Monotypic low-level HIV viremias during antiretroviral therapy are associated with disproportionate production of X4 virions and systemic immune activation

Abstract

Objective:During effective antiretroviral therapy (ART), low-level plasma viremias (LLV) (HIV RNA >30–1000 copies/ml) can be detected intermittently. We hypothesized that systemic inflammation is associated with LLV either as the cause or result of the production of virions from clonally expanded cells.Methods:Prospective cohort study of HIV-infected ART-naive Peruvians enrolled prior to ART and followed for 2 years. Plasma HIV RNA and peripheral blood mononuclear cell (PBMC) HIV DNA concentrations were quantified pre-ART from individuals whose plasma HIV RNA was ART-suppressed. Inflammatory biomarker concentrations were measured pre and during ART. Single-genome amplification (SGA) derived HIV env and pol genotypes from pre-ART and LLV specimens. Antiretroviral levels during ART assessed adherence. Statistical associations and phylogenetic relationships were examined.Results:Among 82 participants with median plasma HIV RNA less than 30 copies/ml, LLV were detected in 33 of 82 (40%), with a LLV median HIV RNA of 73 copies/ml. Participants with vs. without LLV had significantly higher pre-ART plasma HIV RNA (P < 0.001) and PBMC HIV DNA (P < 0.007); but, during ART, their antiretroviral drug levels were similar. LLV env sequences were monotypic in 17 of 28 (61%) and diverse in 11 of 28 (39%) participants. Those with the monotypic vs. diverse LLV pattern had elevated hsCRP and sCD163 (P = 0.004) and LLV with more X4 variants (P = 0.02).Conclusion:In individuals with monotypic LLV sequences, higher levels of pre-ART HIV DNA and RNA, systemic inflammation and X4 viruses suggest an interaction between inflammation and the production of virions from proliferating infected cells, and that naïve T cells may be a source of LLV.

Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment

“…While previous studies of low-level intermittent viremias (plasma HIV RNA 50-400 c/mL) [29,50] occasionally detected evidence of HIV replication, genetic divergence of our participants' sequences was detected only after frequent or prolonged ART-interruptions. No significant increase in viral divergence was observed among plasma sequences imputed to use the CCR5 co-receptor during the first period of ART suppression in all 3 participants, suggesting the lack of ongoing viral replication during effective ART.…”

“…However, the absence of detectable divergence despite viremia during ART-interruptions of Participants 1 and 2 demonstrates that divergence is insensitive to short periods of low-level virus replication, and emphasizes that a lack of divergence does not provide certainty that HIV replication did not contribute to RV. The detection of multiple RV sequences predicted to use the X4 co-receptor that cluster closely in the phylogenetic analyses of Participant 1, and in multiple individuals in previous studies of low-level viremias [29,50] leads us to speculate that X4 tropism is selected for persistence and/or replication during ART-suppression.…”

All-Cause Mortality and Serious Non-AIDS Events in Adults With Low-level Human Immunodeficiency Virus Viremia During Combination Antiretroviral Therapy: Results From a Swedish Nationwide Observational Study

“…Low-level viremia during ART can be due to separate mechanisms: release of viral particles from latently infected cells and active replication [ 27 ]. Interestingly, different profiles of inflammatory cytokines have been associated with 2 distinct HIV env sequence patterns, monotypic and diverse LLV [ 28 ]. Biological pathways might therefore explain an association between LLV and adverse clinical outcomes.…”

Phylogenetic Analyses Comparing HIV Sequences from Plasma at Virologic Failure to Cervix Versus Blood Sequences from Antecedent Antiretroviral Therapy Suppression

“…Variants predicted to use the X4 receptor were found in the plasma viral rebound in a minority of participants (3/7, 43%). Previously we 47 and others 44 found that X4 variants are prevalent in low-level viremias of otherwise ART-suppressed participants. The presence of X4 variants in the plasma rebound might reflect the late disease stage of participants [48][49][50] or it could indicate a previously unappreciated latent reservoir in naive T cells or those of the myeloid lineage that express high concentrations of the CXCR4 receptor.…”