Background: Recent reports suggest that early treatment intervention during primary HIV infection has a profound impact on the viral reservoir. Indeed, the case of the Mississippi baby and the VISCONTI cohort suggests that reservoirs established early during acute HIV replication may be quantitatively and qualitatively different from reservoirs established later in chronic infection and perhaps be more amenable to cure. Here we sought to investigate the effect of early treatment on the viral reservoir in SIV-infected rhesus macaques (RM) when antiretroviral therapy (ART) is initiated either prior to peak viral replication, at or near peak viral replication, or in early chronic infection. Methodology: To test the effect of timing of treatment on viral reservoirs, RM infected intravenously with SIVmac239 were subjected to multi-drug ART consisting of tenofovir, emtricitabine, dolutegravir and darunavir boosted with ritonavir starting day 7 (group A), day 10 (group B) or day 42 (group C) postchallenge. Plasma viral loads (pvl) and cell-associated viral loads of peripheral blood mononucleocytes (PBMC), bone marrow (BM), small intestinal mucosa (GUT) and lymph node (LN) biopsy samples were assessed by real-time quantitative PCR/RT-PCR at various time points. Results: In group A (n=2), pvl continued to rise after therapy was initiated, peaking by day 12 to an average of 71000 SIV RNA copies/ml then declined below the limit of detection (<30 copies/ml) after just 6 weeks of ART. In group B (n=2), pvl peaked on day 12 to an average of 1.8x10e6 copies/ml and required 18 weeks of ART to decline below the limit of detection. In group C (n=18), peak pvl was reached between days 12-14 to an average of 1.4x10e7 copies/ml but complete virus suppression was not achieved in all RM even after 20 weeks of ART. SIV DNA per 10e8 PBMC were on average 1020, 8606, 43914 copies in groups A, B and C, respectively, at 17 weeks post-challenge and a combined analysis showed there was a significant correlation between peak plasma SIV RNA and the levels of total SIV DNA in PBMC (p=0.03). In addition, SIV DNA in LN, BM and GUT were lower, on average 497, 1929 and 324 copies/10e8 cells, respectively, in group A, compared with an average of 9647, 4069 and 35090 copies/10e8 cells, respectively, in group B 17 weeks post-challenge. Conclusions: These results demonstrate that early ART, when initiated prior to peak virus replication, limits systemic virus dissemination and seeding of the reservoir in peripheral and extra lymphoid mucosal compartments. A delay as short as three days during the “hyperacute” phase can result in over a log higher tissue-based reservoir size, once therapy is started and maintained. Aggressive monitoring for acute infection with immediate introduction of ART could profoundly influence treatment outcomes.
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