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Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys.

Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M, Parenteau L, Cabral C, Shields J, Blackmore S, Smith JY, Brinkman AL, Peter LE, Mathew SI, Smith KM, Borducchi EN, Rosenbloom DI, Lewis MG, Hattersley J, Li B, Hesselgesser J, Geleziunas R, Robb ML, Kim JH, Michael NL, Barouch DH - Nature (2014)

Bottom Line: Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points.The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation.This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

View Article: PubMed Central - PubMed

Affiliation: 1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.

ABSTRACT
The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

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Ultrasensitive plasma viral loads in monkeys during ART.Log plasma viral RNA (copies/ml) at week 20 in rhesus monkeys infected with SIVmac251 and following initiation of ART on days 3, 7, 10, and 14 of infection. Assay sensitivity is 6 RNA copies/ml.
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Figure 7: Ultrasensitive plasma viral loads in monkeys during ART.Log plasma viral RNA (copies/ml) at week 20 in rhesus monkeys infected with SIVmac251 and following initiation of ART on days 3, 7, 10, and 14 of infection. Assay sensitivity is 6 RNA copies/ml.

Mentions: Following initial control of viremia, all animals treated with ART exhibited undetectable plasma viral loads (<50 RNA copies/ml) for the full 24 week course of suppressive therapy with no detectable viral blips (Fig. 1a), demonstrating the potency and consistency of this ART regimen. Moreover, ultrasensitive plasma viral load assays at week 20 also proved negative (<6 RNA copies/ml)13 in all animals (Extended Data Fig. 2). In addition, viral sequences from stimulated PBMC from ART suppressed, SIV-infected monkeys using the same ART regimen revealed no viral sequence evolution over 6 months in a separate study (J.B.W., unpublished data). Furthermore, treatment intensification studies in SIV-infected rhesus monkeys in which the protease inhibitor darunavir was added to the current ART regimen did not lead to improved virologic control (R.G., unpublished data). Taken together, these data suggest that the ART regimen that was utilized in the present study was fully suppressive.


Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys.

Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M, Parenteau L, Cabral C, Shields J, Blackmore S, Smith JY, Brinkman AL, Peter LE, Mathew SI, Smith KM, Borducchi EN, Rosenbloom DI, Lewis MG, Hattersley J, Li B, Hesselgesser J, Geleziunas R, Robb ML, Kim JH, Michael NL, Barouch DH - Nature (2014)

Ultrasensitive plasma viral loads in monkeys during ART.Log plasma viral RNA (copies/ml) at week 20 in rhesus monkeys infected with SIVmac251 and following initiation of ART on days 3, 7, 10, and 14 of infection. Assay sensitivity is 6 RNA copies/ml.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126858&req=5

Figure 7: Ultrasensitive plasma viral loads in monkeys during ART.Log plasma viral RNA (copies/ml) at week 20 in rhesus monkeys infected with SIVmac251 and following initiation of ART on days 3, 7, 10, and 14 of infection. Assay sensitivity is 6 RNA copies/ml.
Mentions: Following initial control of viremia, all animals treated with ART exhibited undetectable plasma viral loads (<50 RNA copies/ml) for the full 24 week course of suppressive therapy with no detectable viral blips (Fig. 1a), demonstrating the potency and consistency of this ART regimen. Moreover, ultrasensitive plasma viral load assays at week 20 also proved negative (<6 RNA copies/ml)13 in all animals (Extended Data Fig. 2). In addition, viral sequences from stimulated PBMC from ART suppressed, SIV-infected monkeys using the same ART regimen revealed no viral sequence evolution over 6 months in a separate study (J.B.W., unpublished data). Furthermore, treatment intensification studies in SIV-infected rhesus monkeys in which the protease inhibitor darunavir was added to the current ART regimen did not lead to improved virologic control (R.G., unpublished data). Taken together, these data suggest that the ART regimen that was utilized in the present study was fully suppressive.

Bottom Line: Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points.The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation.This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

View Article: PubMed Central - PubMed

Affiliation: 1] Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.

ABSTRACT
The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.

Show MeSH
Related in: MedlinePlus