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.

Fig. 1

Study schema of 126 HIV-infected antiretroviral therapy-naive adult participants with AIDS-defining illness or a CD4⁺ T-lymphocytes less than 250 cells/μl enrolled in this observational cohort study in Lima, Peru.

Fig. 2

Representative phylogenetic trees, divergence, and plasma HIV RNA plots from four of 28 participants who had sequences generated from plasma low-level viremias (a–c) or viremias below the limit of quantification (d) (month specimens collected, in parenthesis).

Fig. 2 (Continued)

Representative phylogenetic trees, divergence, and plasma HIV RNA plots from four of 28 participants who had sequences generated from plasma low-level viremias (a–c) or viremias below the limit of quantification (d) (month specimens collected, in parenthesis).

Fig. 2 (Continued)

Representative phylogenetic trees, divergence, and plasma HIV RNA plots from four of 28 participants who had sequences generated from plasma low-level viremias (a–c) or viremias below the limit of quantification (d) (month specimens collected, in parenthesis).

Fig. 2 (Continued)

Representative phylogenetic trees, divergence, and plasma HIV RNA plots from four of 28 participants who had sequences generated from plasma low-level viremias (a–c) or viremias below the limit of quantification (d) (month specimens collected, in parenthesis).

Fig. 3

Concentrations of biomarkers of inflammation and cellular determined before and during antiretroviral therapy, including comparisons between participants with monotypic low-level viremia compared with those with diverse low-level viremia.