Abstract
The aim of early combined antiretroviral therapy (cART) of HIV is to limit the seeding of the viral reservoir during the initial phase of infection and, consequently, decrease intrahost viral diversity. Here, we assessed the effect of early cART on size and complexity of the proviral reservoir. Peripheral blood mononuclear cell (PBMC) and plasma samples were obtained from ten HIV-infected Brazilian individuals diagnosed at the acute phase of infection, before (PREART) and 12 months (M12ART) after suppressive cART. HIV proviral reservoir size was determined by quantitative real-time PCR; intrahost viral diversity of the env C2-V3 region was assessed by single genome amplification or next-generation sequencing in PBMC and plasma, respectively. Mean nucleotide diversity (π) and normalized Shannon entropy (HSN) were used to infer the complexity of the viral population. Compared to PREART, M12ART saw an immunological recovery with a gain of ∼200 CD4+ T cells (P = 0.008) and a normalization of the CD4/CD8 ratio [1.0 (IQR: 0.88–1.18), P = 0.016], as well as a significant decrease in HIV-1 RNA (∼4 log, P = 0.004) and DNA (∼1 log, P = 0.002) levels. The median time to achieve viral suppression was 3 months (IQR: 2.8–5.8 months). The high intermixing between sequences from both visits suggests that the HIV-1 DNA reservoir remained remarkably stable under cART. After 1 year of cART, there was a minor reduction in proviral π (PreART = 0.20 vs. M12ART = 0.10; P = 0.156) but a significant decrease in HSN (PreART = 0.41 vs. M12ART = 0.25; P = 0.019). We found no correlation between π or HSN at PreART and the rate of HIV DNA decay, T CD4+ counts, or CD4/CD8 ratio at M12ART. Based on a small cohort of Brazilian infected individuals under early cART and analyses of the env region, 1 year of follow-up suggested a reservoir size reduction, allowed a significant decrease of HIV-1 complexity, and achieved immunological restoration regardless of the initial HIV-1 plasma viral load, CD4+ T cell counts, or HIV-1 subtype. However, further studies in the Brazilian setting aiming a longer follow-up and larger cohort are required in this field.
Highlights
Combined antiretroviral therapy suppresses HIV-1 replication and reduces morbidity and mortality, but does not eradicate HIV-1 infection, as a low but persistent level of HIV1 can still be detected in plasma and cell reservoirs (Chun et al, 1997; Kiselinova et al, 2015; Ghosn et al, 2018)
The study included ten HIV-1-infected Brazilian individuals diagnosed during the acute phase of infection, with a median age at diagnosis of 28 years [interquartile range (IQR): 26– 42 years]
A latent HIV-1 reservoir in resting memory CD4+ T cells is recognized as the major barrier to HIV-1 eradication, as its establishment and long-term persistence enables renewed viremia after treatment failure or interruption
Summary
Combined antiretroviral therapy (cART) suppresses HIV-1 replication and reduces morbidity and mortality, but does not eradicate HIV-1 infection, as a low but persistent level of HIV1 can still be detected in plasma and cell reservoirs (Chun et al, 1997; Kiselinova et al, 2015; Ghosn et al, 2018). Latent infected resting memory CD4+ T lymphocytes are the best known HIV1 reservoir, which is established already during early infection. This reservoir includes cells with an integrated copy of the HIV-1 genome that is not expressed while the cells remain in a resting state (Chun et al, 2002; Douek et al, 2002) and is maintained mainly by the cells’ clonal expansion (Chomont et al, 2009, 2011; von Stockenstrom et al, 2015). As the reservoir is established during the acute phase of infection, early cART has been proposed as a means to restrict reservoir size and genetic complexity (Lori et al, 1999; Strain et al, 2005; Chomont et al, 2009; Josefsson et al, 2013)
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