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.HIV latency | viral kinetics

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

“…Mathematical models have a long tradition of informing HIV-1 research and have been particularly useful in understanding HIV-1 treatment. Previous models have explained the multiphasic decay of viremia during ART (29), the initial seeding of the LR during acute infection (30), the limited inflow to the LR during treatment (31), the dynamics of viral blips (32), and the contributions of the LR to drug resistance (33). No model has yet been offered to describe the effect of LRAs.…”

Post-treatment control of HIV infection

“…As in previous modeling work, we assume that the fraction of infections that result in latency α L = 10 −6 and the death rate of these cells is d L = 0.004 d −1 (38). The results in Archin et al (40) suggest that βα L , where β is the mass-action infection rate constant, is of the order of 10 −14 mL per cell per d, and our values of β (41, 42) and α L (SI Appendix, Table S1) are consistent with this estimate. Latently infected cells are isolated from resting CD4 + T memory cells, whose lifespan has been estimated to be ∼6 mo (43,44), consistent with our choice of d L .…”

“…Measurements of latent reservoir sizes vary widely (1,22,40), likely due to interpatient variability (15) and inherent stochasticity (46-48), so we would anticipate variation in L 0 . We take L 0 in the range 10 −1 to 10 2 per 10 6 CD4 + T cells, consistent with published ranges (21,40).…”

Might dolutegravir be part of a functional cure for HIV?

“…It has been reported that early ART during acute HIV infection reduced the reservoir size (Archin et al 2012;Ananworanich et al 2015Ananworanich et al , 2012 and it is possible that very early ART may be curative for HIV. A French girl was infected with HIV when she was born in 1996.…”