Reactivation of ancestral strains of HIV-1 in the gp120 V3 env region in patients failing antiretroviral therapy and subjected to structured treatment interruption

Abstract

We analyzed gp120V3 HIV-1 env region genetic diversity of 27 patients failing antiretrovirals and subjected to 12-week structured treatment interruption (STI). Based on heteroduplex mobility assays, eight patients presented low pre- and post-STI genetic diversity (G1); five presented high pre-STI but low post-STI diversity (G2); five presented low pre-STI and high post-STI diversity (G3); and nine, high pre- and post-STI diversity (G4). One patient from G1, two from G2 and two from G3 were subjected to proviral DNA end-point PCR and sequencing. In three patients, the dramatic disturbance caused by STI resulted in ancestral viral progeny activation, which repopulated the cell reservoir. In two patients presenting highly homogeneous sequences and low immune selective pressure (dN/dS ratio <1), this phenomenon was not observed. The mechanisms involved in viral evolution, in which antiretroviral therapy also applies selective pressure, sometimes affects coreceptor usage of circulating viruses, leading to the suppression of x4 strains.

Envelope Gene Evolution and HIV-1 Neuropathogenesis

“…Thus, HIV-1 env evolution plays a key role in and significantly influences HAND progression. To date, neurological comorbidities due to HIV-1 infection continue to be a significant clinical challenge, despite ongoing long-term cART, as the reactivation of latent virus may continue to burden HIV + subjects (77). Although cART does not eradicate HIV-infection, studies should aim to understand whether env evolution in viral reservoirs causes the neurotoxic and neurovirulent attributes in neuronal and glial cultures and animal models to be retained.…”

“…For example, in some patients, C2V3 plasma variants have been recovered despite those patients having undergone successful therapy (76). Reactivation of HIV-1 strains occurs because of therapy failure or after antiretroviral treatment interruption (77). The interruption of antiretroviral regimens often triggers rebound viremia that is genetically similar to isolated latent reservoirs (78).…”

“…Changes in the genetic composition within the V3 region of env can show there to be either an increase or decrease in genetic diversity (77). Moreover, the genetic complexity of the gp120 V3 region of the viruses in 17 out of 27 patients who interrupted antiretroviral therapy changed over a period of 12 weeks (77).…”

“…Moreover, the genetic complexity of the gp120 V3 region of the viruses in 17 out of 27 patients who interrupted antiretroviral therapy changed over a period of 12 weeks (77). The genetic diversity of the HIV-1 viral pool often remains low during suppressive antiretroviral therapy (75, 79).…”

Treatment interruption in chronic HIV-1 infection: does it deliver?

“…The re-emergence of R5 viral strains has been shown during treatment interruption, whereas the dominant X4 strain was suppressed [25]. Both archived drug-resistant viruses and newly selected drug-resistant viruses have, however, been measured upon the re-initiation of treatment [5,26].…”