Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: Implications for eradication

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
AIDS (London, England) (Impact Factor: 5.55). 10/2010; 24(18):2803-8. DOI: 10.1097/QAD.0b013e328340a239
Source: PubMed


Sustained suppression of plasma viremia in HIV-infected individuals is attainable with antiretroviral therapy (ART); however, eradication of virus that would allow discontinuation of ART has been hampered by the persistence of HIV reservoirs. It is of great interest to identify individuals who had received ART for prolonged periods of time with extremely low or undetectable HIV reservoirs and monitor plasma viremia following discontinuation of therapy.
We measured the size of HIV reservoirs in CD4(+) T cells of individuals on long-term ART and monitored plasma viremia following cessation of ART in one individual with an exceptionally low viral burden after a decade of therapy.
We demonstrated undetectable levels of HIV DNA in the blood of eight of 45 infected individuals on long-term ART. Among those eight individuals, the frequency of cells carrying infectious virus was significantly lower in those who initiated ART during the early versus the chronic phase of infection. One individual with undetectable HIV DNA in both blood and tissue and a profoundly low level of infectious virus experienced plasma viral rebound 50 days following discontinuation of ART.
Our data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection. However, given re-emergence of plasma viremia in an individual with an extraordinarily low viral burden, therapeutic strategies aimed at specifically targeting these extremely rare HIV-infected cells with novel interventions may be necessary in order to achieve eradication of virus.

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    • "This viral rebound is due to release of HIV from reservoirs throughout the body (Blankson et al., 2002). Within these reservoirs, HIV is kept in a transcriptionally silent or latent state, but can reactivate to undergo HIV replication following appropriate stimulation (Bukrinsky et al., 1991; Chun et al., 1997) or cessation of antiretroviral pressures (Chun et al., 2010). Given that viral reservoirs are the main reason for our inability to eradicate HIV, there is strong interest in understanding the processes involved in the formation and persistence of these reservoirs. "
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    • "Treatment during PHI seems to result in broad and strong HIV- 1 specific immune responses (Hecht et al., 2006; Kaufmann et al., 2004; Lisziewicz et al., 1999; Moir et al., 2010; Ortiz et al., 1999; Oxenius et al., 2000; Rosenberg et al., 2000), reduced immune activation (Volberding et al., 2009), immune restoration in the gastrointestinal mucosa (Guadalupe et al., 2006) and limited viral evolution (Chamberland et al., 2011). Additionally, initiation of cART during PHI may limit the establishment of viral reservoirs (Archin et al., 2012b; Chun et al., 2010; Gianella et al., 2011; Pires et al., 2004; Schmid et al., 2010; Wyl et al., 2011). Central memory CD4 þ T cells (T CM ) are a key component of the long-lasting HIV reservoir (Chomont et al., 2009), and recent studies have demonstrated that very early cART limits the seeding of the HIV reservoir in long-lived T CM (Fig. 2) (Ananworanich et al., 2013. "
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    • "The most frequently cited explanations are: 1) the preservation of an efficient immune response [34,35], 2) the induction of a “self-vaccination” after multiple STIs [16,18], and 3) the impairment of viral reservoir formation [27,29,36-38]. A reduced viral reservoir size does not per se guarantee successful ART withdrawal [39], but is, even in the most conservative scenario, a promising platform in the quest of a cure. The overwhelming majority of HIV+ individuals, however, are diagnosed during the chronic phase of the infection, and a large body of evidence shows that STI protocols (even in the form of short “drug holidays”) are not effective in improving the course of the disease once the chronic phase is established ([40-42], reviewed in: [43]). "
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