title: Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques.
abstract: AIDS virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from CD4+T-cell infection. One likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. To test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-simian immunodeficiency virus (anti-SIV) activity into rhesus macaques 3 days following an intrarectal SIV inoculation. To measure in vivo antiviral activity, we assessed the number of viruses transmitted using SIVmac239X, a molecularly tagged viral stock containing 10 genotypic variants, at a dose calculated to transmit 12 founder viruses. Single-genome sequencing of plasma virus revealed that the two animals receiving T cells expressing SIV-specific T-cell receptors (TCRs) had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (means of 4.0 versus 7.5 transmitted viral genotypes; P = 0.044). Accounting for the likelihood of transmission of multiple viruses of a particular genotype, the calculated means of the total number of founder viruses transmitted were 4.5 and 14.5 in the experimental and control groups, respectively (P = 0.021). Thus, a large antiviral T-cell response timed with virus exposure can limit viral transmission. The presence of strong, preexisting T-cell responses, including those induced by vaccines, might help prevent the establishment of infection at the lower-exposure doses in humans that typically transmit only a single virus.
  
  
  OBJECTIVE
  The establishment of AIDS virus infection in an individual is essentially a race between the spreading virus and host immune defenses. Cell-mediated immune responses induced by infection or vaccination are important contributors in limiting viral replication. However, in human immunodeficiency virus (HIV)/SIV infection, the virus usually wins the race, irreversibly crippling the immune system before an effective cellular immune response is developed and active. We found that providing an accelerated response by adoptively transferring large numbers of antiviral T cells shortly after a high-dose mucosal inoculation, while not preventing infection altogether, limited the number of individual viruses transmitted. Thus, the presence of strong, preexisting T-cell responses, including those induced by vaccines, might prevent infection in humans, where the virus exposure is considerably lower.
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Victor I
authors: VI
authors: Ayala
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Matthew T
authors: MT
authors: Trivett
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Eugene V
authors: EV
authors: Barsov
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Sumiti
authors: S
authors: Jain
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Michael
authors: M
authors: Piatak
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Charles M
authors: CM
authors: Trubey
authors: DMS Applied Information & Management Sciences, Frederick National Laboratory for Cancer Research, Maryland, USA.
authors: W Gregory
authors: WG
authors: Alvord
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Elena
authors: E
authors: Chertova
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: James D
authors: JD
authors: Roser
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Jeremy
authors: J
authors: Smedley
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Alexander
authors: A
authors: Komin
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Brandon F
authors: BF
authors: Keele
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors: Claes
authors: C
authors: Ohlen
authors: AIDS and Cancer Virus Program and Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA ottde@mail.nih.gov.
authors: David E
authors: DE
authors: Ott
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002478:Cells, Cultured; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D008253:Macaca mulatta / Q000276:immunology* / Q000821:virology*; D018449:SAIDS Vaccines / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D014779:Virus Replication / Q000235:genetics
chemical_list: D018449:SAIDS Vaccines