Antiretroviral Therapy in Simian Immunodeficiency Virus-Infected Sooty Mangabeys: Implications for AIDS Pathogenesis.
Simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) do not develop AIDS despite high levels of viremia. Key factors involved in the benign course of SIV infection in SMs are the absence of chronic immune activation and low levels of infection of CD4(+) central memory (TCM) and stem cell memory (TSCM) T cells. To better understand the role of virus replication in determining the main features of SIV infection in SMs, we treated 12 SMs with a potent antiretroviral therapy (ART) regimen for 2 to 12 months. We observed that ART suppressed viremia to <60 copies/ml of plasma in 10 of 12 animals and induced a variable decrease in the level of cell-associated SIV DNA in peripheral blood (average changes of 0.9-, 1.1-, 1.5-, and 3.7-fold for CD4(+) transitional memory [TTM], TCM, effector memory [TEM], and TSCM cells, respectively). ART-treated SIV-infected SMs showed (i) increased percentages of circulating CD4(+) TCM cells, (ii) increased levels of CD4(+) T cells in the rectal mucosa, and (iii) significant declines in the frequencies of HLA-DR(+) CD8(+) T cells in the blood and rectal mucosa. In addition, we observed that ART interruption resulted in rapid viral rebound in all SIV-infected SMs, indicating that the virus reservoir persists for at least a year under ART despite lower infection levels of CD4(+) TCM and TSCM cells than those seen in pathogenic SIV infections of macaques. Overall, these data indicate that ART induces specific immunological changes in SIV-infected SMs, thus suggesting that virus replication affects immune function even in the context of this clinically benign infection.



Studies of natural, nonpathogenic simian immunodeficiency virus (SIV) infection of African monkeys have provided important insights into the mechanisms responsible for the progression to AIDS during pathogenic human immunodeficiency virus (HIV) infection of humans and SIV infection of Asian macaques. In this study, for the first time, we treated SIV-infected sooty mangabeys, a natural host for the infection, with a potent antiretroviral therapy (ART) regimen for periods ranging from 2 to 12 months and monitored in detail how suppression of virus replication affected the main virological and immunological features of this nonpathogenic infection. The observed findings provide novel information on both the pathogenesis of residual immunological disease under ART during pathogenic infection and the mechanisms involved in virus persistence during primate lentiviral infections.
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.|L. Sacco Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy.
Francesca
F
Calascibetta
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Luca
L
Micci
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Diane
D
Carnathan
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Benton
B
Lawson
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Thomas H
TH
Vanderford
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Steven E
SE
Bosinger
Department of Biostatistics & Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
Kirk
K
Easley
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.|Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Ann
A
Chahroudi
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Joseph
J
Mackel
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Brandon F
BF
Keele
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Samuel
S
Long
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Jeffrey
J
Lifson
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
Mirko
M
Paiardini
Yerkes National Primate Research Center and Emory Vaccine Center, Emory University, Atlanta, Georgia, USA gsilves@emory.edu.|Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Guido
G
Silvestri
D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D001769:Blood / Q000276:immunology / Q000821:virology; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016665:Cercocebus atys; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D016180:Lentivirus Infections / Q000188:drug therapy / Q000473:pathology / Q000662:veterinary* / Q000821:virology; D018419:Primate Diseases / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000302:isolation & purification; D019562:Viral Load
D044966:Anti-Retroviral Agents