Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection

Abstract

HIV type 1 (HIV-1) persists within resting CD4(+) T cells despite antiretroviral therapy (ART). To better understand the kinetics by which resting cell infection (RCI) is established, we developed a mathematical model that accurately predicts (r = 0.65, P = 2.5 × 10(-4)) the initial frequency of RCI measured about 1 year postinfection, based on the time of ART initiation and the dynamic changes in viremia and CD4(+) T cells. In the largest cohort of patients treated during acute seronegative HIV infection (AHI) in whom RCI has been stringently quantified, we found that early ART reduced the generation of latently infected cells. Although RCI declined after the first year of ART in most acutely infected patients, there was a striking absence of decline when initial RCI frequency was less than 0.5 per million. Notably, low-level viremia was observed more frequently as RCI increased. Together these observations suggest that (i) the degree of RCI is directly related to the availability of CD4(+) T cells susceptible to HIV, whether viremia is controlled by the immune response and/or ART; and (ii) that two pools of infected resting CD4(+) T cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART. These findings reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Spline curve fit to the patient viral load data and a biphasic linear fit to the patient CD4 count data for four representative patients. Vertical dashed line indicates the time of ART initiation; horizontal dash–dot line represents the assay detection limit. Filled circles denote measured HIV RNA copies/mL; open circles denote values below the limit of quantification. The x axis for each patient extends from the estimated time of infection to the time of first leukopheresis, at which time the RCI frequency was measured.

Fig. 2.

Correlation between model prediction and the measured frequency of latently infected cells. Predicted infectious units per million resting CD4+ T cells (IUPM) was computed as [L(tF)/(fβ T(tF))] x 106, i.e., the fraction of CD4+ T cells at the time of leukopheresis, tF, that are predicted to be latently infected in 1 million resting CD4+ T cells, and is expressed in arbitrary units of 1014fβ.

Fig. 3.

Dynamics of the latently infected cell frequency predicted by the model. Vertical dashed line indicates the time of ART initiation; final point represents the time of the first leukopheresis. Predicted IUPM was computed as [L/(fβ T)] x 106, i.e., the fraction of CD4+ T cells that are predicted to be latently infected in 1 million resting CD4+ T cells, and is expressed in arbitrary units of 1014fβ.

Fig. 4.

Comparison of low-level viremia (single-copy assay) and RCI frequency in (A) acutely treated and (B) chronically treated HIV-1–infected patients labeled A–L.

Fig. 5.

Frequency of RCI in 9 of 11 patients on stable ART that exhibited RCI decay. Lines drawn between data points are for ease of viewing and are not meant to predict future trajectories. Dashed line is the best-fit regression line for the data from patient S25.