Low Human Immunodeficiency Virus Envelope Diversity Correlates with Low In Vitro Replication Capacity and Predicts Spontaneous Control of Plasma Viremia after Treatment Interruptions

Abstract

Genetic diversity of viral isolates in human immunodeficiency virus (HIV)-infected individuals variessubstantially. However, it remains unclear whether HIV-related disease progresses more rapidly in patients harboring virus swarms with low or high diversity and, in the same context, whether high or low diversity is required to induce potent humoral and cellular immune responses. To explore whether viral diversity predicts virologic control, we studied HIV-infected patients who received antiretroviral therapy (ART) for years before undergoing structured treatment interruptions (STI). Viral diversity before initiation of ART and the ability of the patients to contain viremia after STI and final cessation of treatment was evaluated. Seven out of 21 patients contained plasma viremia at low levels after the final treatment cessation. Clonal sequences encompassing the envelope C2V3C3 domain derived from plasma prior to treatment, exhibited significantly lower diversity in these patients compared to those derived from patients with poor control of viremia. Viral diversity pre-ART correlated with the viral replication capacity of rebounding virus isolates during STI. Neutralizing antibody activity against autologous virus was significantly higher in patients who controlled viremia and was associated with lower pretreatment diversity. No such association was found with binding antibodies directed to gp120. In summary, lower pretreatment viral diversity was associated with spontaneous control of viremia, reduced viral replication capacity and higher neutralizing antibody titers, suggesting a link between viral diversity, replication capacity, and neutralizing antibody activity.

Neutralizing Antibodies Do Not Mediate Suppression of Human Immunodeficiency Virus Type 1 in Elite Suppressors or Selection of Plasma Virus Variants in Patients on Highly Active Antiretroviral Therapy

“…The diversity of the viral quasispecies may be a key determinant of the development and maintenance of NAb against autologous virus (47). In a study of patients undergoing structured treatment interruption, lower diversity prior to treatment correlated with better autologous virus neutralization and better viral suppression after HAART interruption (25). The diversity of env sequences of plasma viruses from ES has not been previously characterized.…”

“…The HLA-B*57 allele is overrepresented in ES (37) and was present in seven of nine of the ES in this study. Low env diversity theoretically favors viral suppression by NAb in these subjects (25,56). Although the low levels of replication occurring in these patients may have limited viral diversification, low antigen levels may also have prevented the stimulation of a high-titer antibody response.…”

Decreased Infectivity of a Neutralization-Resistant Equine Infectious Anemia Virus Variant Can Be Overcome by Efficient Cell-to-Cell Spread

“…Genetic differences in the PND region included amino acid substitutions, size variation, and changes in the numbers and locations of predicted N-linked glycosylation sites. Similar changes in HIV-1 env that mask immune epitopes have been associated with a loss of virus replicative fitness (8)(9)(10)(11), suggesting that resistance to bNAb may incur a cost in virus fitness. In the present study, we used growth competition and infectivity assays to determine if EIAV PND variants that differ in sensitivity to neutralization also differ in replicative capacity in vitro.…”

The Gut Mucosal Viral Reservoir in HIV-Infected Patients Is Not the Major Source of Rebound Plasma Viremia following Interruption of Highly Active Antiretroviral Therapy

“…Limiting dilution to approximately one copy was performed on postinterruption plasma samples from patient 116 (based on real-time PCR viral loads) and yielded very similar sequences, indicating that PCR recombination might not have been a problem. Using a very similar molecular cloning approach for a comparable region of envelope, others found PCR misincorporation artifacts to be minimal (27). Furthermore, Jordan et al found no difference in population structure or genetic diversity between terminal dilution cloning and conventional cloning for 14 of 17 subjects studied, demonstrating both methods are suitable for the study of viral genomic diversity (28).…”