a set of cell genes that are essential for viral expression (or latency) and cell survival [8,9]. In other words, the host infected cell reservoirs activate a specific programme to manage the presence of HIV-1 without succumbing to infection. Thus, investigation in this host response could help in the identification of potential new drug targets.
Few years ago we provided the first evidence that HIV-1 infection of human macrophages is associated with expression and phosphorylation of STAT-1. STAT-1 is a survival factor in infected macrophages and its elimination results in the killing of the infected cells. Is this feasible in the clinic? Probably yes. Experiments in spontaneously simian immunodeficiency infected sooty mangabeys have documented that the targeted administration of Fludarabine (drug that target phosphoSTAT-1) to infected macrophages results in the elimination of these cells saving the non-infected ones [10]. In conclusion, I agree with Berger & Pastan [1] about the possibility of developing new strategies aiming at clearing the infected reservoirs. Because of the risk associated with the immunotoxin approach I’m convinced that we must explore also alternative approaches. In particular, the identification of new cell targets, indispensable for the survival of infected cells, could represent a reasonable alternative to be complemented with the current HAART treatments.

1. Berger EA, Pastan I. (2010) Immunotoxin complementation of HAART to deplete persisting HIV-infected cell reservoirs. PLoS Pathog. 2010 Jun 10;6(6):e1000803.

2. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. (2009) The challenge of finding a cure for HIV infection. Science. 323(5919):1304-7.

3. Ramachandran RV, Katzenstein DA, Wood R, Batts DH, Merigan TC.(1994) Failure of short-term CD4-PE40 infusions to reduce virus load in human immunodeficiency virus-infected persons. J Infect Dis. 170(4):1009-13.

4. Wolf P, Elsässer-Beile U. (2009) Pseudomonas exotoxin A: from virulence factor to anti-cancer agent. Int J Med Microbiol. 299(3):161-76.

5. Nowroozalizadeh S, Månsson F, da Silva Z, Repits J, Dabo B, Pereira C, Biague A, Albert J, Nielsen J, Aaby P, Fenyö EM, Norrgren H, Holmgren B, Jansson M (2010) Microbial translocation correlates with the severity of both HIV-1 and HIV-2 infections. J Infect Dis. 201(8):1150-4.

6. Wallet MA, Rodriguez CA, Yin L, Saporta S, Chinratanapisit S, Hou W, Sleasman JW, Goodenow MM. (2010) Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T-cell activation following therapy. AIDS 24(9):1281-90.

7. Chuang HL, Chiu CC, Chen TH, Chen HH, Chu YY, Huang YT. (2009) Different bacteria species lipopolysaccharide co-exposure with Pseudomonas exotoxin A on multiple organ injury induction. Immunopharmacol Immunotoxicol. 31(4):616-24.

8. Vázquez N, Greenwell-Wild T, Marinos NJ, Swaim WD, Nares S, Ott DE, Schubert U, Henklein P, Orenstein JM, Sporn MB, Wahl SM. (2005) Human immunodeficiency virus type 1-induced macrophage gene expression includes the p21 gene, a target for viral regulation. J Virol. 79(7):4479-91.

9. Giri MS, Nebozhyn M, Showe L, Montaner LJ. (2006) Microarray data on gene modulation by HIV-1 in immune cells: 2000-2006. J Leukoc Biol. 80(5):1031-43.

10. Cervasi B, Paiardini M, Serafini S, Fraternale A, Menotta M, Engram J, Lawson B, Staprans SI, Piedimonte G, Perno CF, Silvestri G, Magnani M. (2006) Administration of fludarabine-loaded autologous red blood cells in simian immunodeficiency virus-infected sooty mangabeys depletes pSTAT-1-expressing macrophages and delays the rebound of viremia after suspension of antiretroviral therapy. J Virol. 80(21):10335-45.

No competing interests declared.