Giving monkeys antiretroviral therapy from just three days after exposure to simian immunodeficiency virus does not prevent a subsequent rebound of viral replication, suggesting that viral reservoirs are established early. See Letter p.74
Although antiretroviral therapy (ART) is successful in controlling HIV-1 replication, the virus persists in a stable latent reservoir in infected cells that have entered a resting state1,2,3,4. In these immune cells, called resting memory CD4+ T cells, the viral genome hides as pure genetic information integrated into the cells' DNA (as proviral DNA), unaffected by ART or immune responses. But when the cells are subsequently activated, this viral reservoir again releases replication-competent HIV-1, and it is therefore considered the main barrier to curing HIV-1 infection5. Despite vigorous efforts to understand the latent reservoir in the hope of finding ways to purge it, it has been unclear when it is seeded and whether early treatment can prevent this. On page 74 of this issue, Whitney et al.6 provide evidence in the simian immunodeficiency virus (SIV) model of HIV-1 infection that the reservoir is seeded very early — during the first few days of infection.
It had been assumed that the initial seeding of the latent reservoir occurs during acute HIV-1 infection, at a point when viraemia — the presence of viruses in the blood — has risen to a high level7. It was proposed that if ART is begun before peak viraemia occurs, this might prevent the reservoir from becoming established, or at least significantly reduce its size. Recent clinical studies confirmed that early ART can indeed reduce the size and dissemination of the viral reservoir8,9,10, and even promote long-term control of the virus in some infected individuals after treatment has ended11,12.
Interest in the possibility of viral-eradication strategies based on early ART initiation was further heightened by the case of the 'Mississippi baby', a child who was born to an infected mother and who had around 20,000 viral copies per millilitre of blood plasma at birth13. The child was started on ART 30 hours after delivery and was treated for 18 months. The virus was undetectable by 29 days, and remained so for 27 months after treatment was stopped, when rebound viraemia was detected14. Delayed and highly variable time to rebound is the predicted outcome of interventions that reduce the reservoir to a very low level15.
To evaluate the temporal dynamics of initial viral-reservoir seeding, Whitney and colleagues treated rhesus macaques starting on days 3, 7, 10 or 14 after SIV infection. Although initiating treatment on days 7, 10 and 14 significantly reduced peak plasma virus levels, treatment from day 3 completely blocked the emergence of detectable viraemia; this was also evidenced by the absence of SIV-specific antibody-based and cellular immune responses in these animals. The authors found no proviral DNA in the animals' peripheral-blood mononuclear cells (which include CD4+ T cells) before treatment initiation on day 3, but proviral DNA was already detectable in their lymph nodes and the mucosal linings of the gastrointestinal tract. This crucial finding suggests that the viral reservoir may be first seeded in the lymphoid and mucosal tissues, a result with important implications for HIV-1 eradication strategies.
Most significantly, the authors observed viral rebound in all animals after ART was stopped. This occurred even when ART that fully suppressed detectable viraemia was initiated at day 3 and continued for 6 months, a treatment period that allows elimination of labile infected cells and thus reveals stable reservoirs. The observed rebound suggests that the viral reservoir is seeded surprisingly early in SIV-infected animals. However, the animals treated from day 3 showed a slightly delayed viral rebound compared with those that started ART at later times. Using a sophisticated model of viral dynamics, the authors show that the time to viral rebound is correlated with total viraemia during the acute phase of infection.
These data indicate that the viral reservoir could be seeded substantially earlier than previously assumed — a sobering finding that poses additional hurdles to HIV-1 eradication efforts. If this evidence from SIV-infected animals reflects what happens early in HIV-1 infection in humans, it would mean that it is nearly impossible to initiate ART before viral reservoirs have seeded, because viraemia is not detectable at this point. In other words, reservoir seeding precedes any clinical evidence of infection. However, although early treatment may not prevent reservoir seeding, it has been consistently shown to reduce the size of the latent reservoir8,9,10, and infected individuals who receive early treatment could have a lower barrier to cure in future eradication strategies.
Whitney and colleagues' findings are of particular interest in light of a study last year16 reporting that a disseminated SIV infection could be cleared by vaccine-induced T-cell-based immune responses. The different outcomes of these two studies may be partly due to the fate of infected cells during acute infection. Early initiation of ART immediately stops subsequent new infection of susceptible cells, but does not affect the fate of cells that are already infected. A small fraction of these infected cells survive and revert back to a resting state, thereby seeding the latent reservoir (Fig. 1). By contrast, vaccinated animals have pre-existing SIV-specific cytotoxic T cells that can clear the infected cells before they go into latency, thus preventing the viral reservoir from becoming established.
It remains to be seen whether clinical studies will confirm Whitney and colleagues' observations, because substantial differences exist between SIV infection in rhesus macaques and HIV-1 infection in humans. As mentioned by the authors, the SIV dose used in their study may be much higher than the typical amount of HIV-1 involved in sexual transmission, perhaps resulting in a higher level of early viral replication. Nevertheless, the striking findings of the early seeding of the viral reservoir in mucosal and lymphoid tissues before viraemia is detected suggest that new approaches, in addition to early treatment, will be necessary to eradicate HIV-1 infection.
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Deng, K., Siliciano, R. Early treatment may not be early enough. Nature 512, 35–36 (2014). https://doi.org/10.1038/nature13647
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