18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

HIV-1 PLASMA VIRUS DIVERSITY PERSISTS DESPITE SUPPRESSION WITH ANTIRETROVIRAL THERAPY

Antivir Ther 2009; 14 Suppl 1:A8 (abstract no. 6)

M Kearney¹, S Yu¹, W Shao¹, JW Mellors², JM Coffin¹ and F Maldarelli^1
1HIV Drug Resistance Program, National Cancer Institute, Frederick, MD, USA; ²Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

BACKGROUND: After initiation of antiretroviral therapy (ART), HIV-1 RNA levels in plasma decrease markedly; however, the effect of ART on plasma HIV-1 diversity has been incompletely characterized. We therefore analysed HIV-1 genetic variation in patients prior to and following initiation of suppressive ART.

METHODS: HIV-1-infected patients (n=10) were sampled frequently for up to 4 years after initiating therapy. A total of 1,105 HIV-1 gag–pro–pol (p6-RT) sequences were obtained by single genome sequencing (SGS) immediately prior to ART, after initiating ART and after HIV-1 RNA decreased to <75 copies/ml. Diversity was measured in aligned sequences by average pairwise difference (APD) and evidence for genetic variation over time was determined by phylogenetic analyses and by a test for panmixia.

RESULTS: Before therapy, HIV-1 sequences had intra- patient APD levels of 0.2–2.5% per site. After initiation of therapy, HIV-1 RNA levels decreased with first phase half-lives of approximately 1–1.5 days. ART reduced plasma viral RNA levels to undetectable (<75 copies/ml) in all patients within 5 months. Phylogenetic analyses and measurements of intrapatient APD revealed no change in diversity or population structure between pre- and post- ART samples despite up to 4 log₁₀ decreases in virus RNA levels for >1 year. After 4 years on suppressive ART, the appearance of a predominant plasma clone (PPC), similar to that described by Bailey et al. was found in one patient. The virus population containing the PPC after therapy was significantly different (P<10^-10) from the pretherapy virus population by tests for panmixia and divergence (2.9% different), although the PPC variant could be at both times. Phylogenetic analyses did not identify new populations emerging during ART in any of the patients. Drug resistance mutations were not detected prior to or during therapy.

CONCLUSIONS: HIV-1 gag-pro-pol genetic diversity did not change significantly despite 10,000-fold reduction in viremia with suppressive ART. These data suggest that both short-and long-lived cells are infected with similar virus populations before therapy is initiated and that active cycles of HIV-1 replication are completely blocked by ART.

2009-06-09
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