Evidence for Persistent Low-Level Viremia in Individuals Who Control Human Immunodeficiency Virus in the Absence of Antiretroviral Therapy

Abstract

A subset of antiretroviral-untreated, human immunodeficiency virus (HIV)-infected individuals are able to maintain undetectable plasma HIV RNA levels in the absence of antiretroviral therapy. These "elite" controllers are of high interest as they may provide novel insights regarding host mechanisms of virus control. The degree to which these individuals have residual plasma viremia has not been well defined. We performed a longitudinal study of 46 elite controllers, defined as HIV-seropositive, antiretroviral-untreated individuals with plasma HIV RNA levels of <50 to 75 copies/ml. The median duration of HIV diagnosis was 13 years, the median baseline CD4؉ T-cell count was 753 cells/mm 3 , and the median duration of follow-up was 16 months. Plasma and cellular HIV RNA levels were measured using the transcription-mediated amplification (TMA) assay (estimated limit of detection of <3.5 copies RNA/ml). A total of 1,117 TMA assays were performed (median of five time points/subject and four replicates/time point). All but one subject had detectable plasma HIV RNA on at least one time point, and 15 (33%) subjects had detectable RNA at all time points. The majority of controllers also had detectable cell-associated RNA and proviral DNA. A mixed-effect linear model showed no strong evidence of change in plasma RNA levels over time. In conclusion, the vast majority (98%) of elite controllers had measurable plasma HIV RNA, often at levels higher than that observed in antiretroviraltreated patients. This confirms the failure to eradicate the virus, even in these unique individuals who are able to reduce plasma viremia to very low levels without antiretroviral therapy.

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…Very low plasma levels of virus can be detected by ultrasensitive RT-PCR assays in HICs, revealing the persistence of viral replication despite maintaining viraemia close to the limit of detection by standard RT-PCR [198]. Although HICs maintain a remarkable control of infection, blips in viral load levels have been observed for many of these individuals [199].…”

Virological, Immune and Host genetics Markers in the Control of HIV Infection

“…In particular, conflicting data exists partly due to the fact that the identification of such attenuated virus strains in vivo is limited to small numbers of subjects and that sequence analyses have often been based on analyzing cellular proviral DNA, thus possibly also including some level of grave-yard sequences. Today, with more sensitive assays, some elite controllers have been shown to have persistent viral replication detectable in plasma at levels below 50 copies/ml [23]. In addition, a recent report by Miura et al for instance did not reveal any gross genetic defects in HIV-1 coding gene sequences derived from plasma viral RNA from a large cohort of elite controllers [24].…”

Potential Implication of Residual Viremia in Patients on Effective Antiretroviral Therapy

“…In fact, residual viremia persists below 50 copies per ml in plasma of these elite controllers. 110 Whether residual viruses play any direct role in causing CIA that persists during ART is not fully clear, but this possibility cannot be ruled out. 111 This is because the persistent production of HIV-1 particles (being infectious or not) below 50 copies/ml should constantly supply viral antigens at low-levels, which should result in some immunological consequences, such as the stimulation of plasmacytoid dendritic cells [112][113][114] and monocytes 115 in the body.…”