HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment

Abstract

Background: Early initiation of combination antiretroviral therapy (cART) to human immunodeficiency virus type 1 (HIV-1)-infected infants controls HIV-1 replication and reduces mortality.

Methods: Plasma viremia (lower limit of detection, <2 copies/mL), T-cell activation, HIV-1-specific immune responses, and the persistence of cells carrying replication-competent virus were quantified during long-term effective combination antiretroviral therapy (cART) in 4 perinatally HIV-1-infected youth who received treatment early (the ET group) and 4 who received treatment late (the LT group). Decay in peripheral blood mononuclear cell (PBMC) proviral DNA levels was also measured over time in the ET youth.

Results: Plasma viremia was not detected in any ET youth but was detected in all LT youth (median, 8 copies/mL; P = .03). PBMC proviral load was significantly lower in ET youth (median, 7 copies per million PBMCs) than in LT youth (median, 181 copies; P = .03). Replication-competent virus was recovered from all LT youth but only 1 ET youth. Decay in proviral DNA was noted in all 4 ET youth in association with limited T-cell activation and with absent to minimal HIV-1-specific immune responses.

Conclusions: Initiation of early effective cART during infancy significantly limits circulating levels of proviral and replication-competent HIV-1 and promotes continuous decay of viral reservoirs. Continued cART with reduction in HIV-1 reservoirs over time may facilitate HIV-1 eradication strategies.

Keywords: continuous HIV-1 decay; early antiretroviral therapy; prolonged viral suppression; proviral reservoirs; reduced HIV reservoirs.

Figure 1.

Circulating human immunodeficiency virus type 1 (HIV-1) RNA levels, CD4⁺ T-cell percentages, and activated CD8⁺ T-cell percentages over time in youth who received early treatment. Abbreviation: cART, combination antiretroviral therapy.

Figure 2.

Human immunodeficiency virus type 1 (HIV-1) antibodies levels over time in youth with long-term suppression of HIV-1 replication who initiated combination antiretroviral therapy early or late. A, Antibody levels in early treated youth, determined by enzyme-linked immunosorbent assay (ELISA). B, Western blot findings for in early treated and late-treated youth. Abbreviations: Neg, negative results; str pos, strongly positive results; wk pos, weekly positive results.

Figure 3.

Decay in human immunodeficiency virus type 1 (HIV-1) proviral DNA level over time in youth with long-term suppression of HIV-1 replication who initiated combination antiretroviral therapy early. A, Variability in HIV-1 proviral DNA levels over time. Data are medians with interquartile ranges. B, HIV-1 proviral DNA decay curves among individual patients. Abbreviation: PBMC, peripheral blood mononuclear cells.

Figure 4.

Human immunodeficiency virus type 1 (HIV-1) proviral DNA levels in memory CD4⁺ T cells from youth with long-term suppression of HIV-1 replication who initiated combination antiretroviral therapy early. A, Normal CD4⁺ memory T-cell subsets for age in early treated youth. B, Proportional contribution of memory CD4⁺ T-cell subsets to the proviral reservoir in early treated youth. Abbreviations: CM, central memory; EM, effector memory; TM, transitional memory.