Effects of monotherapy with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) on the evolution of a primary Simian immunodeficiency virus (SIV) isolate.
Determining the impact of antiretroviral therapy on virus evolution could advance the development of improved therapeutics/vaccines against HIV. Toward this goal, we analyzed virus burden, quasispecies complexity, and T cell responses in SIV/DeltaB670-infected rhesus macaques+/-treatment for 7 months with PMPA (2-30 weeks postinfection). Treatment divided the animals into two groups: poor responders (a reduction of < or =1 log) and responders (> or =2 log reduction) in virus burden. Virus evolution in poor responders and untreated controls was characterized by expression of a complex quasispecies that evolved as the disease progressed. This included the universal loss of a viral genotype selected against by in vitro passage in monkey cells and selected for by propagation in human cells. In contrast, a good response to PMPA was characterized by infection with a less complex quasispecies that evolved more slowly. Interestingly, in 2 of the best responders, the human-preferred genotype persisted until the study was discontinued (89 weeks p.i.). Neither virus burden nor the magnitude of the T cell response at 2 weeks postinfection predicted PMPA responsiveness. However, responders expressed a less complex quasispecies than nonresponders prior to treatment. These data suggest a role for intrinsic host factors in treatment responsiveness, and lend support for therapeutic vaccination as an adjunct to effective therapy.
Taber
Rachel
R
Department of Molecular Genetics and Biochemistry, BSTWR E1240, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Rajakumar
Premeela A
PA
Fuller
Deborah Heydenburg
DH
Trichel
Anita M
AM
Dowling
Patricia
P
Meleason
David
D
Amedee
Angela
A
Murphey-Corb
Michael
M
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D016679:Genome, Viral; D005838:Genotype; D006031:Glycosylation; D020180:Heteroduplex Analysis; D006801:Humans; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D017385:Sequence Homology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D000068698:Tenofovir; D019562:Viral Load; D014779:Virus Replication
D000998:Antiviral Agents; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine