Human cytomegalovirus double resistance in a donor-positive/recipient-negative lung transplant patient with an impaired CD4-mediated specific immune response.
BACKGROUND
Emergence of human cytomegalovirus (HCMV) resistance to ganciclovir in solid-organ transplant recipients has been found to be mostly associated with primary HCMV infection.


METHODS
The case of a donor-positive/recipient-negative (D(+)/R(-)) lung transplant patient developing ganciclovir and cidofovir resistance is described. HCMV infection was monitored by weekly determination of antigenaemia, viraemia and DNAaemia. HCMV-specific CD4 cell immunity was determined by cytokine flow cytometry. The emergence of drug-resistant HCMV strains was documented by sequencing of UL97 and UL54 genes of HCMV directly in blood samples.


RESULTS
Following primary HCMV infection, the patient showed repeated reactivations for over a year, eventually resulting in the selection of a ganciclovir-resistant HCMV strain with a mutation in the UL97 gene product (A594V). Determination of HCMV-specific CD4 cell immunity showed a persistently impaired immune response. Subsequent foscarnet treatment allowed only transitory virus clearance from blood owing to renal toxicity. Further ganciclovir treatment induced a new mutation in both UL97 (H520Q) and UL54 (P522S) with final emergence of double resistance to both ganciclovir and cidofovir. The patient eventually died of lung failure.


CONCLUSIONS
Determination of HCMV-specific CD4 cell immunity could be of help in predicting the emergence of drug-resistant strains in D(+)/R(-) transplant recipients.
Baldanti
Fausto
F
Servizio di Virologia and Laboratori Sperimentali di Ricerca, IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
Lilleri
Daniele
D
Campanini
Giulia
G
Comolli
Giuditta
G
Ridolfo
Anna Lisa
AL
Rusconi
Stefano
S
Gerna
Giuseppe
G
D000956:Antigens, Viral / Q000032:analysis / Q000096:biosynthesis; D000998:Antiviral Agents / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000077404:Cidofovir; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000097:blood / Q000821:virology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004279:DNA, Viral / Q000032:analysis; D024882:Drug Resistance, Viral; D015774:Ganciclovir / Q000494:pharmacology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D008168:Lung / Q000821:virology*; D016040:Lung Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology
D000956:Antigens, Viral; D000998:Antiviral Agents; D016207:Cytokines; D004279:DNA, Viral; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir; D015774:Ganciclovir