Continued Production of Drug-Sensitive Human Immunodeficiency Virus Type 1 in Children on Combination Antiretroviral Therapy Who Have Undetectable Viral Loads

Department of Pediatrics, Johns Hopkins University School of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21205, USA.
Journal of Virology (Impact Factor: 4.44). 02/2004; 78(2):968-79. DOI: 10.1128/JVI.78.2.968-979.2004
Source: PubMed


Highly active antiretroviral therapy (HAART) can suppress plasma human immunodeficiency virus type 1 (HIV-1) levels to below
the detection limit of ultrasensitive clinical assays. However, HIV-1 persists in cellular reservoirs, and in adults, persistent
low-level viremia is detected with more sensitive assays. The nature of this viremia is poorly understood, and it is unclear
whether viremia persists in children on HAART, particularly those who start therapy shortly after birth. We therefore developed
a reverse transcriptase PCR (RT-PCR) assay that allows genotyping of HIV-1 protease even when viremia is present at levels
as low as 5 copies of HIV-1 RNA/ml. We demonstrated that viremia persists in children with plasma virus levels below the limit
of detection of clinical assays. Viremia was detected even in children who began HAART in early infancy and maintained such
strong suppression of viremia that HIV-1-specific antibody responses were absent or minimal. The low-level plasma virus lacked
protease inhibitor resistance mutations despite the frequent use of nelfinavir, which has a low mutational barrier to resistance.
Protease sequences resembled those of viruses in the latent reservoir in resting CD4+ T cells. Thus, in most children on HAART with clinically undetectable viremia, there is continued virus production without
evolution of resistance in the protease gene.

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Available from: George Siberry, Oct 20, 2014
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    • "These few cells capable of producing infectious virions are thought to replenish the viral load back to the levels that were present before treatment was initiated (Dahl and Palmer, 2009; Lassen et al., 2004a,b; Pierson et al., 2000b). There are several consequences of reservoir formation beyond creating treatment resistant sources of virus, including the ability to archive drug resistant virus (Nettles et al., 2005; Persaud et al., 2004). Once a drug resistant virus forms, the virus can be archived in the reservoir and so last for the lifetime of the patient. "
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    ABSTRACT: The main impediment to a cure for HIV is the existence of long-lasting treatment resistant viral reservoirs. In this review, we discuss what is currently known about reservoirs, including their formation and maintenance, while focusing on latently infected CD4+ T cells. In addition, we compare several different in vivo and in vitro models of latency. We comment on how each model may reflect the properties of reservoirs in vivo, especially with regard to cell phenotype, since recent studies demonstrate that multiple CD4+ T cell subsets contribute to HIV reservoirs and that with HAART and disease progression the relative contribution of different subsets may change. Finally, we focus on the direct infection of resting CD4+ T cells as a source of reservoir formation and as a model of latency, since recent results help explain the misconception that resting CD4+ T cells appeared to be resistant to HIV in vitro.
    Full-text · Article · Mar 2011 · Virology
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    • "However, it is currently unclear how much residual replication contributes to HIV persistence. There are several pieces of evidence that argue against residual replication, including the very stable sequence of low-level viremia in plasma [45,46] and the absence of drug-resistant virus in either plasma or CD4+ T cells [47,48]. "
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    ABSTRACT: Combination antiretroviral therapy (cART) has led to a major reduction in HIV-related mortality and morbidity. However, HIV still cannot be cured. With the absence of an effective prophylactic or therapeutic vaccine, increasing numbers of infected people, emerging new toxicities secondary to cART and the need for life-long treatment, there is now a real urgency to find a cure for HIV. There are currently multiple barriers to curing HIV. The most significant barrier is the establishment of a latent or "silent" infection in resting CD4+ T cells. In latent HIV infection, the virus is able to integrate into the host cell genome, but does not proceed to active replication. As a consequence, antiviral agents, as well as the immune system, are unable to eliminate these long-lived, latently infected cells. Reactivation of latently infected resting CD4+ T cells can then re-establish infection once cART is stopped. Other significant barriers to cure include residual viral replication in patients receiving cART, even when the virus is not detectable by conventional assays. In addition, HIV can be sequestered in anatomical reservoirs, such as the brain, gastrointestinal tract and genitourinary tract. Achieving either a functional cure (long-term control of HIV in the absence of cART) or a sterilizing cure (elimination of all HIV-infected cells) remains a major challenge. Several studies have now demonstrated that treatment intensification appears to have little impact on latent reservoirs. Some potential and promising approaches that may reduce the latent reservoir include very early initiation of cART and the use of agents that could potentially reverse latent infection. Agents that reverse latent infection will promote viral production; however, simultaneous administration of cART will prevent subsequent rounds of viral replication. Such drugs as histone deacetylase inhibitors, currently used and licensed for the treatment of some cancers, or activating latently infected resting cells with cytokines, such as IL-7 or prostratin, show promising results in reversing latency in vitro when used either alone or in combination. In order to move forward toward clinical trials that target eradication, there needs to be careful consideration of the risks and benefits of these approaches, agreement on the most informative endpoints for eradication studies and greater engagement of the infected community.
    Full-text · Article · Jan 2011 · Journal of the International AIDS Society
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    • "This low level of ongoing viral replication could contribute to the replenishment of the latent reservoir in at least a subset of patients (Buzon et al., 2010; Ramratnam et al., 2000; Ramratnam et al., 2004). Any level of viral replication would have to be quite low, because several studies indicate that drug resistance does not frequently develop on HAART (Hermankova et al., 2001; Persaud et al., 2004) and viral evolution cannot be detected in many patients on HAART (Kieffer et al., 2004; Nettles et al., 2004; Nottet et al., 2009; Shen and Siliciano, 2008; Tobin et al., 2005). Alternative explanations, such as undetected viral blips or undetected low level viremia and 2-LTR circles that have accumulated over time prior to the initiation of therapy, could also account for this excess of total HIV DNA. "
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    ABSTRACT: HIV establishes a latent reservoir early in infection that is resistant to anti-retroviral therapy and has a slow rate of decay. It is thought that the majority of HIV DNA in treated patients is integrated since unintegrated HIV DNA appears to be unstable. Thus, to monitor the HIV latent reservoir, total HIV DNA is commonly measured in PBMC from infected individuals. We investigated how often total approaches integrated HIV DNA in treated patients. To do this, we first assessed how accurate our integration assay is and determined the error in our measurements of total and integrated HIV DNA. We demonstrated an excess of total over integrated HIV DNA was present in a subset of patients, suggesting that measurements of total HIV DNA do not always correlate to the level of integration. Determining the cause of this excess and its frequency may have important implications for understanding HIV latent reservoir maintenance.
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