Alteration of cytokine levels in murine retrovirus infection: modulation by combination therapy.
Immunoregulatory cytokines may regulate the resistance or susceptibility of a host to retroviral infection. These cytokines may be therapeutically modulated to prevent or limit the progression of infection. The non-progression to AIDS of some HIV+ patients has been related to a strong type 1 cytokine response (IL-2, IL-12, and IFNgamma). For this reason, we investigated the ability of combination therapeutics to modulate cytokines in vivo towards a type 1 cytokine response in a murine retroviral infection using Friend leukemia virus (FLV). BALB/c mice were infected with FLV and treated with either 3'-azido-3'-deoxythymidine (AZT), the immunomodulator methionine enkephalin (MENK), or a combination of both AZT and MENK starting 3 d post infection. Splenocytes were harvested on days 1, 3, 7, 14, 21 and 28 post treatment initiation and cultured with 1 microg/ml concanavalin A (ConA) for 24 h. Supernatants were examined for IL-2, IL-4, IL-10, IL-12, and IFNgamma cytokine production using cytokine specific ELISAs. The levels of type 2 cytokines were not significantly changed by any treatment group over the course of the disease. However, although decreased in all infected animals, type 1 cytokines were partially maintained by the combination treatment through day 21. RT-PCR for cytokine specific mRNA confirmed these results, with expression of the type 1 cytokines, especially IFNgamma, being maintained through day 21. Establishment of a treatment regime that can maintain protective cytokine activities against disease progression may prove applicable to other retroviral infections.
Bowden
R
R
Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa 33612, USA.
Tate
S M
SM
Soto
S
S
Specter
S
S
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D004744:Enkephalin, Methionine / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005622:Friend murine leukemia virus; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D007942:Leukemia, Experimental / Q000097:blood* / Q000188:drug therapy / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D012192:Retroviridae Infections / Q000097:blood* / Q000188:drug therapy / Q000628:therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014412:Tumor Virus Infections / Q000097:blood* / Q000188:drug therapy / Q000628:therapy; D015215:Zidovudine / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D015215:Zidovudine; D004744:Enkephalin, Methionine