Abstract
Resting CD4+ T cells are a reservoir of latent HIV-1. Understanding the turnover of HIV DNA in these cells has implications for the development of eradication strategies. Most studies of viral latency focus on viral persistence under antiretroviral therapy (ART). We studied the turnover of SIV DNA resting CD4+ T cells during active infection in a cohort of 20 SIV-infected pigtail macaques. We compared SIV sequences at two Mane-A1*084:01-restricted CTL epitopes using serial plasma RNA and resting CD4+ T cell DNA samples by pyrosequencing, and used a mathematical modeling approach to estimate SIV DNA turnover. We found SIV DNA turnover in resting CD4+ T cells was slow in animals with low chronic viral loads, consistent with the long persistence of latency seen under ART. However, in animals with high levels of chronic viral replication, turnover was high. SIV DNA half-life within resting CD4 cells correleated with viral load (p = 0.0052) at the Gag KP9 CTL epitope. At a second CTL epitope in Tat (KVA10) there was a trend towards an association of SIV DNA half-life in resting CD4 cells and viral load (p = 0.0971). Further, we found that the turnover of resting CD4+ T cell SIV DNA was higher for escape during early infection than for escape later in infection (p = 0.0084). Our results suggest viral DNA within resting CD4 T cells is more labile and may be more susceptible to reactivation/eradication treatments when there are higher levels of virus replication and during early/acute infection.
Highlights
The clinical outcome for HIV-infected individuals has improved dramatically since the development of potent combination antiretroviral therapies [1,2]
KP9 escape using pyrosequencing compared to qRT-PCR We first analysed the evolution of immune escape at the KP9 epitope in resting CD4 T cells comparing the pyrosequencing data to the qRT-PCR data
We found that the proportion of KP9 wild type (WT) virus in resting CD4+ T cell SIV DNA from animals obtained using nested pyrosequencing was very similar to the proportion of KP9 WT virus estimated using the nested KP9-specific qRT-PCR (Figure 1A)
Summary
The clinical outcome for HIV-infected individuals has improved dramatically since the development of potent combination antiretroviral therapies (cART) [1,2]. Several eradication studies aimed at purging HIV-1 from the latent reservoir are currently in progress [7,8,9]. Preliminary results of clinical studies of purging using current drugs suggests that these may have only a small impact on the total latent reservoir [10,11,12,13,14]. It is likely there will need to be a better use of current agents, perhaps in combination with newer agents, to have a clinically useful benefit in reducing the latent reservoir. Little is known about the turnover of HIV DNA during active infection, and whether this may be a better time for interventions to reduce latency. SIV infection of macques provides a model to study the dynamics of latent HIV infection where the timing and strain of the infection is known
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