Neutralization Patterns and Evolution of Sequential HIV Type 1 Envelope Sequences in HIV Type 1 Subtype B-Infected Drug-Naive Individuals

Abstract

To design a vaccine that will remain potent against HIV-1, the immunogenic regions in the viral envelope that tend to change as well as those that remain constant over time must be identified. To determine the neutralization profiles of sequential viruses over time and study whether neutralization patterns correlate with sequence evolution, 12 broadly neutralizing plasmas from HIV-1 subtype B-infected individuals were tested for their ability to neutralize sequential primary HIV-1 subtype B viruses from four individuals. Three patterns of neutralization were observed, including a loss of neutralization sensitivity by viruses over time, an increase in neutralization sensitivity by sequential viruses, or a similarity in the sensitivity of sequential viruses to neutralization. Seven to 11 gp160 clones from each sequential virus sample were sequenced and analyzed to identify mutational patterns. Analysis of the envelope sequences of the sequential viruses revealed changes characteristic of the neutralization patterns. Viruses that evolved to become resistant to neutralizing antibodies also evolved with diverse sequences, with most of the changes being due to nonsynonymous mutations occurring in the V1/V2, as well as in the constant regions (C2, C3, C4), the most changes occurring in the C3. Viruses from the patient that evolved to become more sensitive to neutralization exhibited less sequence diversity with fewer nonsynonymous changes that occurred mainly in the V1/V2 region. The V3 region remained constant over time for all the viruses tested. This study demonstrates that as viruses evolve in their host, they either become sensitive or resistant to neutralization by antibodies in heterologous plasma and mutations in different envelope regions account for these changes in their neutralization profiles.

Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses

“…CH0457 Env sequences did not show accumulation of Env mutations at nAb contact sites suggested by epitope mapping (Tables S2–S4). Other studies have shown that V3 in chronic infection either did not change (Nyambi et al, 2008) or accumulated sensitivity mutations over time (Haldar et al, 2011), and V3 epitopes otherwise sensitive to mAbs can be occluded by other regions of Env (Upadhyay et al, 2014). Thus, both common CD4bs and V3 tier 1 virus-nAbs can select virus escape mutants that shape the autologous virus reservoir towards neutralization resistance.…”

“…In chronic infection breadth develops for heterologous tier 1 viruses and viruses can evolve in response to those nAbs (Haldar et al, 2011; Kelly et al, 2005; Nyambi et al, 2008). However, autologous virus-neutralizing mAbs isolated from HIV-1-infected people have been strictly strain-specific with no detectable heterologous tier 1 or tier 2 HIV-1 neutralization (Derdeyn et al, 2014) (DC Montefiori, personal communication).…”

HIV gp120 H375 Is Unique to HIV-1 Subtype CRF01_AE and Confers Strong Resistance to the Entry Inhibitor BMS-599793, a Candidate Microbicide Drug

“…A high mutation rate, coupled with the production of up to 10 10 to 10 12 virions per day (24,59), permits the founder HIV-1 to rapidly adapt to in vivo selective pressures, such as immune and/or drug pressure (21). HIV-1 genetic variability, both within and among hosts, contributes to the complexity of both vaccine and drug development (4,10,28,34,43,46,48,50,51,54,57,61,63,69,81).…”

Neutralizing Antibody Responses and Evolution of the Viral Envelope in the Course of HIV-1 Korean Clade B Infection

“…HIV-1 envelope glycoprotein (Env) is the primary viral antigen that is targeted by neutralizing antibodies, so genetic variation in the env gene of HIV-1 is closely related to the neutralizing antibody response [3,4].…”