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Adoptive Transfer of Engineered Rhesus SIV-Specific CD8+ T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques.

Adoptive Transfer of Engineered Rhesus SIV-Specific CD8+ T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques.
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Ayala VI, Trivett MT, Barsov EV, Jain S, Piatak M, Trubey CM, Alvord WG, Chertova E, Roser JD, Smedley J, Komin A, Keele BF, Ohlen C, Ott DE,


Ayala VI, Trivett MT, Barsov EV, Jain S, Piatak M, Trubey CM, Alvord WG, Chertova E, Roser JD, Smedley J, Komin A, Keele BF, Ohlen C, Ott DE, (click to view)

Ayala VI, Trivett MT, Barsov EV, Jain S, Piatak M, Trubey CM, Alvord WG, Chertova E, Roser JD, Smedley J, Komin A, Keele BF, Ohlen C, Ott DE,

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Journal of virology 2016 8 24() pii

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 a large, timely, and effective response could potentially reduce the establishment of infection from a high dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-SIV activity into rhesus macaques three 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 TCRs had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (mean 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 mean of total founder viruses transmitted is 4.5 versus 14.5 in the experimental and control groups respectively, p=0.021. Thus, a large antiviral T-cell response temporally 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.

IMPORTANCE
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 to infection or induced by vaccination are important contributors in limiting viral replication. However, in 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.

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