Rapid, Transient Changes at the env Locus of Plasma Human Immunodeficiency Virus Type 1 Populations during the Emergence of Protease Inhibitor Resistance

Abstract

Plasma human immunodeficiency virus type 1 (HIV-1) populations were genetically analyzed at their most variable locus, the envelope gene, during the rapid emergence of resistance to protease inhibitor monotherapy. Plasma virus populations remained genetically constant prior to drug treatment and during the 1 to 2 weeks following initiation of therapy, while viremia fell 10- to 100-fold. Concomitant with rapid plasma viremia rebounds associated with the emergence of drug-resistant virus, marked alterations were then detected at the env locus. Plasma population changes lasted only a few weeks before the reappearance of the pretreatment envelope variants. The emergence of resistance to single protease inhibitors was therefore associated with major but transient changes at a nonselected locus. Selection for resistance to single protease inhibitors thus appears to be more complex than the continued replication of a large, random, and therefore genetically representative sampling of the pretreatment plasma population. The possibility that drug-privileged anatomical sites containing distinct envelope variants and/or a small effective HIV-1 population size account for these results is discussed.

Antiretroviral-Drug Concentrations in Semen: Implications for Sexual Transmission of Human Immunodeficiency Virus Type 1

“…Delwart and coworkers reported that plasma viral rebound after suppression by protease inhibitors was associated with the initial appearance of viral populations (present before the initiation of drug treatment) containing envelope sequences distinct from those in the wild-type population (22). This finding suggests the possibility of repopulation from a viral sanctuary (such as the genital tract) where drug concentrations and viral suppression may have been inadequate.…”

Evolution of the Hepatitis C Virus Second Envelope Protein Hypervariable Region in Chronically Infected Patients Receiving Alpha Interferon Therapy

“…Similar phenomena could also occur in other genomic regions, such as the core, E1, NS2, and NS3, which are known to change during therapy but to a lesser extent than HVR1 and the NS5A gene central region (16), as a result of the interaction with other IFN-induced selection pressures. Changes in different regions may even be linked, as has already been suggested for other viruses (11).…”

Impact of antiretroviral pressure on selection of primary human immunodeficiency virus type 1 envelope sequences in vitro

“…Because viruses were placed under in vivo selective pressure using at least two anti-HIV drugs and by the host immune response, it is difficult to separate the different effects and to draw clear conclusions, particularly in vivo. Delwart et al (1998) and Kitrinos et al (2005) avoided some of these limitations by employing a heteroduplex tracking assay, although in vivo peculiarities still remained. Therefore, we used an in vitro selection system using unique bulk primary isolates established in our laboratory (Hatada et al, 2010;Shibata et al, 2007;Yoshimura et al, 2006Yoshimura et al, , 2010b to observe the effects of the anti-retroviral druginduced bottleneck on the IN and env genes.…”

“…Combination antiretroviral (ARV) therapy results in a contraction of the viral population, which represents a potential genetic bottleneck (Charpentier et al, 2006;Delwart et al, 1998;Ibáñez et al, 2000;Kitrinos et al, 2005;Nijhuis et al, 1998;Nora et al, 2007;Sheehy et al, 1996;Zhang et al, 1994). Whilst this bottleneck has a direct effect on the region that is being targeted by the drugs (e.g.…”

“…protease or reverse transcriptase), it also affects other regions of the viral genome. Indeed, the effect of the druginduced genetic bottleneck on the population dynamics of the envelope (Env) regions has been addressed in several in vivo studies (Charpentier et al, 2006;Delwart et al, 1998;Ibáñez et al, 2000;Kitrinos et al, 2005;Nijhuis et al, 1998;Nora et al, 2007;Sheehy et al, 1996;Zhang et al, 1994).…”