Non-suppressible HIV viremia sustained by clonally expanded CD4+ T cells harboring a genomically defective provirus with an immune-evasive protein expression profile

Antiretroviral therapy (ART) potently inhibits HIV replication but does not eliminate HIV proviruses integrated within the genomes of infected cells. Though ART normally suppresses HIV to clinically undetectable levels in blood, some individuals experience non-suppressible viremia (NSV) that is not attributable to suboptimal drug exposure (e.g<i>.</i>, incomplete medication adherence or pharmacological issues) nor emerging HIV drug resistance, and that does not resolve following ART regimen modification. We now understand that NSV can originate from expanded cell clones harboring genetically identical proviruses that reactivate to produce clinically detectable viremia. NSV can even originate from proviruses with genomic defects, particularly within HIV's major splice donor (MSD) site, which render the viremia non-infectious. But, because only a limited number of such cases have been described, all in HIV subtype B, the mechanisms that allow cells harboring such proviruses to produce prolonged viremia without being eliminated remain incompletely understood. We characterized a case of MSD-defective, replication-impaired NSV that lasted >4 years in an individual with non-B HIV. Our results reveal that proviruses with MSD deletions can persist by integrating into minimally differentiated CD4+ T-cell subsets that then give rise to the full spectrum of memory and effector subpopulations, and by exhibiting an HIV protein expression profile that would allow these cells to evade both cellular and humoral immunity. Our results highlight the need to better understand the biological implications of persistent HIV protein and virion production by clonally expanded cells harboring genomically defective proviruses, and for clinical guidelines to acknowledge this type of viremia.IMPORTANCEHIV cure efforts focus on eliminating the viral reservoir, strictly defined as cells harboring proviruses that can produce infectious HIV. But this definition excludes proviruses with defects in HIV's major splice donor site (MSD), which persist readily. Our results confirm that clonally expanded, MSD-defective proviruses can produce HIV transcripts, proteins, and clinically detectable viremia over long periods, underscoring the need to investigate the biological consequences of these activities. Our findings also have clinical implications. Most HIV treatment guidelines do not acknowledge that persistent viremia during ART can originate from clonally expanded infected cells, and all recommend that viremia >200 HIV copies/mL be managed as virologic failure. Clear clinical frameworks should be developed to discriminate persistent viremia that is due to suboptimal drug exposure and/or emerging drug resistance (that is clinically actionable), from NSV (that is not). HIV MSD genotyping could also help assess viral infectivity, and thus potential transmission risk, during NSV.