CMV is a double-stranded DNA virus that, in normal individuals, induces a febrile illness that resembles mononucleosis from EBV, with chills, fatigue, headache, and malaise (Gandhi and Khanna 2004). In immunocompromised patients, such as those who have undergone bone marrow or other organ transplantation or who have advanced human immunodeficiency virus (HIV) disease, CMV can cause considerable morbidity and mortality. CMV may be reactivated in a previously infected person who becomes immunosuppressed. Alternatively, a de novo CMV infection may be transmitted to a CMV-negative recipient of an organ from a CMV-positive donor. Many organs can be affected by CMV infection, including the retina, lung, liver, esophagus, or colon. CMV can also cause complications to a fetus infected in utero, including hearing loss, visual loss, and neurological complications (Fowler et al. 1992). CMV hyperimmune globulins (CMVIG) first demonstrated efficacy in the treatment of disease associated with kidney transplants (Snydman et al. 1987). Since then, CMVIG has been approved by the FDA for treatment of CMV reactivation in patients with transplants of the kidney, heart, lung, liver, and pancreas (Sawyer 2000). Evidence does not clearly support the use of IVIG or CMVIG in allogeneic bone marrow transplant patients (Zikos et al. 1998; Sokos et al. 2002). The utility of CMVIG in organ transplant settings has been lessened by the availability of potent small molecule anti-CMV drugs, such as ganciclovir, valganciclo-vir, foscarnet, and cidofovir, even though these drugs have significant toxicities (Biron 2006). It is possible that CMVIG may synergize with small molecule anti-CMV drugs in some clinical situations (Kocher et al. 2003; Varga et al. 2005; Ruttmann et al. 2006).
Many native human monoclonal antibodies specific for CMV have been described (Emanuel et al. 1984; Redmond et al. 1986; Foung et al. 1989; Bron et al. 1990; Kitamura et al. 1990; Drobyski et al. 1991; Gustafsson et al. 1991; Ohizumi et al. 1992; Ohlin et al. 1993; Rioux et al. 1994). Some of these were found to be capable of neutralizing CMV in vitro (Redmond et al. 1986; Foung et al. 1989; Ohizumi et al. 1992; Ohlin et al. 1993). The native human CMV antibody, MSL-109, has been tested for clinical efficacy (Drobyski et al. 1991). In a randomized controlled trial of allogeneic hematopoietic stem cell transplant patients, no benefit from the antibody was seen in terms of the time to development of CMV viremia or pp65 antigenemia (Boeckh et al. 2001). Studies of the MSL-109 antibody in AIDS patients with newly diagnosed or recurrent CMV retinitis did not show a reduction in the progression of CMV disease (CDC 1997a; Borucki et al. 2004). The explanation for these disappointing results is unclear.
The MSL-109 antibody is specific for the H glycoprotein (gp86). It is possible that an antibody specific for the B glycoprotein complex (gp58/116), a major target of CMV neutralizing antibodies, may be useful alone or in combination with an anti-H antibody (Ohlin et al. 1993). Nonetheless, the most likely explanation may be that T cell function is essential for CMV control in vivo and that neutralizing antibodies are minimally active in the absence of robust T cell activity (Boeckh et al. 2003).
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