 |
|
|
| |
Early Results With Antiretrovirals Plus Immunotoxins That Target Viral Reservoirs
|
| |
| |
HIV DART 2008,
December 9-12, 2008,
Rio Grande, Puerto Rico
Mark Mascolini
Immunotoxins that target resting HIV-infected cells could prove a valuable adjunct to antiretroviral therapy, according to Edward Berger of the National Institute of Allergy and Infectious Diseases, who discovered the CXCR4 coreceptor on CD4 cells [1]. Several years of immunotoxin research show that combining these agents with antiretrovirals prevents viral rebound after antiretroviral treatment stops in a mouse model of HIV infection. Immunotoxins alone kill cells chronically infected with HIV while largely sparing uninfected cells.
Berger outlined results on two immunotoxins. CD-PE40 is a recombinant single-chain chimeric protein containing the translocation and cytotoxic domains of Pseudomonas aeruginosa exotoxin A linked to a specific protein that binds to HIV-1 Env. This immunotoxin targets Env with soluble CD4. 3B3-PE38 is a similar construct, but it homes in on Env with a single-chain antibody fragment (scFv) of the 3B3 monoclonal antibody.
CD4-PE40 killed chronically HIV-infected cells at a 50% inhibitory concentration (IC50) of approximately 2 nM. 3B3-PE38 killed the cells much more efficiently, at an IC50 of 0.03 nM. Both immunotoxins limited viral spread in peripheral blood mononuclear cells in experiments using HIV-1 isolates of various strains, with 3B3-PE38 again flexing more antiviral muscle [2]. 3B3-PE38 also blocked spreading infection in primary macrophages. The immunotoxins had negligible activity against cells not infected by HIV.
In a mouse model of HIV infection, antiretrovirals strongly suppressed viral replication, but viral loads rebounded as soon as treatment stopped [3]. When the investigators treated mice with both antiretrovirals and CD4-PE40 or 3B3-PE38, viral load did not rebound for up to 1 month after treatment stopped.
The investigators observed liver toxicity when administering high-level CD4-PE40 to rhesus macaques. But monkeys treated with high-level 3B3-PE38 showed no signs of hepatotoxicity. The latter result is consistent with trials of anticancer PE-based immunotoxins in humans [4]. In those studies the immunotoxins induced remission of leukemias and lymphomas without serious liver toxicity.
Berger and colleagues hope to launch a clinical trial in 2009 to see if pairing immunotoxins with antiretrovirals "might deplete infected reservoirs sufficiently to enable prolonged cessation of therapy without viral rebound." He acknowledged, though, that many questions remain in developing immunotoxins as antiretroviral adjuncts, including which cellular reservoirs and anatomic sites they should target, whether latently infected cells will have to be activated for immunotoxins to work, whether immunotoxins will have to mop up every infected cell to work, and whether toxicity will limit their use.
References
1. Berger EA, Kennedy PE, Bera TK, Gallo M, I Pastan I. Immunotoxins to selectively deplete reservoirs of HIV-infected cells that persist in the face of highly suppressive antiretroviral therapy. HIV DART 2008, December 9-12, 2008, Rio Grande, Puerto Rico. Abstract 09.
2. Kennedy PE, Bera TK, Wang QC, et al. Anti-HIV-1 immunotoxin 3B3(Fv)-PE38: enhanced potency against clinical isolates in human PBMCs and macrophages, and negligible hepatotoxicity in macaques. J Leukoc Biol. 2006;80:1175-1182.
3. Goldstein H, Pettoello-Mantovani M, Bera TK, Pastan IH, Berger EA. Chimeric toxins targeted to the human immunodeficiency virus type 1 envelope glycoprotein augment the in vivo activity of combination antiretroviral therapy in thy/liv-SCID-Hu mice. J Infect Dis. 2000;181:921-926.
4. Kreitman RJ, Wilson WH, Bergeron K, et al. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med. 2001;345:241-247.
|
| |
|
|
|
|
|
