Identification of Ongoing Human Immunodeficiency Virus Type 1 (HIV-1) Replication in Residual Viremia during Recombinant HIV-1 Poxvirus Immunizations in Patients with Clinically Undetectable Viral Loads on Durable Suppressive Highly Active Antiretroviral Therapy

Johns Hopkins University, Baltimore, MD 21287, USA.
Journal of Virology (Impact Factor: 4.44). 07/2009; 83(19):9731-42. DOI: 10.1128/JVI.00570-09
Source: PubMed


In most human immunodeficiency virus type 1 (HIV-1)-infected individuals who achieve viral loads of <50 copies/ml during highly active antiretroviral therapy (HAART), low levels of plasma virus remain detectable for years by ultrasensitive methods. The relative contributions of ongoing virus replication and virus production from HIV-1 reservoirs to persistent low-level viremia during HAART remain controversial. HIV-1 vaccination of HAART-treated individuals provides a model for examining low-level viremia, as immunizations may facilitate virus replication and sequence evolution. In a phase 1 trial of modified vaccinia virus Ankara/fowlpox virus-based HIV-1 vaccines in 20 HIV-infected young adults receiving HAART, we assessed the prevalence of low-level viremia and sequence evolution, using ultrasensitive viral load (<6.5 copies/ml) and genotyping (five-copy sensitivity) assays. Viral evolution, consisting of new drug resistance mutations and novel amino acid changes within a relevant HLA-restricted allele (e.g., methionine, isoleucine, glutamine, or arginine for leucine at position 205 of RT), was found in 1 and 3 of 20 subjects, respectively. Sequence evolution was significantly correlated with levels of viremia of between 6.5 and <50 copies/ml (P = 0.03) and was more likely to occur within epitopes presented by relevant HLA alleles (P < 0.001). These findings suggest that ongoing virus replication contributes to low-level viremia in patients on HAART and that this ongoing replication is subject to CD8(+) T-cell selective pressures.

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Available from: Stuart C Ray, Dec 22, 2014
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    • "Similarly , in a more recent study of 20 patients with VL < 50 copies/mL, sequences were obtained for 12 study participants, and evidence for selection of CTL escape mutations was found in three patients (Shiu et al., 2009). These five studies all found evidence of accumulation of CTL escape mutations during ART, with the rate of accumulation correlated with the level of ongoing viral replication in two studies (Shiu et al., 2009; Knapp et al., 2012). This observation may indicate that at lower VLs, CTL responses exert less pressure on the virus, due to the reduced number of circulating HIV-specific CTL (see below). "
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    • "Neutralization and inhibition assays using human monoclonal antibodies, pooled HIV-positive patient sera, autologous maternal plasma, or HIV-1 entry inhibitors were performed as previously described [22,23,56-58], using 200 sfu of pseudovirus to infect TZMbl cells, with residual infection measured using the β-galactosidase readout. To determine the activity of CCR5 antagonists, the assay was modified such that cell monolayers were incubated with serial dilutions of the inhibitors for one hour before the addition of virus. "
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    • "Additional evidence includes that viral RNA in the ileum and cellular activation decreases with integrase inhibitors (Yukl et al., 2010), that activated CD4+ T cells have higher levels of DNA than resting CD4+ T cells in patients on HAART (Chun et al., 2005), and that the apparent in vivo half-life of unintegrated HIV DNA is greater than the in vitro half-life (Koelsch et al., 2008). In addition, studies following patients who are vaccinated suggest that there are bursts of replication that occur at times of hyper-immune activation (Shiu et al., 2009). Arguments against this theory include the lack of viral evolution in a subset of patients on HAART (Dahl and Palmer, 2009; Joos et al., 2008; Shen and Siliciano, 2008) and the fact that intensification regimens appear to have no effect on reservoir size (Dinoso et al., 2009a; Gandhi et al., 2010; Jones et al., 2009). "
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