Absent HIV-specific Immune Responses and Replication-competent HIV Reservoirs in Perinatally Infected Youth Treated from Infancy: Towards Cure
Katherine Luzuriaga*1, YH Chen2, C Ziemniak2, G Siberry3, M Strain4, D Richman4, T-W Chun5, C Cunningham6, and D Persaud2
1Univ of Massachusetts Med Sch, Worcester, US; 2Johns Hopkins Univ Sch of Med, Baltimore, MD, US; 3Maternal and Pediatric Infectious Disease Branch, NICHD, NIH, Bethesda, MD, US; 4Univ of California San Diego, La Jolla and VA San Diego Hlthcare System, US; 5NIAID, NIH, Bethesda, MD, US; and 6Duke Univ Sch of Med, Durham, NC, US
Background: Persistence of HIV reservoirs precludes HIV cure despite potent ART. HIV treatment strategies that lead to extinction of viral reservoirs may facilitate HIV cure. We report marked restriction of proviral and replication-competent reservoirs in perinatally infected youth initiating ART as infants.
Methods: 5 perinatally HIV-infected youth (median age 16 years) who began ART at a median of 2 months of age (early-treated, ET) underwent extensive virologic and immunologic evaluation to assess HIV persistence. HIV proviral burden in peripheral blood mononuclear cells (PBMC) was quantified using droplet digital polymerase chain reaction (PCR). Residual plasma viremia and frequencies of resting CD4+ T cells bearing replication competent HIV (infectious units per million, IUPM) were quantified using an ultrasensitive (<2 copy) viral load assay and enhanced quantitative co-culture assay, respectively. HIV-specific antibody responses were assessed using ELISA and Western Blot. ELISpot assays were used to detect HIV-specific CD8+ T cell responses. Similar analyses were carried out on a control group of 4 age-matched, perinatally infected youth who suppressed HIV replication after ART initiation ART in late-childhood (late-treated, LT).
Results: Replication-competent virus was not recovered from any of the 5 ET perinatally infected youth (median <0.1 IUPM), whereas all 4 LT perinatally infected youth had detectable replication-competent reservoirs (median 1.08 IUPM); p = 0.002. HIV proviral DNA was substantially lower in ET (median 7 copies; range 0-15) than in LT perinatally infected (median 182 copies/million PBMC; range 69-345); p = 0.014. Only 1 of 5 ET youth had detectable residual plasma viremia (median 0 copies/mL; range 0-4) whereas all 4 LT had detectable viremia (median 8 copies/mL; range 4-14 copies/mL); p = 0.048. HIV-specific antibody and CD8+ T cell responses were identified in only 1 of 5 ET youth whereas all 4 LT youth had detectable HIV-specific antibodies and CD8+ T cell responses to 4 or more HIV gene products (p = 0.048).
Conclusions: Long-term control of HIV replication following early ART in infancy results in a paucity of resting CD4+ T cells bearing proviral DNA and replication-competent virus, and residual plasma viremia and is associated with absent or diminished HIV-specific immune responses. Perinatally infected youth with marked curtailment of HIV reservoirs following early therapy are prime candidates for interventions to achieve functional cure or eradication.