Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy

Mary F Kearney,John W Mellors,Carry Poethke,John M Coffin,Wei Shao,Sloane Yu,Elizabeth M Anderson,Frank Maldarelli,Catherine Rehm,Angeline O'Shea,Jonathan Spindler,Nicholas Kovacs

doi:10.1371/journal.ppat.1004010

Abstract

A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1–15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident.

Highlights

The HIV-1 lifecycle includes rapid and error prone nucleic acid replication that results in large and genetically diverse virus populations in vivo
By characterizing genetic sequences of HIV in patients before and during antiviral treatment, we found that the low levels of virus detected in the blood of treated patients did not result from newly infected cells but originated from cells, or the daughters of cells, that were already infected when treatment was initiated
This finding demonstrates that HIV present in blood after prolonged antiviral treatment is derived from cells infected prior to treatment which likely expanded over time through cell division

Summary

Introduction

The HIV-1 lifecycle includes rapid and error prone nucleic acid replication that results in large and genetically diverse virus populations in vivo. The consequences of broad HIV-1 genetic diversity include the presence of viral variants containing mutations that escape immune responses or confer resistance to individual antiretroviral agents. The use of antiretroviral agents in combination results in potent suppression of HIV-1 replication and reverses immune deficiency, at least in part. Despite the ability of cART to inhibit HIV-1 replication, treatment does not eradicate infection and plasma viremia persists at low levels in the majority of patients [1,2]. Determining the sources and mechanisms for viral persistence during cART and rebound after interruption is essential for designing strategies to eradicate infection

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Discussion

Conclusion