title: Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection.
abstract: Off-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4+ T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir.
  
  
  OBJECTIVE
  The HIV reservoir in CD4+ T cells represents one main obstacle to HIV eradication. Recent studies, however, show that a drastic reduction of this reservoir is insufficient for inducing a functional cure of AIDS. In the present work, we thoroughly studied and subjected to long-term follow-up two macaques showing intermittent control of the virus following suspension of antiretroviral therapy plus an experimental antireservoir treatment, i.e., the gold salt auranofin and the investigational chemotherapeutic agent buthionione sulfoximine (BSO). We found that these drugs were able to decrease the number of activated CD4+ T cells, which are preferential targets for HIV infection. Then, efficient immune responses against the virus were developed in the macaques, which remained healthy during 2 years of follow-up. This result may furnish another building block for future attempts to cure HIV/AIDS.
authors.affiliation: Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Iart Luca
authors.initials: IL
authors.lastname: Shytaj
authors.affiliation: Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Nickel
authors.affiliation: Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Arts
authors.affiliation: Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Farrell
authors.affiliation: Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.affiliation: ABL, Rockville, Maryland, USA.
authors.forename: Ranajit
authors.initials: R
authors.lastname: Pal
authors.affiliation: ABL, Rockville, Maryland, USA.
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Chung
authors.affiliation: Duke University, Durham, North Carolina, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: LaBranche
authors.affiliation: Duke University, Durham, North Carolina, USA.
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.affiliation: Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Vargas-Inchaustegui
authors.affiliation: Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Robert-Guroff
authors.affiliation: Bioqual, Inc., Rockville, Maryland, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Lewis
authors.affiliation: Vaccine and Gene Therapy Institute and Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health Science University, Portland, Oregon, USA.
authors.forename: Jonah B
authors.initials: JB
authors.lastname: Sacha
authors.affiliation: Department of Public Health and Infectious Diseases, Pasteur Institute-Fondazione Cenci-Bolognetti Istitute, Sapienza University of Rome, Rome, Italy IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Palamara
authors.affiliation: Istituto Superiore di Sanità, Rome, Italy andrea.savarino@iss.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Savarino
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D015683:Gene Products, gag; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D006801:Humans; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D015683:Gene Products, gag