Intrapatient Diversity and Its Correlation with Viral Setpoint in Human Immunodeficiency Virus Type 1 CRF02_A/G-IbNG Infection

Abstract

The human immunodeficiency virus type 1 (HIV-1) viral setpoint during the disease-free interval has been strongly associated with future risk of disease progression. An awareness of the correlation between viral setpoint and HIV-1 genetic evolution over time is important in the understanding of viral dynamics and infection. We examined genetic diversity in HIV-1 CRF02_A/G-IbNG-infected seroincident women in Dakar, Senegal; determined whether a viral setpoint kinetic pattern existed for CRF02_A/G-IbNG during the diseasefree interval; and correlated viral load level and diversity. Samples were drawn during the disease-free interval from consenting CRF02_A/G-IbNG-infected, antiretroviral therapy-naïve female commercial sex workers in Dakar, Senegal. Based on sequential plasma RNA values, low and high viral setpoint groups were established. Intrapatient diversity and divergence over time was determined from earlier and later time point DNA samples from each person. Most individuals followed the viral setpoint paradigm. For each 1|؊|log 10 copy/ml of plasma increase in viral load, intrapatient diversity increased by 1.4% (P ‫؍‬ 0.028). A greater diversification rate was observed in the high viral setpoint group than in the low viral setpoint group (P ‫؍‬ 0.01). Greater nucleotide (P ‫؍‬ 0.015) and amino acid (P ‫؍‬ 0.048) divergences and a greater nucleotide divergence rate (P ‫؍‬ 0.03) were found in the high viral setpoint group. There was no difference between the groups in the ratio of the number of nonsynonymous substitutions per nonsynonymous site to the number of synonymous substitutions per synonymous site. The greater intrapatient diversity, divergence, and diversification rates observed in the high viral setpoint group supports the notion that diversity is driven by cycles of viral replication resulting in accumulated mutations. Recognizing diversity potential based on viral load levels in individuals may inform the design of vaccines and therapies.

Infection with Multiple Human Immunodeficiency Virus Type 1 Variants Is Associated with Faster Disease Progression

“…These studies have not produced a consistent model perhaps, in part, because only small numbers of selected subjects were evaluated in any given study. Some of these studies have suggested that greater viral replication and faster progression to AIDS are correlated with greater viral diversity (18,19,22), while others have proposed that a stronger immune response and slower disease progression lead to greater genetic complexity (5,8,9,17,21,30,35). In aggregate, these studies have focused on virus-host factors after primary infection that may influence the generation of viral diversity over time.…”

Incidence of HIV‐1 Dual Infection and Its Association with Increased Viral Load Set Point in a Cohort of HIV‐1 Subtype C–Infected Female Sex Workers

“…Shortly after infection, intraperson diversity is usually low, although 1 study of women has shown that there may be sex differences, with recently infected women harboring highly heterogeneous viral populations [1]. The virus evolves over time in response to selective pressure; some studies have shown a direct relationship between diversity and disease progression, and others have not [2,3]. Recent studies have shown that dual infection with 2 HIV strains [4] or infection with multiple diverse variants [5] may be associated with faster disease progression.…”

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

“…While some have argued that higher viral diversity may induce broader HIV-specific immune responses, which subsequently could contain viral replication more efficiently (96), others have found that patients with limited genetic diversity showed delayed disease progression and mounted stronger immune responses than rapid progressors (49,50,80). In the simian immunodeficiency virus (SIV) model viral properties were found to substantially impact disease progression (40).…”