Limits...
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.

Show MeSH

Related in: MedlinePlus

Viral rebound kinetics after ART discontinuationLog plasma viral RNA (copies/ml) in animals following discontinuation of ART at week 24 in monkeys that initiated ART on days 3, 7, 10, and 14 of infection (a). Assay sensitivity is 50 RNA copies/ml. Median times to viral rebound, defined as the first timepoint at which plasma viral RNA was >50 copies/ml, is also shown by the red bars (b). Median setpoint viral loads following viral rebound, defined as day 56–112 following ART discontinuation, are also shown by the red bars in ART treated monkeys compared with untreated monkeys (c). P-values reflect one-sided t-tests.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126858&req=5

Figure 4: Viral rebound kinetics after ART discontinuationLog plasma viral RNA (copies/ml) in animals following discontinuation of ART at week 24 in monkeys that initiated ART on days 3, 7, 10, and 14 of infection (a). Assay sensitivity is 50 RNA copies/ml. Median times to viral rebound, defined as the first timepoint at which plasma viral RNA was >50 copies/ml, is also shown by the red bars (b). Median setpoint viral loads following viral rebound, defined as day 56–112 following ART discontinuation, are also shown by the red bars in ART treated monkeys compared with untreated monkeys (c). P-values reflect one-sided t-tests.

Mentions: At week 24, ART was discontinued, and animals were monitored twice weekly for evidence of viral rebound. Viral rebound, defined as plasma viral RNA >50 copies/ml, occurred in all animals (Fig. 4a). In particular, viral rebound occurred in 4 of 4 animals that initiated ART on day 3, albeit with 3-fold delayed kinetics as compared with animals that initiated ART at later timepoints (median 21 days to viral rebound in the day 3 treated animals compared with 7 days in the day 14 treated animals; P<0.001; Fig. 4b). The median log setpoint viral load following rebound, defined as viral loads on days 56–112 following ART discontinuation, was also 1.04 log RNA copies/ml lower for all the ART treated animals as compared with untreated controls (4.59 log RNA copies/ml for all treatment groups combined vs. 5.63 log RNA copies/ml for untreated animals; P=0.01; Fig. 4c), suggesting a benefit to early ART, although no significant differences were observed among setpoint viral loads in the day 3, 7, 10, and 14 treatment groups. Setpoint viral loads in the untreated animals were comparable with historical controls9,10. Taken together, these data show that the persistent viral reservoir was seeded by day 3 of infection and led to viral rebound in all animals following ART discontinuation.


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)

Viral rebound kinetics after ART discontinuationLog plasma viral RNA (copies/ml) in animals following discontinuation of ART at week 24 in monkeys that initiated ART on days 3, 7, 10, and 14 of infection (a). Assay sensitivity is 50 RNA copies/ml. Median times to viral rebound, defined as the first timepoint at which plasma viral RNA was >50 copies/ml, is also shown by the red bars (b). Median setpoint viral loads following viral rebound, defined as day 56–112 following ART discontinuation, are also shown by the red bars in ART treated monkeys compared with untreated monkeys (c). P-values reflect one-sided t-tests.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Viral rebound kinetics after ART discontinuationLog plasma viral RNA (copies/ml) in animals following discontinuation of ART at week 24 in monkeys that initiated ART on days 3, 7, 10, and 14 of infection (a). Assay sensitivity is 50 RNA copies/ml. Median times to viral rebound, defined as the first timepoint at which plasma viral RNA was >50 copies/ml, is also shown by the red bars (b). Median setpoint viral loads following viral rebound, defined as day 56–112 following ART discontinuation, are also shown by the red bars in ART treated monkeys compared with untreated monkeys (c). P-values reflect one-sided t-tests.
Mentions: At week 24, ART was discontinued, and animals were monitored twice weekly for evidence of viral rebound. Viral rebound, defined as plasma viral RNA >50 copies/ml, occurred in all animals (Fig. 4a). In particular, viral rebound occurred in 4 of 4 animals that initiated ART on day 3, albeit with 3-fold delayed kinetics as compared with animals that initiated ART at later timepoints (median 21 days to viral rebound in the day 3 treated animals compared with 7 days in the day 14 treated animals; P<0.001; Fig. 4b). The median log setpoint viral load following rebound, defined as viral loads on days 56–112 following ART discontinuation, was also 1.04 log RNA copies/ml lower for all the ART treated animals as compared with untreated controls (4.59 log RNA copies/ml for all treatment groups combined vs. 5.63 log RNA copies/ml for untreated animals; P=0.01; Fig. 4c), suggesting a benefit to early ART, although no significant differences were observed among setpoint viral loads in the day 3, 7, 10, and 14 treatment groups. Setpoint viral loads in the untreated animals were comparable with historical controls9,10. Taken together, these data show that the persistent viral reservoir was seeded by day 3 of infection and led to viral rebound in all animals following ART discontinuation.

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