HIV-1 genetic variation and drug resistance development

Abstract

Up until 10 years ago, basic and clinical HIV-1 research was mainly performed on HIV-1 subtype B that predominated in resource-rich settings. Over the past decade, HIV-1 care and therapy has been scaled up substantially in Latin America, Africa and Asia. These regions are largely dominated by non-B subtype infections, and especially the African continent is affected by the HIV pandemic. Insight on the potency of antiviral drugs and regimens as well as on the emergence of drug resistance in non-B subtypes was lacking triggering research in this field, also partly driven by the introduction and spreading of HIV-1 non-B subtypes in Europe. The scope of this article was to review and discuss the state-of-the-art on the impact of HIV-1 genetic variation on the in vitro activity of antiviral drugs and in vivo response to antiviral therapy; as well as on the in vitro and in vivo emergence of drug resistance.

Keywords::

• genetic variation
• HIV-1
• mutation
• resistance
• subtype
• susceptibility
• treatment outcome

Financial & competing interests disclosure

K Van Laethem was supported by the AIDS Reference Laboratory of Leuven that receives support from the Belgian Ministry of Social Affairs 805 through a fund within the Health Insurance System. S Megens was supported by the University of Leuven (Program Financing no. PF/10/018). This work was partly supported by Fonds voor Wetenschappelijk Onderzoek Vlaanderen (grants 1.5.236.11N and G.06.11.09) and by the European Community's Seventh Framework Programme (FP7/2007-2013) under the project ‘Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)’ grant agreement number 223131. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Human immunodeficiency virus (HIV-1) genetic variation has resulted into the emergence of several subtypes and recombinant forms.

• • In vitro susceptibility testing toward all antiviral drug classes displays broad activity against all HIV-1 group M strains with evidence of low-level reduced and increased susceptibility against particular strains, due to the technical assay variability and the presence of particular polymorphisms.

• • Therapy-naïve HIV-1 group O strains are characterized with similar in vitro susceptibilities toward the majority of antiviral drugs as HIV-1 group M strains, but display resistance against non-nucleoside RTI (NNRTI).

• • Differences in genetic barrier and phenotypic interactions between codons at the NT and AA level result in different frequencies of typical drug resistance mutations and the emergence of atypical drug resistance mutations among subtypes.

• • The HIV-1 genetic variation might impact the in vivo response to antiviral therapy, but evidence from recent clinical and cohort studies reveals mostly comparable responses among HIV-1 group M subtypes.

• • The performance of laboratory tests should be permanently evaluated and they should be adapted to the changing (sub-) epidemic and to the state-of-the art.